Hepatic carboxylesterase 1 is essential for both normal and farnesoid X receptor-controlled lipid homeostasis.
*Homeostasis; *Lipid Metabolism; Animals; Carboxylic Ester Hydrolases/*physiology; Cholesterol/blood; Cytoplasmic and Nuclear/*physiology; Fatty Acids/metabolism; Inbred C57BL; Lipogenesis; Liver/*enzymology; Mice; Receptors; Sterol Regulatory Element Binding Protein 1/physiology; Triglycerides/metabolism
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is one of the major health concerns worldwide. Farnesoid X receptor (FXR) is considered a therapeutic target for treatment of NAFLD. However, the mechanism by which activation of FXR lowers hepatic triglyceride (TG) levels remains unknown. Here we investigated the role of hepatic carboxylesterase 1 (CES1) in regulating both normal and FXR-controlled lipid homeostasis. Overexpression of hepatic CES1 lowered hepatic TG and plasma glucose levels in both wild-type and diabetic mice. In contrast, knockdown of hepatic CES1 increased hepatic TG and plasma cholesterol levels. These effects likely resulted from the TG hydrolase activity of CES1, with subsequent changes in fatty acid oxidation and/or de novo lipogenesis. Activation of FXR induced hepatic CES1, and reduced the levels of hepatic and plasma TG as well as plasma cholesterol in a CES1-dependent manner. CONCLUSION: Hepatic CES1 plays a critical role in regulating both lipid and carbohydrate metabolism and FXR-controlled lipid homeostasis.
Xu Jiesi; Li Yuanyuan; Chen Wei-Dong; Xu Yang; Yin Liya; Ge Xuemei; Jadhav Kavita; Adorini Luciano; Zhang Yanqiao
Hepatology (Baltimore, Md.)
2014
2014-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.26714" target="_blank" rel="noreferrer noopener">10.1002/hep.26714</a>
Carboxylesterase 2 prevents liver steatosis by modulating lipolysis, endoplasmic reticulum stress, and lipogenesis and is regulated by hepatocyte nuclear factor 4 alpha in mice.
*Lipid Metabolism; Adiposity; Animals; Carboxylesterase/*metabolism; Carboxylic Ester Hydrolases/genetics/*metabolism; Diabetes Mellitus; Diet; Endoplasmic Reticulum Stress; Energy Metabolism; Experimental/enzymology; Gene Knockdown Techniques; Glucose Tolerance Test; Glucose/metabolism; Hepatocyte Nuclear Factor 4/*metabolism; High-Fat/adverse effects; Homeostasis; Humans; Inbred C57BL; Lipogenesis; Lipolysis; Liver/enzymology; Male; Mice; Non-alcoholic Fatty Liver Disease/*etiology/metabolism; Obesity/enzymology/etiology; Sterol Regulatory Element Binding Protein 1/metabolism
UNLABELLED: Nonalcoholic fatty liver disease (NAFLD) is a common liver disease that ranges from simple steatosis to nonalcoholic steatohepatitis (NASH). So far, the underlying mechanism remains poorly understood. Here, we show that hepatic carboxylesterase 2 (CES2) is markedly reduced in NASH patients, diabetic db/db mice, and high-fat diet (HFD)-fed mice. Restoration of hepatic CES2 expression in db/db or HFD-fed mice markedly ameliorates liver steatosis and insulin resistance. In contrast, knockdown of hepatic CES2 causes liver steatosis and damage in chow- or Western diet-fed C57BL/6 mice. Mechanistically, we demonstrate that CES2 has triglyceride hydrolase activity. As a result, gain of hepatic CES2 function increases fatty acid oxidation and inhibits lipogenesis, whereas loss of hepatic CES2 stimulates lipogenesis by inducing endoplasmic reticulum stress. We further show that loss of hepatic CES2 stimulates lipogenesis in a sterol regulatory element-binding protein 1 (SREBP-1)-dependent manner. Finally, we show that hepatocyte nuclear factor 4 alpha (HNF-4alpha) plays a key role in controlling hepatic CES2 expression in diabetes, obesity, or NASH. CONCLUSION: CES2 plays a protective role in development of NAFLD. Targeting the
Li Yuanyuan; Zalzala Munaf; Jadhav Kavita; Xu Yang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Hepatology (Baltimore, Md.)
2016
2016-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.28472" target="_blank" rel="noreferrer noopener">10.1002/hep.28472</a>
Farnesoid X receptor activation increases reverse cholesterol transport by modulating bile acid composition and cholesterol absorption in mice.
*Intestinal Absorption; Animals; Bile Acids and Salts/*chemistry; Biological Transport; Cholesterol/*metabolism; Cytoplasmic and Nuclear/*physiology; Inbred C57BL; Mice; Receptors
UNLABELLED: Activation of farnesoid X receptor (FXR) markedly attenuates development of atherosclerosis in animal models. However, the underlying mechanism is not well elucidated. Here, we show that the FXR agonist, obeticholic acid (OCA), increases fecal cholesterol excretion and macrophage reverse cholesterol transport (RCT) dependent on activation of hepatic FXR. OCA does not increase biliary cholesterol secretion, but inhibits intestinal cholesterol absorption. OCA markedly inhibits hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) and sterol 12alpha-hydroxylase (Cyp8b1) partly through inducing small heterodimer partner, leading to reduced bile acid pool size and altered bile acid composition, with the alpha/beta-muricholic acid proportion in bile increased by 2.6-fold and taurocholic acid (TCA) level reduced by 71%. Overexpression of Cyp8b1 or concurrent overexpression of Cyp7a1 and Cyp8b1 normalizes TCA level, bile acid composition, and intestinal cholesterol absorption. CONCLUSION: Activation of FXR inhibits intestinal cholesterol absorption by modulation of bile acid pool size and composition, thus leading to increased RCT. Targeting hepatic FXR and/or bile acids may be useful for boosting RCT and preventing the development of atherosclerosis. (Hepatology 2016;64:1072-1085).
Xu Yang; Li Fei; Zalzala Munaf; Xu Jiesi; Gonzalez Frank J; Adorini Luciano; Lee Yoon-Kwang; Yin Liya; Zhang Yanqiao
Hepatology (Baltimore, Md.)
2016
2016-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1002/hep.28712" target="_blank" rel="noreferrer noopener">10.1002/hep.28712</a>
Novel thiazolidinedione mitoNEET ligand-1 acutely improves cardiac stem cell survival under oxidative stress.
Animals; Cardiac/cytology/*drug effects; Cell Differentiation/drug effects; Flow Cytometry; Knockout; Male; Mice; Mitochondrial Membranes/metabolism; Mitochondrial Proteins/metabolism; Myocytes; Oxidative Stress/drug effects/*physiology; Rats; Real-Time Polymerase Chain Reaction; Stem Cells/cytology/*drug effects; Thiazolidinediones/*pharmacology; Zucker
Ischemic heart disease (IHD) is a leading cause of death worldwide, and regenerative therapies through exogenous stem cell delivery hold promising potential. One limitation of such therapies is the vulnerability of stem cells to the oxidative environment associated with IHD. Accordingly, manipulation of stem cell mitochondrial metabolism may be an effective strategy to improve survival of stem cells under oxidative stress. MitoNEET is a redox-sensitive, mitochondrial target of thiazolidinediones (TZDs), and influences cellular oxidative capacity. Pharmacological targeting of mitoNEET with the novel TZD, mitoNEET Ligand-1 (NL-1), improved cardiac stem cell (CSC) survival compared to vehicle (0.1% DMSO) during in vitro oxidative stress (H2O2). 10 muM NL-1 also reduced CSC maximal oxygen consumption rate (OCR) compared to vehicle. Following treatment with dexamethasone, CSC maximal OCR increased compared to baseline, but NL-1 prevented this effect. Smooth muscle alpha-actin expression increased significantly in CSC following differentiation compared to baseline, irrespective of NL-1 treatment. When CSCs were treated with glucose oxidase for 7 days, NL-1 significantly improved cell survival compared to vehicle (trypan blue exclusion). NL-1 treatment of cells isolated from mitoNEET knockout mice did not increase CSC survival with H2O2 treatment. Following intramyocardial injection of CSCs into Zucker obese fatty rats, NL-1 significantly improved CSC survival after 24 h, but not after 10 days. These data suggest that pharmacological targeting of mitoNEET with TZDs may acutely protect stem cells following transplantation into an oxidative environment. Continued treatment or manipulation of mitochondrial metabolism may be necessary to produce long-term benefits related to stem cell therapies.
Logan Suzanna J; Yin Liya; Geldenhuys Werner J; Enrick Molly K; Stevanov Kelly M; Carroll Richard T; Ohanyan Vahagn A; Kolz Christopher L; Chilian William M
Basic research in cardiology
2015
2015-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-015-0471-z" target="_blank" rel="noreferrer noopener">10.1007/s00395-015-0471-z</a>
Impaired coronary metabolic dilation in the metabolic syndrome is linked to mitochondrial dysfunction and mitochondrial DNA damage.
Animal; Animals; Coronary circulation; Coronary microcirculation; Coronary Vessels/metabolism/*physiopathology; Diabetes; Disease Models; DNA; DNA Damage/physiology; DNA Fragmentation; Metabolic Syndrome/metabolism/*physiopathology; Mitochondria; Mitochondria/*metabolism; Mitochondrial/*metabolism; Obesity; Oxidative Stress/physiology; Rats; Reactive Oxygen Species/metabolism; Vasodilation/physiology; Zucker
Mitochondrial dysfunction in obesity and diabetes can be caused by excessive production of free radicals, which can damage mitochondrial DNA. Because mitochondrial DNA plays a key role in the production of ATP necessary for cardiac work, we hypothesized that mitochondrial dysfunction, induced by mitochondrial DNA damage, uncouples coronary blood flow from cardiac work. Myocardial blood flow (contrast echocardiography) was measured in Zucker lean (ZLN) and obese fatty (ZOF) rats during increased cardiac metabolism (product of heart rate and arterial pressure, i.v. norepinephrine). In ZLN increased metabolism augmented coronary blood flow, but in ZOF metabolic hyperemia was attenuated. Mitochondrial respiration was impaired and ROS production was greater in ZOF than ZLN. These were associated with mitochondrial DNA (mtDNA) damage in ZOF. To determine if coronary metabolic dilation, the hyperemic response induced by heightened cardiac metabolism, is linked to mitochondrial function we introduced recombinant proteins (intravenously or intraperitoneally) in ZLN and ZOF to fragment or repair mtDNA, respectively. Repair of mtDNA damage restored mitochondrial function and metabolic dilation, and reduced ROS production in ZOF; whereas induction of mtDNA damage in ZLN reduced mitochondrial function, increased ROS production, and attenuated metabolic dilation. Adequate metabolic dilation was also associated with the extracellular release of ADP, ATP, and H2O2 by cardiac myocytes; whereas myocytes from rats with impaired dilation released only H2O2. In conclusion, our results suggest that mitochondrial function plays a seminal role in connecting myocardial blood flow to metabolism, and integrity of mtDNA is central to this process.
Guarini Giacinta; Kiyooka Takahiko; Ohanyan Vahagn; Pung Yuh Fen; Marzilli Mario; Chen Yeong-Renn; Chen Chwen-Lih; Kang Patrick T; Hardwick James P; Kolz Christopher L; Yin Liya; Wilson Glenn L; Shokolenko Inna; Dobson James G Jr; Fenton Richard; Chilian William M
Basic research in cardiology
2016
2016-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-016-0547-4" target="_blank" rel="noreferrer noopener">10.1007/s00395-016-0547-4</a>
Alignment of inducible vascular progenitor cells on a micro-bundle scaffold improves cardiac repair following myocardial infarction.
*Cardiovascular regeneration; *Ischemic heart diseases; *Micro-bundle scaffold; *Myocardial infarction; *Neovascularization; *Stem cells; *Tissue Scaffolds; *Vascular progenitor cells; Animal; Animals; Cell Differentiation; Cell Proliferation; Cell Survival; Cells; Coculture Techniques; Cultured; Disease Models; Endothelial Progenitor Cells/metabolism/*transplantation; Fibroblast Growth Factor 2/metabolism; Lactic Acid/*chemistry; Muscle; Myocardial Infarction/metabolism/pathology/physiopathology/*surgery; Myocardium/metabolism/*pathology; Myocytes; Paracrine Communication; Phenotype; Physiologic; Polyglycolic Acid/*chemistry; Polylactic Acid-Polyglycolic Acid Copolymer; Rats; Signal Transduction; Smooth; Smooth Muscle/metabolism/*transplantation; Sprague-Dawley; Time Factors; Tissue Engineering/*methods; Vascular Endothelial Growth Factor A/metabolism; Vascular/metabolism/*transplantation; Ventricular Remodeling
Ischemic heart disease is still the leading cause of death even with the advancement of pharmaceutical therapies and surgical procedures. Early vascularization in the ischemic heart is critical for a better outcome. Although stem cell therapy has great potential for cardiovascular regeneration, the ideal cell type and delivery method of cells have not been resolved. We tested a new approach of stem cell therapy by delivery of induced vascular progenitor cells (iVPCs) grown on polymer micro-bundle scaffolds in a rat model of myocardial infarction. iVPCs partially reprogrammed from vascular endothelial cells (ECs) had potent angiogenic potential and were able to simultaneously differentiate into vascular smooth muscle cells (SMCs) and ECs in 2D culture. Under hypoxic conditions, iVPCs also secreted angiogenic cytokines such as vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) as measured by enzyme-linked immunosorbent assay (ELISA). A longitudinal micro-scaffold made from poly(lactic-co-glycolic acid) was sufficient for the growth and delivery of iVPCs. Co-cultured ECs and SMCs aligned well on the micro-bundle scaffold similarly as in the vessels. 3D cell/polymer micro-bundles formed by iVPCs and micro-scaffolds were transplanted into the ischemic myocardium in a rat model of myocardial infarction (MI) with ligation of the left anterior descending artery. Our in vivo data showed that iVPCs on the micro-bundle scaffold had higher survival, and better retention and engraftment in the myocardium than free iVPCs. iVPCs on the micro-bundles promoted better cardiomyocyte survival than free iVPCs. Moreover, iVPCs and iVPC/polymer micro-bundles treatment improved cardiac function (ejection fraction and fractional shortening, endocardial systolic volume) measured by echocardiography, increased vessel density, and decreased infarction size [endocardial and epicardial infarct (scar) length] better than untreated controls at 8 weeks after MI. We conclude that iVPCs grown on a polymer micro-bundle scaffold are new promising approach for cell-based therapy designed for cardiovascular regeneration in ischemic heart disease.
Jamaiyar Anurag; Wan Weiguo; Ohanyan Vahagn; Enrick Molly; Janota Danielle; Cumpston Devan; Song Hokyung; Stevanov Kelly; Kolz Christopher L; Hakobyan Tatev; Dong Feng; Newby Bi-Min Zhang; Chilian William M; Yin Liya
Basic research in cardiology
2017
2017-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1007/s00395-017-0631-4" target="_blank" rel="noreferrer noopener">10.1007/s00395-017-0631-4</a>
Epigenetic regulation in diabetes-associated oxidative stress and myocardial dysfunction.
*Epigenesis; *Oxidative Stress; Cardiomyopathies; Genetic; Humans
Yin Liya; Chilian William M; Dong Feng
International journal of cardiology
2018
2018-10
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.ijcard.2018.05.058" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2018.05.058</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
*Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon-Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Dewetting based fabrication of fibrous micro-scaffolds as potential injectable cell carriers.
Animals; Cell retention; Cells; Dewetting; Fibrous micro-constructs; Immobilized/metabolism/transplantation; Injectable constructs; Myocardial Infarction/metabolism/pathology/*therapy; Rats; Sprague-Dawley; Stem Cell Transplantation/*methods; Stem Cells/*metabolism; Tissue engineering and regeneration; Tissue Scaffolds/*chemistry
Although regenerative medicine utilizing tissue scaffolds has made enormous strides in recent years, many constraints still hamper their effectiveness. A limitation of many scaffolds is that they form surface patches, which are not particularly effective for some types of "wounds" that are deep within tissues, e.g., stroke and myocardial infarction. In this study, we reported the generation of fibrous micro-scaffolds feasible for delivering cells by injection into the tissue parenchyma. The micro-scaffolds (widths\textless100mum) were made by dewetting of poly(lactic-co-glycolic acid) thin films containing parallel strips, and cells were seeded to form cell/polymer micro-constructs during or post the micro-scaffold fabrication process. Five types of cells including rat induced vascular progenitor cells were assessed for the formation of the micro-constructs. Critical factors in forming fibrous micro-scaffolds via dewetting of polymer thin films were found to be properties of polymers and supporting substrates, temperature, and proteins in the culture medium. Also, the ability of cells to attach to the micro-scaffolds was essential in forming cell/polymer micro-constructs. Both in vitro and in vivo assessments of injecting these micro-scaffolding constructs showed, as compared to free cells, enhanced cell retention at the injected site, which could lead to improved tissue engineering and regeneration.
Song Hokyung; Yin Liya; Chilian William M; Newby Bi-Min Zhang
Materials science & engineering. C, Materials for biological applications
2015
2015-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.msec.2014.12.062" target="_blank" rel="noreferrer noopener">10.1016/j.msec.2014.12.062</a>
Vascular precursor cells in tissue injury repair.
*Wound Healing; Animals; Cell Differentiation; Cell Physiology; Cell Proliferation; Endothelium; Humans; Neovascularization; Physiologic; Regeneration – Physiology; Regeneration/*physiology; Stem Cells; Stem Cells – Physiology; Stem Cells/cytology/*physiology; Vascular/cytology; Wound Healing
Vascular precursor cells include stem cells and progenitor cells giving rise to all mature cell types in the wall of blood vessels. When tissue injury occurs, local hypoxia and inflammation result in the generation of vasculogenic mediators which orchestrate migration of vascular precursor cells from their niche environment to the site of tissue injury. The intricate crosstalk among signaling pathways coordinates vascular precursor cell proliferation and differentiation during neovascularization. Establishment of normal blood perfusion plays an essential role in the effective repair of the injured tissue. In recent years, studies on molecular mechanisms underlying the regulation of vascular precursor cell function have achieved substantial progress, which promotes exploration of vascular precursor cell-based approaches to treat chronic wounds and ischemic diseases in vital organ systems. Verification of safety and establishment of specific guidelines for the clinical application of vascular precursor cell-based therapy remain major challenges in the field.
Shi Xin; Zhang Weihong; Yin Liya; Chilian William M; Krieger Jessica; Zhang Ping
Translational research : the journal of laboratory and clinical medicine
2017
2017-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.trsl.2017.02.002" target="_blank" rel="noreferrer noopener">10.1016/j.trsl.2017.02.002</a>
Coronary collateral growth–back to the future.
Collateral Circulation/*physiology; Coronary Artery Disease/physiopathology/therapy; Coronary Circulation/physiology; Humans; Myocardial Ischemia/physiopathology/therapy; Neovascularization; Physiologic/physiology
The coronary collateral circulation is critically important as an adaptation of the heart to prevent the damage from ischemic insults. In their native state, collaterals in the heart would be classified as part of the microcirculation, existing as arterial-arterial anastomotic connections in the range of 30 to 100 muM in diameter. However, these vessels also show a propensity to remodel into components of the macrocirculation and can become arteries larger than 1000 muM in diameter. This process of outward remodeling is critically important in the adaptation of the heart to ischemia because the resistance to blood flow is inversely related to the fourth power of the diameter of the vessel. Thus, an expansion of a vessel from 100 to 1000 muM would reduce resistance (in this part of the circuit) to a negligible amount and enable delivery of flow to the region at risk. Our goal in this review is to highlight the voids in understanding this adaptation to ischemia-the growth of the coronary collateral circulation. In doing so we discuss the controversies and unknown aspects of the causal factors that stimulate growth of the collateral circulation, the role of genetics, and the role of endogenous stem and progenitor cells in the context of the normal, physiological situation and under more pathological conditions of ischemic heart disease or with some of the underlying risk factors, e.g., diabetes. The major conclusion of this review is that there are many gaps in our knowledge of coronary collateral growth and this knowledge is critical before the potential of stimulating collateralization in the hearts of patients can be realized. This article is part of a Special Issue entitled "Coronary Blood Flow".
Chilian William M; Penn Marc S; Pung Yuh Fen; Dong Feng; Mayorga Maritza; Ohanyan Vahagn; Logan Suzanna; Yin Liya
Journal of molecular and cellular cardiology
2012
2012-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1016/j.yjmcc.2011.12.006" target="_blank" rel="noreferrer noopener">10.1016/j.yjmcc.2011.12.006</a>
A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism.
Animals; Apolipoproteins E/genetics; Atherosclerosis/genetics/metabolism; Diabetes Mellitus; Experimental/genetics/metabolism; Hep G2 Cells; Hepatocyte Nuclear Factor 4/*genetics/metabolism; Humans; Knockout; LDL/genetics; Lipid Metabolism/*genetics; Lipoproteins/metabolism; Liver/metabolism; Mice; MicroRNAs/*genetics/metabolism; Middle Aged; Non-alcoholic Fatty Liver Disease/*genetics/metabolism; Physiological/*genetics; Receptors; Stress; Triglycerides/*metabolism
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, but its underlying mechanism is poorly understood. Here we show that hepatocyte nuclear factor 4alpha (HNF4alpha), a liver-enriched nuclear hormone receptor, is markedly inhibited, whereas miR-34a is highly induced in patients with non-alcoholic steatohepatitis, diabetic mice and mice fed a high-fat diet. miR-34a is essential for HNF4alpha expression and regulates triglyceride accumulation in human and murine hepatocytes. miR-34a inhibits very low-density lipoprotein secretion and promotes liver steatosis and hypolipidemia in an HNF4alpha-dependent manner. As a result, increased miR-34a or reduced HNF4alpha expression in the liver attenuates the development of atherosclerosis in Apoe(-/-) or Ldlr(-/-) mice. These data indicate that the miR-34a-HNF4alpha pathway is activated under common conditions of metabolic stress and may have a role in the pathogenesis of NAFLD and in regulating plasma lipoprotein metabolism. Targeting this pathway may represent a novel approach for the treatment of NAFLD.
Xu Yang; Zalzala Munaf; Xu Jiesi; Li Yuanyuan; Yin Liya; Zhang Yanqiao
Nature communications
2015
2015-06
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/ncomms8466" target="_blank" rel="noreferrer noopener">10.1038/ncomms8466</a>
Global inactivation of carboxylesterase 1 (Ces1/Ces1g) protects against atherosclerosis in Ldlr (-/-) mice.
Atherosclerotic cardiovascular disease is a leading cause of death in the western world. Increased plasma triglyceride and cholesterol levels are major risk factors for this disease. Carboxylesterase 1 (Ces1/Ces1g) has been shown to play a role in metabolic control. So far, the role of mouse Ces1/Ces1g deficiency in atherosclerosis is not elucidated. We generated Ces1/Ces1g (-/-) mice. Compared to wild-type mice, Ces1/Ces1g (-/-) mice had reduced plasma cholesterol levels. We then generated Ces1g (-/-) Ldlr (-/-) double knockout (DKO) mice, which were fed a Western diet for 16 weeks. Compared to Ldlr (-/-) mice, DKO mice displayed decreased plasma cholesterol and TG levels and reduced atherosclerotic lesions. Interestingly, knockdown of hepatic Ces1/Ces1g in Apoe (-/-) mice resulted in hyperlipidemia and exacerbated Western diet-induced atherogenesis. Mechanistically, global inactivation of Ces1/Ces1g inhibited intestinal cholesterol and fat absorption and Niemann-Pick C1 like 1 expression, and increased macrophage cholesterol efflux by inducing ATP-binding cassette subfamily A member 1 (ABCA1) and ABCG1. Ces1/Ces1g ablation also promoted M2 macrophage polarization and induced hepatic cholesterol 7alpha-hydroxylase and sterol 12alpha-hydroxylase expression. In conclusion, global loss of Ces1/Ces1g protects against the development of atherosclerosis by inhibiting intestinal cholesterol and triglyceride absorption and promoting macrophage cholesterol efflux.
Xu Jiesi; Xu Yang; Xu Yanyong; Yin Liya; Zhang Yanqiao
Scientific reports
2017
2017-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/s41598-017-18232-x" target="_blank" rel="noreferrer noopener">10.1038/s41598-017-18232-x</a>
Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4alpha and Protects Against Alcohol- and MCD diet-induced Liver Injury.
Alcoholic/*pathology; Alcohols/*toxicity; Animals; Carboxylic Ester Hydrolases/*metabolism; Chemical and Drug Induced Liver Injury/*pathology; Diet/*adverse effects; Fatty Liver; Gene Expression Regulation; Genetic; Hepatocyte Nuclear Factor 4/*metabolism; Hepatocytes/metabolism; Humans; Inbred C57BL; Knockout; Mice; Promoter Regions; Protein Binding
The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4alpha (HNF4alpha) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4alpha and CES1 expression in primary hepatocytes. HNF4alpha regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.
Xu Jiesi; Xu Yang; Li Yuanyuan; Jadhav Kavita; You Min; Yin Liya; Zhang Yanqiao
Scientific reports
2016
2016-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1038/srep24277" target="_blank" rel="noreferrer noopener">10.1038/srep24277</a>
Identification of novel pathways that control farnesoid X receptor-mediated hypocholesterolemia.
Absorption; Animals; Biological; Cell Line; Cholesterol/*metabolism; Class B/*genetics/metabolism; Coronary Disease/metabolism; Cytoplasmic and Nuclear/*metabolism; Glucose/metabolism; Hepatocyte Nuclear Factor 4/metabolism; Homeostasis; Humans; Lipoproteins/metabolism; Liver/metabolism; Mice; Models; Receptors; Scavenger Receptors
Farnesoid X receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized Fxr(-/-) mice and mice deficient in scavenger receptor class B type I (SR-BI), together with an
Zhang Yanqiao; Yin Liya; Anderson Jody; Ma Huiyan; Gonzalez Frank J; Willson Timothy M; Edwards Peter A
The Journal of biological chemistry
2010
2010-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M109.083899" target="_blank" rel="noreferrer noopener">10.1074/jbc.M109.083899</a>
Kv1.3 channels facilitate the connection between metabolism and blood flow in the heart.
*contrast echocardiography; *coronary blood flow; *Coronary Circulation/drug effects; *coronary microcirculation; *Kv 1.3 channels; Animals; Kv1.3 Potassium Channel/*physiology; Mice; Myocardium/*metabolism; Potassium Channel Blockers/pharmacology; Regional Blood Flow/drug effects; Triterpenes/pharmacology; Vasodilation/drug effects
The connection between metabolism and flow in the heart, metabolic dilation, is essential for cardiac function. We recently found redox-sensitive Kv1.5 channels play a role in coronary metabolic dilation; however, more than one ion channel likely plays a role in this process as animals null for these channels still showed limited coronary metabolic dilation. Accordingly, we examined the role of another Kv1 family channel, the energetically linked Kv1.3 channel, in coronary metabolic dilation. We measured myocardial blood flow (contrast echocardiography) during norepinephrine-induced increases in cardiac work (heart rate x mean arterial pressure) in WT, WT mice given correolide (preferential Kv1.3 antagonist), and Kv1.3-null mice (Kv1.3(-/-) ). We also measured relaxation of isolated small arteries mounted in a myograph. During increased cardiac work, myocardial blood flow was attenuated in Kv1.3(-/-) and in correolide-treated mice. In isolated vessels from Kv1.3(-/-) mice, relaxation to H2 O2 was impaired (vs WT), but responses to adenosine and acetylcholine were equivalent to WT. Correolide reduced dilation to adenosine and acetylcholine in WT and Kv1.3(-/-) , but had no effect on H2 O2 -dependent dilation in vessels from Kv1.3(-/-) mice. We conclude that Kv1.3 channels participate in the connection between myocardial blood flow and cardiac metabolism.
Ohanyan Vahagn; Yin Liya; Bardakjian Raffi; Kolz Christopher; Enrick Molly; Hakobyan Tatevik; Luli Jordan; Graham Kathleen; Khayata Mohamed; Logan Suzanna; Kmetz John; Chilian William M
Microcirculation (New York, N.Y. : 1994)
2017
2017-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1111/micc.12334" target="_blank" rel="noreferrer noopener">10.1111/micc.12334</a>
The role of mitochondrial bioenergetics and reactive oxygen species in coronary collateral growth.
*Collateral Circulation; *Coronary Circulation; *Energy Metabolism; *Neovascularization; angiogenesis; Animals; arteriogenesis; Coronary Vessels/metabolism; Humans; mitochondria; Mitochondria; Mitochondrial Proteins/metabolism; Muscle; Muscle/*metabolism; Myocytes; Oxidative Stress; Phenotype; Physiologic; Reactive Oxygen Species/*metabolism; redox-dependent signaling; Signal Transduction; Smooth; Smooth Muscle/*metabolism; Vascular/*metabolism
Coronary collateral growth is a process involving coordination between growth factors expressed in response to ischemia and mechanical forces. Underlying this response is proliferation of vascular smooth muscle and endothelial cells, resulting in an enlargement in the caliber of arterial-arterial anastomoses, i.e., a collateral vessel, sometimes as much as an order of magnitude. An integral element of this cell proliferation is the process known as phenotypic switching in which cells of a particular phenotype, e.g., contractile vascular smooth muscle, must change their phenotype to proliferate. Phenotypic switching requires that protein synthesis occurs and different kinase signaling pathways become activated, necessitating energy to make the switch. Moreover, kinases, using ATP to phosphorylate their targets, have an energy requirement themselves. Mitochondria play a key role in the energy production that enables phenotypic switching, but under conditions where mitochondrial energy production is constrained, e.g., mitochondrial oxidative stress, this switch is impaired. In addition, we discuss the potential importance of uncoupling proteins as modulators of mitochondrial reactive oxygen species production and bioenergetics, as well as the role of AMP kinase as an energy sensor upstream of mammalian target of rapamycin, the master regulator of protein synthesis.
Pung Yuh Fen; Sam Wai Johnn; Hardwick James P; Yin Liya; Ohanyan Vahagn; Logan Suzanna; Di Vincenzo Lola; Chilian William M
American journal of physiology. Heart and circulatory physiology
2013
2013-11
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00077.2013" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00077.2013</a>
Cardioprotection during ischemia by coronary collateral growth.
cardioprotection; coronary circulation; coronary collateral growth; ischemia
Ischemic heart diseases (IHD) cause millions of deaths around the world annually. While surgical and pharmacological interventions are commonly used to treat patients with IHD, their efficacy varies from patient to patient and is limited by the severity of the disease. One promising, at least theoretically, approach for treating IHD is induction of coronary collateral growth (CCG). Coronary collaterals are arteriole-to-arteriole anastomoses that can undergo expansion and remodeling in the setting of coronary disease when the disease elicits myocardial ischemia and creates a pressure difference across the collateral vessel that creates unidirectional flow. Well-developed collaterals can restore blood flow in the ischemic area of the myocardium and protect the myocardium at risk. Moreover, such collaterals are correlated to reduced mortality and infarct size and better cardiac function during occlusion of coronary arteries. Therefore, understanding the process of CCG is highly important as a potentially viable treatment of IHD. While there are several excellent review articles on this topic, this review will provide a unified overview of the various aspects related to CCG as well as an update of the advancements in the field. We also call for more detailed studies with an interdisciplinary approach to advance our knowledge of CCG. In this review, we will describe growth of coronary collaterals, the various factors that contribute to CCG, animal models used to study CCG, and the cardioprotective effects of coronary collaterals during ischemia. We will also discuss the impairment of CCG in metabolic syndrome and the therapeutic potentials of CCG in IHD.
Jamaiyar Anurag; Juguilon Cody; Dong Feng; Cumpston Devan; Enrick Molly; Chilian William M; Yin Liya
American journal of physiology. Heart and circulatory physiology
2019
2019-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1152/ajpheart.00145.2018" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00145.2018</a>
Hepatic hepatocyte nuclear factor 4alpha is essential for maintaining triglyceride and cholesterol homeostasis.
Adenoviridae/genetics; Animal; Animals; Cells; Cholesterol; Cholesterol/*metabolism; Cultured; Fatty Liver/metabolism/physiopathology; HDL/metabolism; Hepatocyte Nuclear Factor 4/drug effects/genetics/*physiology; Hepatocytes/cytology/*metabolism; Homeostasis/genetics/*physiology; Inbred C57BL; Lipid Metabolism/genetics/physiology; Mice; Models; RNA; Small Interfering/genetics/pharmacology; Triglycerides/*metabolism; VLDL/metabolism
OBJECTIVE: Loss-of-function mutations in human hepatocyte nuclear factor 4alpha (HNF4alpha) are associated with maturity-onset diabetes of the young and lipid disorders. However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4alpha function on lipid homeostasis. METHODS AND RESULTS: We generated an adenovirus expressing LacZ (Ad-shLacZ) or short hairpin RNA of Hnf4alpha (Ad-shHnf4alpha). Tail vain injection of C57BL/6J mice with Ad-shHnf4alpha reduced hepatic Hnf4alpha expression and resulted in striking phenotypes, including the development of fatty liver and a \textgreater80% decrease in plasma levels of triglycerides, total cholesterol, and high-density lipoprotein cholesterol. These latter changes were associated with reduced hepatic lipogenesis and impaired very-low-density lipoprotein secretion. Deficiency in hepatic Hnf4alpha did not affect intestinal cholesterol absorption despite decreased expression of genes involved in bile acid synthesis. Consistent with the loss-of-function data, overexpression of Hnf4alpha induced numerous genes involved in lipid metabolism in isolated primary hepatocytes. Interestingly, many of these HNF4alpha-regulated genes were not induced in wild-type mice that overexpressed hepatic Hnf4alpha. Because of selective gene regulation, mice overexpressing hepatic Hnf4alpha had unchanged plasma triglyceride levels and decreased plasma cholesterol levels. CONCLUSIONS: Loss of hepatic HNF4alpha results in severe lipid disorder as a result of dysregulation of multiple genes involved in lipid metabolism. In contrast, augmentation of hepatic HNF4alpha activity lowers plasma cholesterol levels but has no effect on plasma triglyceride levels because of selective gene regulation. Our data indicate that hepatic HNF4alpha is essential for controlling the basal expression of numerous genes involved in lipid metabolism and is indispensable for maintaining normal lipid homeostasis.
Yin Liya; Ma Huiyan; Ge Xuemei; Edwards Peter A; Zhang Yanqiao
Arteriosclerosis, thrombosis, and vascular biology
2011
2011-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.110.217828" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.110.217828</a>
Resolution of mitochondrial oxidative stress rescues coronary collateral growth in Zucker obese fatty rats.
Animal; Animals; Antioxidants/*pharmacology; Collateral Circulation/*drug effects/physiology; Coronary Vessels/drug effects/*growth & development; Disease Models; Heart/*drug effects/physiology; Lipid Peroxidation/drug effects/physiology; Lipid Peroxides/metabolism; Male; Metabolic Syndrome/*metabolism/physiopathology; Mitochondria; Mitochondrial Proteins/metabolism; Obesity/*metabolism/physiopathology; Organophosphorus Compounds/pharmacology; Oxidative Stress/*drug effects/physiology; Piperidines/pharmacology; Rats; Reactive Oxygen Species/metabolism; Ubiquinone/pharmacology; Zucker
OBJECTIVE: We have previously found abrogated ischemia-induced coronary collateral growth in Zucker obese fatty (ZOF) rats compared with Zucker lean (ZLN) rats. Because ZOF rats have structural abnormalities in their mitochondria suggesting dysfunction and also show increased production of O(2), we hypothesized that mitochondrial dysfunction caused by oxidative stress impairs coronary collateral growth in ZOF. METHODS AND RESULTS: Increased levels of reactive oxygen species were observed in aortic endothelium and smooth muscle cells in ZOF rats compared with ZLN rats. Reactive oxygen species levels were decreased by the mitochondria-targeted antioxidants MitoQuinone (MQ) and MitoTempol (MT) as assessed by MitoSox Red and dihydroethidine staining. Lipid peroxides (a marker of oxidized lipids) were increased in ZOF by approximately 47% compared with ZLN rats. The elevation in oxidative stress was accompanied by increased antioxidant enzymes, except glutathione peroxidase-1, and by increased uncoupling protein-2 in ZOF versus ZLN rats. In addition, elevated respiration rates were also observed in the obese compared with lean rats. Administration of MQ significantly normalized the metabolic profiles and reduced lipid peroxides in ZOF rats to the same level observed in lean rats. The protective effect of MQ also suppressed the induction of uncoupling protein-2 in the obese rats. Resolution of mitochondrial oxidative stress by MQ or MT restored coronary collateral growth to the same magnitude observed in ZLN rats in response to repetitive ischemia. CONCLUSIONS: We conclude that mitochondrial oxidative stress and dysfunction play a key role in disrupting coronary collateral growth in obesity and the metabolic syndrome, and elimination of the mitochondrial oxidative stress with MQ or MT rescues collateral growth.
Pung Yuh Fen; Rocic Petra; Murphy Michael P; Smith Robin A J; Hafemeister Jennifer; Ohanyan Vahagn; Guarini Giacinta; Yin Liya; Chilian William M
Arteriosclerosis, thrombosis, and vascular biology
2012
2012-02
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.111.241802" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.111.241802</a>
Mitochondrial oxidative stress corrupts coronary collateral growth by activating adenosine monophosphate activated kinase-alpha signaling.
AMP-Activated Protein Kinases/*metabolism; Animal; Animals; Body Weight/physiology; Cells; collateral circulation; coronary circulation; Coronary Vessels/cytology/*enzymology; Cultured; Disease Models; Endothelial Cells/cytology/*enzymology; Humans; Inbred WKY; Ischemia/metabolism/pathology; mitochondria; Mitochondria/drug effects/*metabolism; Myocardium/enzymology/pathology; Oxidative Stress/*physiology; Rats; reactive oxygen species; Rotenone/pharmacology; Signal Transduction/*physiology; TOR Serine-Threonine Kinases/metabolism; Uncoupling Agents/pharmacology
OBJECTIVE: Our goal was to determine the mechanism by which mitochondrial oxidative stress impairs collateral growth in the heart. APPROACH AND RESULTS: Rats were treated with rotenone (mitochondrial complex I inhibitor that increases reactive oxygen species production) or sham-treated with vehicle and subjected to repetitive ischemia protocol for 10 days to induce coronary collateral growth. In control rats, repetitive ischemia increased flow to the collateral-dependent zone; however, rotenone treatment prevented this increase suggesting that mitochondrial oxidative stress compromises coronary collateral growth. In addition, rotenone also attenuated mitochondrial complex I activity and led to excessive mitochondrial aggregation. To further understand the mechanistic pathway(s) involved, human coronary artery endothelial cells were treated with 50 ng/mL vascular endothelial growth factor, 1 micromol/L rotenone, and rotenone/vascular endothelial growth factor for 48 hours. Vascular endothelial growth factor induced robust tube formation; however, rotenone completely inhibited this effect (P\textless0.05 rotenone versus vascular endothelial growth factor treatment). Inhibition of tube formation by rotenone was also associated with significant increase in mitochondrial superoxide generation. Immunoblot analyses of human coronary artery endothelial cells with rotenone treatment showed significant activation of adenosine monophosphate activated kinase (AMPK)-alpha and inhibition of mammalian target of rapamycin and p70 ribosomal S6 kinase. Activation of AMPK-alpha suggested impairments in energy production, which was reflected by decrease in O2 consumption and bioenergetic reserve capacity of cultured cells. Knockdown of AMPK-alpha (siRNA) also preserved tube formation during rotenone, suggesting the negative effects were mediated by the activation of AMPK-alpha. Conversely, expression of a constitutively active AMPK-alpha blocked tube formation. CONCLUSIONS: We conclude that activation of AMPK-alpha during mitochondrial oxidative stress inhibits mammalian target of rapamycin signaling, which impairs phenotypic switching necessary for the growth of blood vessels.
Pung Yuh Fen; Sam Wai Johnn; Stevanov Kelly; Enrick Molly; Chen Chwen-Lih; Kolz Christopher; Thakker Prashanth; Hardwick James P; Chen Yeong-Renn; Dyck Jason R B; Yin Liya; Chilian William M
Arteriosclerosis, thrombosis, and vascular biology
2013
2013-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/ATVBAHA.113.301591" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.113.301591</a>
Induction of vascular progenitor cells from endothelial cells stimulates coronary collateral growth.
*Collateral Circulation; *Coronary Circulation; Animal; Animals; Biomarkers/metabolism; Cell Differentiation; Cell Lineage; Cells; Coronary Occlusion/genetics/metabolism/pathology/physiopathology/*surgery; Coronary Vessels/metabolism/pathology/*physiopathology; Cultured; Developmental; Disease Models; Endothelial Cells/metabolism/pathology/*transplantation; Epigenesis; Gene Expression Profiling; Gene Expression Regulation; Genetic; Induced Pluripotent Stem Cells/metabolism/*transplantation; Mice; Muscle; Myocytes; Neovascularization; Physiologic; Rats; Regenerative Medicine/methods; Regional Blood Flow; Reverse Transcriptase Polymerase Chain Reaction; SCID; Smooth; Smooth Muscle/metabolism/pathology/*transplantation; Sprague-Dawley; Teratoma/metabolism/pathology; Time Factors; Transcription Factors/genetics/metabolism; Transduction; Vascular/metabolism/pathology/*physiopathology
RATIONALE: A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved. OBJECTIVE: To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth. METHODS AND RESULTS: We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments. CONCLUSIONS: We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
Yin Liya; Ohanyan Vahagn; Pung Yuh Fen; Delucia Angelo; Bailey Erin; Enrick Molly; Stevanov Kelly; Kolz Christopher L; Guarini Giacinta; Chilian William M
Circulation research
2012
2012-01
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.111.250126" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.111.250126</a>
Requisite Role of Kv1.5 Channels in Coronary Metabolic Dilation.
129 Strain; Animals; cardiac function; contrast echocardiography; Coronary Circulation/*physiology; Coronary Vessels/*metabolism; hydrogen peroxide; Inbred C57BL; ion channel; Knockout; Kv1.5 Potassium Channel/*physiology; Mice; Muscle; Smooth; Transgenic; transgenic mice; Vascular/*metabolism; vasodilation; Vasodilation/*physiology; voltage-gated potassium channels
RATIONALE: In the working heart, coronary blood flow is linked to the production of metabolites, which modulate tone of smooth muscle in a redox-dependent manner. Voltage-gated potassium channels (Kv), which play a role in controlling membrane potential in vascular smooth muscle, have certain members that are redox-sensitive. OBJECTIVE: To determine the role of redox-sensitive Kv1.5 channels in coronary metabolic flow regulation. METHODS AND RESULTS: In mice (wild-type [WT], Kv1.5 null [Kv1.5(-/-)], and Kv1.5(-/-) and WT with inducible, smooth muscle-specific expression of Kv1.5 channels), we measured mean arterial pressure, myocardial blood flow, myocardial tissue oxygen tension, and ejection fraction before and after inducing cardiac stress with norepinephrine. Cardiac work was estimated as the product of mean arterial pressure and heart rate. Isolated arteries were studied to establish whether genetic alterations modified vascular reactivity. Despite higher levels of cardiac work in the Kv1.5(-/-) mice (versus WT mice at baseline and all doses of norepinephrine), myocardial blood flow was lower in Kv1.5(-/-) mice than in WT mice. At high levels of cardiac work, tissue oxygen tension dropped significantly along with ejection fraction. Expression of Kv1.5 channels in smooth muscle in the null background rescued this phenotype of impaired metabolic dilation. In isolated vessels from Kv1.5(-/-) mice, relaxation to H2O2 was impaired, but responses to adenosine and acetylcholine were normal compared with those from WT mice. CONCLUSIONS: Kv1.5 channels in vascular smooth muscle play a critical role in coupling myocardial blood flow to cardiac metabolism. Absence of these channels disassociates metabolism from flow, resulting in cardiac pump dysfunction and tissue hypoxia.
Ohanyan Vahagn; Yin Liya; Bardakjian Raffi; Kolz Christopher; Enrick Molly; Hakobyan Tatevik; Kmetz John; Bratz Ian; Luli Jordan; Nagane Masaki; Khan Nadeem; Hou Huagang; Kuppusamy Periannan; Graham Jacqueline; Fu Frances Kwan; Janota Danielle; Oyewumi Moses O; Logan Suzanna; Lindner Jonathan R; Chilian William M
Circulation research
2015
2015-09
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1161/CIRCRESAHA.115.306642" target="_blank" rel="noreferrer noopener">10.1161/CIRCRESAHA.115.306642</a>
Aldo-keto reductase 1B7 is a target gene of FXR and regulates lipid and glucose homeostasis.
*Aldehyde Reductase/genetics/metabolism; Adenoviridae; Animal; Animals; Blood Glucose/*metabolism; Cholesterol/analysis; Cytoplasmic and Nuclear/genetics/*metabolism; Diabetes Mellitus/genetics/*metabolism/physiopathology; Disease Models; Fatty Liver/genetics/*metabolism/physiopathology; Gene Expression; Genetic Vectors; Gluconeogenesis/genetics; Homeostasis; Humans; Liver/*metabolism/physiopathology; Malondialdehyde/blood; Mice; Polymerase Chain Reaction; Receptors; Transfection; Transgenic; Triglycerides/analysis
Aldo-keto reductase 1B7 (AKR1B7) is proposed to play a role in detoxification of by-products of lipid peroxidation. In this article, we show that activation of the nuclear receptor farnesoid X receptor (FXR) induces AKR1B7 expression in the liver and intestine, and reduces the levels of malondialdehyde (MDA), the end product of lipid peroxidation, in the intestine but not in the liver. To determine whether AKR1B7 regulates MDA levels in vivo, we overexpressed AKR1B7 in the liver. Overexpression of AKR1B7 in the liver had no effect on hepatic or plasma MDA levels. Interestingly, hepatic expression of AKR1B7 significantly lowered plasma glucose levels in both wild-type and diabetic db/db mice, which was associated with reduced hepatic gluconeogenesis. Hepatic expression of AKR1B7 also significantly lowered hepatic triglyceride and cholesterol levels in db/db mice. These data reveal a novel function for AKR1B7 in lipid and glucose metabolism and suggest that AKR1B7 may not play a role in detoxification of lipid peroxides in the liver. AKR1B7 may be a therapeutic target for treatment of fatty liver disease associated with diabetes mellitus.
Ge Xuemei; Yin Liya; Ma Huiyan; Li Tiangang; Chiang John Y L; Zhang Yanqiao
Journal of lipid research
2011
2011-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1194/jlr.M015859" target="_blank" rel="noreferrer noopener">10.1194/jlr.M015859</a>
Hepatic carboxylesterase 1 is induced by glucose and regulates postprandial glucose levels.
Male; Animals; Mice; Blood Glucose/*metabolism; Histones/metabolism; Gene Expression Regulation; Acetylation/drug effects; Glucose/*pharmacology; Homeostasis; Carboxylic Ester Hydrolases/*metabolism; Nutritional Status; *Postprandial Period; ATP Citrate (pro-S)-Lyase/metabolism; Chromatin/metabolism; Liver/*enzymology; Inbred C57BL; Enzymologic/drug effects
Metabolic syndrome, characterized by obesity, hyperglycemia, dyslipidemia and hypertension, increases the risks for cardiovascular disease, diabetes and stroke. Carboxylesterase 1 (CES1) is an enzyme that hydrolyzes triglycerides and cholesterol esters, and is important for lipid metabolism. Our previous data show that over-expression of mouse hepatic CES1 lowers plasma glucose levels and improves insulin sensitivity in diabetic ob/ob mice. In the present study, we determined the physiological role of hepatic CES1 in glucose homeostasis. Hepatic CES1 expression was reduced by fasting but increased in diabetic mice. Treatment of mice with glucose induced hepatic CES1 expression. Consistent with the in vivo study, glucose stimulated CES1 promoter activity and increased acetylation of histone 3 and histone 4 in the CES1 chromatin. Knockdown of ATP-citrate lyase (ACL), an enzyme that regulates histone acetylation, abolished glucose-mediated histone acetylation in the CES1 chromatin and glucose-induced hepatic CES1 expression. Finally, knockdown of hepatic CES1 significantly increased postprandial blood glucose levels. In conclusion, the present study uncovers a novel glucose-CES1-glucose pathway which may play an important role in regulating postprandial blood glucose levels.
Xu Jiesi; Yin Liya; Xu Yang; Li Yuanyuan; Zalzala Munaf; Cheng Gang; Zhang Yanqiao
PloS one
2014
2014
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1371/journal.pone.0109663" target="_blank" rel="noreferrer noopener">10.1371/journal.pone.0109663</a>
Knowns and unknowns of coronary artery development and anomalies.
Dong Feng; Chilian William M; Yin Liya
International journal of cardiology
2019
2019-04
<a href="http://doi.org/10.1016/j.ijcard.2019.01.073" target="_blank" rel="noreferrer noopener">10.1016/j.ijcard.2019.01.073</a>
Reversal of metabolic disorders by pharmacological activation of bile acid receptors TGR5 and FXR.
Humans; Male; Animals; Mice; *Atherosclerosis; *Farnesoid X receptor; *NAFLD; *Obesity; *TGR5; Diet; Hep G2 Cells; Receptors; Inbred C57BL; High-Fat/adverse effects; Cytoplasmic and Nuclear/*agonists; Bile Acids and Salts/pharmacology/*therapeutic use; Hypercholesterolemia/*drug therapy/etiology/metabolism; Non-alcoholic Fatty Liver Disease/*drug therapy/etiology/metabolism; Obesity/*drug therapy/etiology/metabolism; G-Protein-Coupled/*agonists
OBJECTIVES: Activation of the bile acid (BA) receptors farnesoid X receptor (FXR) or G protein-coupled bile acid receptor (GPBAR1; TGR5) improves metabolic homeostasis. In this study, we aim to determine the impact of pharmacological activation of bile acid receptors by INT-767 on reversal of diet-induced metabolic disorders, and the relative contribution of FXR vs. TGR5 to INT-767's effects on metabolic parameters. METHODS: Wild-type (WT), Tgr5(-/-), Fxr(-/-), Apoe(-/-) and Shp(-/-) mice were used to investigate whether and how BA receptor activation by INT-767, a semisynthetic agonist for both FXR and TGR5, could reverse diet-induced metabolic disorders. RESULTS: INT-767 reversed HFD-induced obesity dependent on activation of both TGR5 and FXR and also reversed the development of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Mechanistically, INT-767 improved hypercholesterolemia by activation of FXR and induced thermogenic genes via activation of TGR5 and/or FXR. Furthermore, INT-767 inhibited several lipogenic genes and de novo lipogenesis in the liver via activation of FXR. We identified peroxisome proliferation-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding protein alpha (CEBPalpha) as novel
Jadhav Kavita; Xu Yang; Xu Yanyong; Li Yuanyuan; Xu Jiesi; Zhu Yingdong; Adorini Luciano; Lee Yoon Kwang; Kasumov Takhar; Yin Liya; Zhang Yanqiao
Molecular metabolism
2018
2018-03
<a href="http://doi.org/10.1016/j.molmet.2018.01.005" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2018.01.005</a>
Exosomes derived from Induced Vascular Progenitor Cells Promote Angiogenesis in vitro and in an in vivo Rat Hindlimb Ischemia Model
angiogenesis; endothelial cell; exosome; microRNA; progenitor cell
Induced vascular progenitor cells (iVPCs) were created as an ideal cell type for regenerative medicine and have been reported to positively promote collateral blood flow and improve cardiac function in a rat model of myocardial ischemia. Exosomes have emerged as a novel biomedicine that mimics the function of the donor cells. We investigated the angiogenic activity of exosomes from induced vascular progenitor cells (iVPC-Exo) as a cell-free therapeutic approach for ischemia. Exosomes from iVPCs and rat aortic endothelial cells (RAECs) were isolated using a combination of ultrafiltration and size-exclusion chromatography. Nanoparticle tracking analysis revealed that exosome isolates fell within the exosomal diameter (<150 nm). These exosomes contained known markers Alix and TSG101, and their morphology was validated using transmission electron microscopy. Compared to RAECs, iVPCs significantly increased the secretion of exosomes. Cardiac microvascular endothelial cells and aortic ring explants were pretreated with RAEC-Exo or iVPC-Exo, and basal medium was used as a control. iVPC-Exo exerted an in vitro angiogenic effect on the proliferation, tube formation, and migration of endothelial cells and stimulated microvessel sprouting in an ex vivo aortic ring assay. Additionally, iVPC-Exo increased blood perfusion in a hindlimb ischemia model. Proangiogenic proteins (pentraxin-3 and insulin-like growth factor-binding protein-3) and microRNAs (-143-3p, -291b, and -20b-5p) were found to be enriched in iVPC-Exo, which may mediate iVPC-Exo induced vascular growth. Our findings demonstrate that treatment with iVPC-Exo promotes angiogenesis in vitro, ex vivo, and in vivo. Collectively, these findings indicate a novel cell-free approach for therapeutic angiogenesis.
Johnson Takerra K; Zhao Lina; Zhu Dihan; Wang Yang; Xiao Yan; Oguljahan Babayewa; Zhao Xueying; Kirlin Ward G; Yin Liya; Chilian William M; Liu Dong
American Journal of Physiology. Heart and Circulatory Physiology
2019
2019-08
<a href="http://doi.org/10.1152/ajpheart.00247.2019" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00247.2019</a>
Hepatic Forkhead Box Protein A3 Regulates ApoA-I (Apolipoprotein A-I) Expression, Cholesterol Efflux, and Atherogenesis
activation; Atherosclerosis; Cardiovascular System & Cardiology; cholesterol efflux; fatty-acids; FOXA3; FOXA3; gene; Hematology; high-density-lipoprotein; increased; Liver; Macrophages; mice lacking; nuclear factor 3-gamma; transport
OBJECTIVE: To determine the role of hepatic FOXA3 (forkhead box A3) in lipid metabolism and atherosclerosis. Approach and Results: Hepatic FOXA3 expression was reduced in diabetic or high fat diet-fed mice or patients with nonalcoholic steatohepatitis. We then used adenoviruses to overexpress or knock down hepatic FOXA3 expression. Overexpression of FOXA3 in the liver increased hepatic ApoA-I (apolipoprotein A-I) expression, plasma HDL-C (high-density lipoprotein cholesterol) level, macrophage cholesterol efflux, and macrophage reverse cholesterol transport. In contrast, knockdown of hepatic FOXA3 expression had opposite effects. We further showed that FOXA3 directly bound to the promoter of the Apoa1 gene to regulate its transcription. Finally, AAV8 (adeno-associated virus serotype 8)-mediated overexpression of human FOXA3 in the hepatocytes of Apoe-/- (apolipoprotein E-deficient) mice raised plasma HDL-C levels and significantly reduced atherosclerotic lesions. CONCLUSIONS: Hepatocyte FOXA3 protects against atherosclerosis by inducing ApoA-I and macrophage reverse cholesterol transport.
Li Yuanyuan; Xu Yanyong; Jadhav Kavita; Zhu Yingdong; Yin Liya; Zhang Yanqiao
Arteriosclerosis, Thrombosis, and Vascular Biology
2019
2019-08
<a href="http://doi.org/10.1161/ATVBAHA.119.312610" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.119.312610</a>
Lipocalin‐2 Protects Against Diet‐Induced Nonalcoholic Fatty Liver Disease by Targeting Hepatocytes.
FATTY liver; LIPOCALIN; LIVER disease treatment
Hepatocytes are the major source of hepatic lipocalin‐2 (LCN2), which is up‐regulated in response to inflammation, injury, or metabolic stress. So far, the role of hepatocyte‐derived LCN2 in the development of nonalcoholic fatty liver disease (NAFLD) remains unknown. Herein we show that overexpression of human LCN2 in hepatocytes protects against high fat/high cholesterol/high fructose (HFCF) diet–induced liver steatosis and nonalcoholic steatohepatitis by promoting lipolysis and fatty acid oxidation (FAO) and inhibiting de novo lipogenesis (DNL), lipid peroxidation, and apoptosis. LCN2 fails to reduce triglyceride accumulation in hepatocytes lacking sterol regulatory element‐binding protein 1. In contrast, Lcn2−/− mice have defective lipolysis, increased lipid peroxidation and apoptosis, and exacerbated NAFLD after being fed an HFCF diet. In primary hepatocytes, Lcn2 deficiency stimulates de novo lipogenesis but inhibits FAO. Conclusion: The current study indicates that hepatocyte LCN2 protects against diet‐induced NAFLD by regulating lipolysis, FAO, DNL, lipid peroxidation, and apoptosis. Targeting hepatocyte LCN2 may be useful for treatment of NAFLD. [ABSTRACT FROM AUTHOR]
Xu Yanyong; Zhu Yingdong; Jadhav Kavita; Li Yuanyuan; Sun Huihui; Yin Liya; Kasumov Takhar; Chen Xiaoli; Zhang Yanqiao
Hepatology Communications
2019
2019-06
<a href="http://doi.org/10.1002/hep4.1341" target="_blank" rel="noreferrer noopener">10.1002/hep4.1341</a>
Macrophage miR-34a Is a Key Regulator of Cholesterol Efflux and Atherosclerosis
atherosclerosis; inflammation; cholesterol efflux; ABCA1; ABCG1; LXR; miR-34a
Macrophages play a crucial role in the pathogenesis of atherosclerosis, but the molecular mechanisms remain poorly understood. Here we show that microRNA-34a (miR-34a) is a key regulator of macrophage cholesterol efflux and reverse cholesterol transport by modulating ATP-binding cassette transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). miR-34a also regulates M1 and M2 macrophage polarization via liver X receptor α. Furthermore, global loss of miR-34a reduces intestinal cholesterol or fat absorption by inhibiting cytochrome P450 enzymes CYP7A1 and sterol 12α-hydroxylase (CYP8B1). Consistent with these findings, macrophage-selective or global ablation of miR-34a markedly inhibits the development of atherosclerosis. Finally, therapeutic inhibition of miR-34a promotes atherosclerosis regression and reverses diet-induced metabolic disorders. Our studies outline a central role of miR-34a in regulating macrophage cholesterol efflux, inflammation, and atherosclerosis, suggesting that miR-34a is a promising target for treatment of cardiometabolic diseases.
Xu Yanyong; Xu Yang; Zhu Yingdong; Sun Huihui; Juguilon Cody; Li Feng; Fan Daping; Yin Liya; Zhang Yanqiao
Molecular Therapy
2019
2019-01-01
Journal Article
<a href="http://doi.org/10.1016/j.ymthe.2019.09.008" target="_blank" rel="noreferrer noopener">10.1016/j.ymthe.2019.09.008</a>
Cardioprotection During Ischemia by Induced Coronary Collateral Growth
Jamaiyar Anurag; Juguilon Cody; Cumpston Devan; Weiguo Wan; Wang Tao; Zhiyuan Wang; Gadd James; Enrick Molly; Chinchilla Sofia; McCabe Caige; Pu Autumn Y; Chilian William; Yin Liya
Circulation Research
2019
2019-08
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1161/res.125.suppl_1.592" target="_blank" rel="noreferrer noopener">10.1161/res.125.suppl_1.592</a>
A Novel Murine Model to Study Postnatal Coronary Collateral Growth by Lineage Tracing
Jamaiyar Anurag; Juguilon Cody; Richardson Devan; Gadd James; Wang Tao; Enrick Molly; Chilian William M; Yin Liya
Circulation Research
2019
2019-12
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1161/RES.0000000000000311" target="_blank" rel="noreferrer noopener">10.1161/RES.0000000000000311</a>
The Role of Kv1.2 Channels in Coronary Metabolic Dilation
Ohanyan Vahagn; Hakobyan Tatevik; Enrick Molly; Shockling Lindsay; Yin Liya; Kolz Christopher L; Chilian William
Faseb Journal
2019
2019-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
Step by Step: Advancing the Understanding of Local Vascular Control.
Editorials; vasodilation; hypoxia; dilation; endothelium; arterial pressure
Chilian William M; Yin Liya; Ohanyan Vahagn
Arteriosclerosis, thrombosis, and vascular biology
2020
2020-03
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Journal Article
<a href="http://doi.org/10.1161/ATVBAHA.120.313811" target="_blank" rel="noreferrer noopener">10.1161/ATVBAHA.120.313811</a>
Hepatocyte-Specific Expression of Human Carboxylesterase 1 Attenuates Diet-Induced Steatohepatitis and Hyperlipidemia in Mice.
decreases blood-lipids; deficiency; dyslipidemia; hepatic steatosis; lipotoxicity; Liver; protects; receptor-alpha; reduces atherosclerosis; transgenic expression
Rodents have at least five carboxylesterase 1 (Ces1) genes, whereas there is only one CES1 gene in humans, raising the question as to whether human CES1 and mouse Ces1 genes share the same functions. In this study, we investigate the role of human CES1 in the development of steatohepatitis or dyslipidemia in C57BL/6 mice. Hepatocyte-specific expression of human CES1 prevented Western diet or alcohol-induced steatohepatitis and hyperlipidemia. Mechanistically, human CES1 induced lipolysis and fatty acid oxidation, leading to a reduction in hepatic triglyceride and free fatty acid levels. Human CES1 also reduced hepatic-free cholesterol levels and induced low-density lipoprotein receptor. In addition, human CES1 induced hepatic lipoprotein lipase and apolipoprotein C-II expression. Conclusion: Hepatocyte-specific overexpression of human CES1 attenuates diet-induced steatohepatitis and hyperlipidemia.
Xu Yanyong; Zhu Yingdong; Bawa Fathima Cassim; Hu Shuwei; Pan Xiaoli; Yin Liya; Zhang Yanqiao
Hepatology communications
2020
2020-04
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
journalArticle
<a href="http://doi.org/10.1002/hep4.1487" target="_blank" rel="noreferrer noopener">10.1002/hep4.1487</a>
Hepatocyte nuclear factor 4α prevents the steatosis-to-NASH progression by regulating p53 and bile acid signaling.
steatohepatitis; apoptosis; bile acid; HNF4α; lipolysis; P53
Hepatocyte nuclear factor 4α (HNF4α) is highly enriched in the liver, but its role in the progression of liver steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) has not been elucidated. In this study, we investigated the effect of gain or loss of hepatocyte HNF4α function on the development and progression of non-alcoholic fatty liver disease (NAFLD) in mice. Over-expression of human HNF4α protected against high fat/cholesterol/fructose (HFCF) diet-induced steatohepatitis whereas loss of hepatocyte Hnf4α had opposite effects. HNF4α prevented hepatic triglyceride accumulation by promoting hepatic triglyceride lipolysis, fatty acid oxidation and VLDL secretion. Furthermore, HNF4α suppressed the progression of NAFL to NASH. Over-expression of human HNF4α inhibited HFCF diet-induced steatohepatitis in control mice but not in hepatocyte-specific p53(-/-) mice. In HFCF diet-fed mice lacking hepatic Hnf4α, recapitulation of hepatic expression of HNF4α targets cholesterol 7α-hydroxylase and sterol 12α-hydroxylase normalized hepatic triglyceride levels and attenuated steatohepatitis. CONCLUSIONS: The current study indicates that hepatocyte HNF4α protects against diet-induced development and progression of NAFLD by coordinating the regulation of lipolytic, p53 and bile acid signaling pathways. Targeting hepatic HNF4α may be useful for treatment of NASH.
Xu Y;Zhu Y;Hu S;Xu Y;Stroup D;Pan X;Bawa FC;Chen S;Gopoju R;Yin Liya;Zhang Y
Hepatology
2020
2020-10-23
journalArticle
<a href="http://doi.org/10.1002/hep.31604" target="_blank" rel="noreferrer noopener">10.1002/hep.31604</a>