Abstract
SummaryNon-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 4α (HNF4α), 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 HNF4α 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 HNF4α-dependent manner. As a result, increased miR-34a or reduced HNF4α expression in the liver attenuates the development of atherosclerosis in Apoe−/− or Ldlr−/− mice. These data indicate that the miR-34a-HNF4α 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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, but its underlying mechanism is poorly understood
As hepatocyte nuclear factor 4a (HNF4a) is highly conserved between humans and rodents, we explored the role of HNF4a in the development of human NAFLD
We report that a novel miR-34a-HNF4a pathway regulates both hepatic TG levels and plasma lipid and lipoprotein metabolism
Summary
Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, but its underlying mechanism is poorly understood. We show that hepatocyte nuclear factor 4a (HNF4a), 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. As a result, increased miR-34a or reduced HNF4a expression in the liver attenuates the development of atherosclerosis in Apoe À / À or Ldlr À/ À mice These data indicate that the miR-34a-HNF4a 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. Hepatocyte nuclear factor 4a (HNF4a) is a nuclear hormone receptor that plays an important role in both development and adult physiology It is highly expressed in the liver, with lower levels in the kidney, intestine and pancreatic b cells[10,11]. Recent studies have shown that hepatic miRNAs may have an important impact on lipid and lipoprotein metabolism[21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
