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>
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 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 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 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 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>