A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism.

A metabolic stress-inducible miR-34a-HNF4alpha pathway regulates lipid and lipoprotein metabolism.

Xu Yang; Zalzala Munaf; Xu Jiesi; Li Yuanyuan; Yin Liya; Zhang Yanqiao

Nature communications

2015

2015-06

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 4alpha (HNF4alpha), 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 HNF4alpha 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 HNF4alpha-dependent manner. As a result, increased miR-34a or reduced HNF4alpha expression in the liver attenuates the development of atherosclerosis in Apoe(-/-) or Ldlr(-/-) mice. These data indicate that the miR-34a-HNF4alpha 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.

Animals; Apolipoproteins E/genetics; Atherosclerosis/genetics/metabolism; Diabetes Mellitus; Experimental/genetics/metabolism; Hep G2 Cells; Hepatocyte Nuclear Factor 4/*genetics/metabolism; Humans; Knockout; LDL/genetics; Lipid Metabolism/*genetics; Lipoproteins/metabolism; Liver/metabolism; Mice; MicroRNAs/*genetics/metabolism; Middle Aged; Non-alcoholic Fatty Liver Disease/*genetics/metabolism; Physiological/*genetics; Receptors; Stress; Triglycerides/*metabolism

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7466–7466

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