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

Yang Xu, Munaf Zalzala, Jiesi Xu, Yuanyuan Li, Liya Yin and Yanqiao Zhang ()
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Yang Xu: Northeast Ohio Medical University
Munaf Zalzala: Northeast Ohio Medical University
Jiesi Xu: Northeast Ohio Medical University
Yuanyuan Li: Northeast Ohio Medical University
Liya Yin: Northeast Ohio Medical University
Yanqiao Zhang: Northeast Ohio Medical University

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract 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.

Date: 2015
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DOI: 10.1038/ncomms8466

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