Hepatocyte miR-34a is a key regulator in the development and progression of non-alcoholic fatty liver disease.
miR-34a; NAFLD; Lipogenesis; bile acids; Bile acids; lipid absorption; lipogenesis; Lipid absorption
Objectives: Hepatic miR-34a expression is elevated in diet-induced or genetically obese mice, and patients with non-alcoholic steatohepatitis (NASH), yet the role of hepatocyte miR-34a in the progression of non-alcoholic fatty liver disease (NAFLD) from non-alcoholic fatty liver (NAFL) to NASH remains to be elucidated.; Methods: Mice over-expressing or deficient in hepatocyte miR-34a and their control mice were fed a diet enriched in fats, cholesterol and fructose (HFCF) to induce NASH. C57BL/6 mice with NASH were treated with an miR-34a inhibitor or a scramble control oligo. The effect of miR-34a on the development, progression or reversal of NAFLD was determined.; Results: Hepatocyte-specific expression of miR-34a aggravated HFCF diet-induced NAFLD. In contrast, germline or adult-onset loss of hepatocyte miR-34a attenuated the development and progression of NAFLD. In addition, pharmacological inhibition of miR-34a reversed HFCF diet-induced steatohepatitis. Mechanistically, hepatocyte miR-34a regulated the development and progression of NAFLD by inducing lipid absorption, lipogenesis, inflammation and apoptosis, and inhibiting fatty acid oxidation.; Conclusions: Hepatocyte miR-34a is an important regulator in the development and progression of NAFLD. MiR-34a may be a useful target for treating NAFLD. (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Xu Y; Zhu Y; Hu S; Pan X; Bawa FC; Wang HH; Wang DQ; Yin L; Zhang Y
Molecular Metabolism
2021
2021-04-27
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/10.1016/j.molmet.2021.101244" target="_blank" rel="noreferrer noopener">10.1016/j.molmet.2021.101244</a>
Hepatocyte-specific expression of human carboxylesterase 2 attenuates nonalcoholic steatohepatitis in mice.
steatohepatitis; LABORATORY mice; FATTY liver; lipotoxicity; CES2; fatty acid oxidation; lipolysis; FATTY acid oxidation; INSULIN sensitivity; STEROL regulatory element-binding proteins
Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were intravenously injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced nonalcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride (T) and free fatty acid (FFA) levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis, and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD. NEW & NOTEWORTHY Human CES2 attenuates high-fat/cholesterol/fructose diet-induced steatohepatitis and reverses steatohepatitis in db/db mice. Mechanistically, human CES2 induces lipolysis, fatty acid and glucose oxidation, and inhibits hepatic glucose production, inflammation, lipid oxidation, and apoptosis. Our data suggest that human CES2 may be targeted for treatment of non-alcoholic steatohepatitis (NASH). [ABSTRACT FROM AUTHOR]
Xu Y;Pan X; Shuwei H;Zhu Y; Bawa FC;Li Y; Yin L; Zhang Y
American Journal Of Physiology: Gastrointestinal & Liver Physiology
2021
2021-02
journalArticle
<a href="http://doi.org/10.1152/ajpgi.00315.2020" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00315.2020</a>
Hepatocyte ATF3 protects against atherosclerosis by regulating HDL and bile acid metabolism.
atherosclerosis
Activating transcription factor (ATF)3 is known to have an anti-inflammatory function, yet the role of hepatic ATF3 in lipoprotein metabolism or atherosclerosis remains unknown. Here we show that overexpression of human ATF3 in hepatocytes reduces the development of atherosclerosis in Western-diet-fed Ldlr(-/-) or Apoe(-/-) mice, whereas hepatocyte-specific ablation of Atf3 has the opposite effect. We further show that hepatic ATF3 expression is inhibited by hydrocortisone. Mechanistically, hepatocyte ATF3 enhances high-density lipoprotein (HDL) uptake, inhibits intestinal fat and cholesterol absorption and promotes macrophage reverse cholesterol transport by inducing scavenger receptor group B type 1 (SR-BI) and repressing cholesterol 12α-hydroxylase (CYP8B1) in the liver through its interaction with p53 and hepatocyte nuclear factor 4α, respectively. Our data demonstrate that hepatocyte ATF3 is a key regulator of HDL and bile acid metabolism and atherosclerosis.
Xu Y;Li Y;Jadhav K;Pan X;Zhu Y;Hu S;Chen S;Chen L;Tang Y;Wang HH;Yang L;Wang DQ;Yin L;Zhang Y
Nature Metabolism
2021
2021-01
journalArticle
<a href="http://doi.org/10.1038/s42255-020-00331-1" target="_blank" rel="noreferrer noopener">10.1038/s42255-020-00331-1</a>
Hepatocyte-specific expression of human carboxylesterase 2 attenuates non-alcoholic steatohepatitis in mice.
CES2; Fatty acid oxidation; Lipolysis; Lipotoxicity; Steatohepatitis
Human carboxylesterase 2 (CES2) has triacylglycerol hydrolase (TGH) activities and plays an important role in lipolysis. In this study, we aim to determine the role of human CES2 in the progression or reversal of steatohepatitis in diet-induced or genetically obese mice. High-fat/high-cholesterol/high-fructose (HFCF) diet-fed C57BL/6 mice or db/db mice were i.v. injected with an adeno-associated virus expressing human CES2 under the control of an albumin promoter. Human CES2 protected against HFCF diet-induced non-alcoholic fatty liver disease (NAFLD) in C57BL/6J mice and reversed steatohepatitis in db/db mice. Human CES2 also improved glucose tolerance and insulin sensitivity. Mechanistically, human CES2 reduced hepatic triglyceride and free fatty acid levels by inducing lipolysis and fatty acid oxidation and inhibiting lipogenesis via suppression of sterol regulatory element-binding protein 1. Furthermore, human CES2 overexpression improved mitochondrial respiration and glycolytic function, and inhibited gluconeogenesis, lipid peroxidation, apoptosis and inflammation. Our data suggest that hepatocyte-specific expression of human CES2 prevents and reverses steatohepatitis. Targeting hepatic CES2 may be an attractive strategy for treatment of NAFLD.
Xu Y; Pan X; Hu S; Zhu Y; Cassim BF; Li Y; Yin L; Zhang Y
American Journal of Physiology-Gastrointestinal and Liver Physiology
2020
2020-12-16
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/10.1152/ajpgi.00315.2020" target="_blank" rel="noreferrer noopener">10.1152/ajpgi.00315.2020</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>
Retinoic acid receptor α signaling protects against diet‐induced hepatosteatosis and obesity in mice
Nonalcoholic fatty liver disease (NAFLD) is often characterized by accumulation of lipids in the liver. It presents a pathological spectrum of changes from simple steatosis to steatohepatitis. It is also often associated with obesity and insulin resistance. Since liver is the main organ involved in retinoid signaling, the impairment of this pathway is shown to increase liver fibrosis with the activation of stellate cells which stores retinoids in liver. However, the role of the retinoid signaling in NAFLD and obesity is not fully understood. Some studies have shown that retinoic acid treatment can ameliorate insulin resistance and obesity. We hypothesize that Retinoic Acid Receptor α (RARα) in hepatocytes play a significant role in mediating retinoid signaling to protect against NAFLD and obesity. To address this hypothesis, we conducted in vivo studies using liver‐specific Rarα knockout mice. Rarα floxed mice were injected with AAV8‐TBG‐Cre or AAV8‐TBG‐Null to generate liver‐specific Rarα knockout mice (L‐Rarα−/−) mice and the control mice (Rarαfl/fl). These mice were gavaged with either vehicle or all‐trans retinoic acid (AtRA; 15mg/kg/day) along with high fat/high cholesterol/high fructose (HFCF) diet for 16 weeks. The data showed that AtRA treatment reduced body fat content and increased energy expenditure in the control mice but not in L‐Rarα−/− mice. In addition, AtRA reduced hepatic triglyceride (TG) levels in both the control mice and L‐Rarα−/− mice with a greater extent in reduction of hepatic TG levels in the control mice. Analysis of hepatic gene expression by qRT‐PCR showed that AtRA reduced hepatic levels of genes involved in lipogenesis and fatty acid uptake (Pparγ, Cd36 and L‐Fabp) or inflammation (Tnf‐α) in the control mice, but not in L‐RARα−/− mice. Similar observations were collected in a different study where control mice and L‐Rara−/− mice were fed an HFCF diet for 20 weeks, followed by 10 weeks of treatment with either vehicle or AtRA. Our data demonstrate that the retinoid signaling protects against the development of hepatosteatosis and obesity in a Rarα‐dependent manner.
Bawa F;Xu Y;Zhu Y;Chen S;Gopoju R;Zhang Y
Faseb Journal
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/10.1096/fasebj.2020.34.s1.09002" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.09002</a>
Regulation of coronary collateral growth by microrna-21 in metabolic syndrome
Well‐developed coronary collaterals prove to be highly beneficial in salvaging ischemic myocardium, preserving cardiac function, and improving patient outcome post‐occlusion. However, this process of coronary collateral growth (CCG) is impaired in patients with metabolic syndrome. A complete understanding of the underlying mechanism, cell types, and genes contributing towards this impairment have yet to be elucidated. Therefore, uncovering more about the process may lead to potential therapeutics to induce CCG in metabolic syndrome. MicroRNA‐21 (miR‐21) is abundantly expressed in vascular and immune cells with numerous implications in cardiovascular disease including atherosclerosis, heart failure, and myocardial infarction. Furthermore, miR‐21 has been shown to regulate processes such as apoptosis, immune cell polarization, and endothelial progenitor proliferation. Additionally, miR‐21 dysregulation has been rooted in the diabetic population where lies a systemic inflammatory state. In this study, we investigated the role of miR‐21 in a mouse model of CCG. Our preliminary data suggested that down‐regulating miR‐21 rescues impaired CCG in a diet‐induced model of metabolic syndrome. Thus, we investigated the underlying mechanism and focused on the roles of miR‐21 in the maintenance of vascular homeostasis, function and inflammatory responses in metabolic syndrome. First, we studied whether miR‐21 regulates endothelial homeostasis by modulating the function and homing of bone marrow stem cells in metabolic syndrome. We analyzed endothelial progenitor cells (CD34+) in bone marrow and peripheral blood, along with endothelial proliferation in WT, miR‐21 knockout, and metabolic syndrome mice. Second, we studied whether miR‐21 regulates the inflammatory response in metabolic syndrome by characterizing bone marrow derived macrophages from WT and miR‐21 knockout animals along with mapping their influence on vascular cells. Third, we utilized a myeloid specific miR‐21 knockout to study its role during CCG in vivo. We found CCG to be blunted in these animals which suggests the importance of myeloid derived miR‐21 in healthy mice. Further studies will give us more insight on miR‐21 and its regulation of CCG in metabolic syndrome.
Juguilon C;Richardson D;Gadd J;Enrick M;Jamaiyar A;Xu Y;Wang Z;Wang T;Kolz C;Chilian W;Yin L
Faseb Journal
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/10.1096/fasebj.2020.34.s1.09506" target="_blank" rel="noreferrer noopener">10.1096/fasebj.2020.34.s1.09506</a>
Bile Acid Receptor Activation Ameliorates Metabolic Disorders By Differentially Activating Fxr Or Tgr5
Cardiovascular System & Cardiology; Hematology; Ligands; Lipids
Jadhav K S; Xu Y; Zhang Y Q
Arteriosclerosis Thrombosis and Vascular Biology
2017
2017-05
Journal Article or Conference Abstract Publication
n/a
Dual Activation Of Bile Acid Receptors Fxr And Tgr5 Plays A Protective Role In Non-alcoholic Fatty Liver Disease And Atherosclerosis
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Jadhav K; Xu Y; Zhang Y Q
Faseb Journal
2016
2016-04
Journal Article or Conference Abstract Publication
n/a
Endothelial NOS activity and myocardial oxygen metabolism define the salvageable ischemic time window for ischemic postconditioning
cardioprotection; mice; inhibition; Physiology; Cardiovascular System & Cardiology; activation; dysfunction; reperfusion injury; tissue oxygenation; consumption; blood flow; electron paramagnetic resonance; infarct size; ischemia and reperfusion; mitochondrial enzyme activity; mitochondrial permeability transition; rabbit hearts; regional
Cai M, Li Y, Xu Y, Swartz HM, Chen C, Chen Y, He G. Endothelial NOS activity and myocardial oxygen metabolism define the salvageable ischemic time window for ischemic postconditioning. Am J Physiol Heart Circ Physiol 300: H1069-H1077, 2011. First published January 7, 2011; doi: 10.1152/ajpheart.00694.2010.-Ischemic postconditioning (IPOC) could be ineffective or even detrimental if the index ischemic duration is either too short or too long. The present study is to demonstrate that oxygen supply and metabolism defines a salvageable ischemic time window of IPOC in mice. C57BL/6 mice underwent coronary artery occlusion followed by reperfusion (I/R), with or without IPOC by three cycles of 10 s/10 s R/I. In vivo myocardial tissue oxygenation was monitored with electron paramagnetic resonance oximetry. Regional blood flow (RBF) was measured with a laser Doppler monitor. At the end of 60 min reperfusion, tissue from the risk area was collected, and mitochondrial enzyme activities were assayed. Tissue oximetry demonstrated that I/R induced a reperfusion hyperoxygenation state in the 30- and 45-min but not 15- and 60-min ischemia groups. IPOC attenuated the hyperoxygenation with 45 but not 30 min ischemia. RBF, eNOS phosphorylation, and mitochondrial enzyme activities were suppressed after I/R with different ischemic time, and IPOC afforded protection with 30 and 45 but not 60 min ischemia. Infarct size measurement indicated that IPOC reduced infarction with 30 and 45 min but not 60 min ischemia. Clearly, IPOC protected mouse heart with a defined ischemic time window between 30 and 45 min. This salvageable time window was accompanied by the improvement of RBF due to increased phosphorylated eNOS and the preservation of mitochondrial oxygen consumption due to conserved mitochondrial enzyme activities. Interestingly, this salvageable ischemic time window was mirrored by tissue hyperoxygenation status in the postischemic heart.
Cai M; Li Y J; Xu Y; Swartz H M; Chen C L; Chen Y R; He G L
American Journal of Physiology-Heart and Circulatory Physiology
2011
2011-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1152/ajpheart.00694.2010" target="_blank" rel="noreferrer noopener">10.1152/ajpheart.00694.2010</a>
Carboxylesterase 1 Protects Against Liver Injury and Is Regulated by Hepatocyte Nuclear Factor 4 alpha
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Xu J S; Xu Y; Zhang Y Q
Faseb Journal
2016
2016-04
Journal Article
n/a
Synthesis and Anticancer Mechanism Investigation of Dual Hsp27 and Tubulin Inhibitors
breast-cancer; c-dependent activation; cancer cells; chaperone activity; cytochrome-c; heat-shock proteins; in-vitro; nimesulide analog jcc76; pancreatic-cancer; Pharmacology & Pharmacy; self-association
Heat shock protein 27 (Hsp27) is a chaperone protein, and its expression is increased in response to various stress stimuli including anticancer chemotherapy, which allows the cells to survive and causes drug resistance. We previously identified lead compounds that bound to Hsp27 and tubulin via proteomic approaches. Systematic ligand based optimization in the current study significantly increased the cell growth inhibition and apoptosis inducing activities of the compounds. Compared to the lead compounds, one of the new derivatives exhibited much better potency to inhibit tubulin polymerization but a decreased activity to inhibit Hsp27 chaperone function, suggesting that the structural modification dissected the dual targeting effects of the compound. The most potent compounds 20 and 22 exhibited strong cell proliferation inhibitory activities at subnanomolar concentration against 60 human cancer cell lines conducted by Developmental Therapeutic Program at the National Cancer Institute and represented promising candidates for anticancer drug development.
Zhong B; Chennamaneni S; Lama R; Yi X; Geldenhuys W J; Pink J J; Dowlati A; Xu Y; Zhou A M; Su B
Journal of Medicinal Chemistry
2013
2013-07
Journal Article
<a href="http://doi.org/10.1021/jm4004736" target="_blank" rel="noreferrer noopener">10.1021/jm4004736</a>
Identification of a Class of Novel Tubulin Inhibitors
agents; analog jcc76; biological evaluation; breast-cancer cells; halichondrin-b; heat-shock proteins; hsp27 phosphorylation; in-vivo; nimesulide; nonsteroidal antiinflammatory drugs; Pharmacology & Pharmacy; tumor-cells
We previously developed a series of anticancer agents based on cyclooxygenase-2 (COX-2) inhibitor nimesulide as a lead compound. However, the molecular targets of these agents still remain unclear. In this study, we synthesized a biotinylated probe based on a representative molecule of the compound library and performed protein pull-down assays to purify the anticancer targets of the compound. Via proteomic approaches, the major proteins bound to the probe were identified to be tubulin and heat shock protein 27 (Hsp27), and the compound inhibited tubulin polymerization by binding at the colchicine domain. However, the tubulin inhibitory effect of the compound activated the Hsp27 phosphorylation and possibly overrode the direct Hsp27 inhibitory effects, which made it difficult to solely validate the Hsp27 target. Taken together, the compound was a dual ligand of tubulin and Hsp27, inhibited tubulin polymerization, and had the potential to be a class of new chemotherapeutic agents.
Yi X; Zhong B; Smith K M; Geldenhuys W J; Feng Y; Pink J J; Dowlati A; Xu Y; Zhou A M; Su B
Journal of Medicinal Chemistry
2012
2012-04
Journal Article
<a href="http://doi.org/10.1021/jm300100d" target="_blank" rel="noreferrer noopener">10.1021/jm300100d</a>
Hepatic Carboxylesterase 1 is Essential for Both Normal and Farnesoid X Receptor-Controlled Lipid Homeostasis
Biochemistry & Molecular Biology; Cell Biology; Life Sciences & Biomedicine - Other; Topics
Xu J S; Li Y Y; Xu Y
Faseb Journal
2015
2015-04
Journal Article
<a href="http://doi.org/10.1002/hep.26714" target="_blank" rel="noreferrer noopener">10.1002/hep.26714</a>