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

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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)

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.

Suggested Citation

  • Yang Xu & Munaf Zalzala & Jiesi Xu & Yuanyuan Li & Liya Yin & Yanqiao Zhang, 2015. "A metabolic stress-inducible miR-34a-HNF4α pathway regulates lipid and lipoprotein metabolism," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8466
    DOI: 10.1038/ncomms8466
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