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>
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>
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>
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>
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>
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>