A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism

• Published in: Nature communications 2015-06, Vol.6 (1), p.7466-7466, Article 7466
• Main Authors: Xu, Yang, Zalzala, Munaf, Xu, Jiesi, Li, Yuanyuan, Yin, Liya, Zhang, Yanqiao
• Format: Article
• Language: English
• Subjects: 13; 14/63; 38/109; 38/15; 38/39; 38/44; 38/61; 38/70; 38/89; 42; 631/337/384/331; 631/443/319; 631/80/86; 64; 64/110; 64/60; 692/699/1503/1607/2750; 82; 82/29; Animals; Apolipoproteins E - genetics; Atherosclerosis - genetics; Atherosclerosis - metabolism; Diabetes Mellitus, Experimental - genetics; Diabetes Mellitus, Experimental - metabolism; Hep G2 Cells; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Humanities and Social Sciences; Humans; Lipid Metabolism - genetics; Lipoproteins - metabolism; Liver - metabolism; Mice, Knockout; MicroRNAs - genetics; MicroRNAs - metabolism; Middle Aged; multidisciplinary; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Receptors, LDL - genetics; Science; Science (multidisciplinary); Stress, Physiological - genetics; Triglycerides - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms8466

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 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. The nuclear hormone receptor HNF4α is important for liver function. Here, Xu et al. show that miR-34a regulates expression of HNF4α and is increased under conditions of metabolic stress, suggesting miR-34a promotes the development of non-alcoholic fatty liver disease.