Hepatocyte miR-33a mediates mitochondrial dysfunction and hepatosteatosis by suppressing NDUFA5

J Cell Mol Med. 2018 Dec;22(12):6285-6293. doi: 10.1111/jcmm.13918. Epub 2018 Oct 16.


Emerging evidence suggests that microRNAs (miRNAs) are essential for metabolic haemostasis of liver tissues. Among them, miR-33a is supposed to modulate the cholesterol export and fatty acid oxidation, but whether miR-33a involves in the process of fatty liver disease is unclear. To disclose the hypothesis, we utilized miR-33a mimic and antisense to explore their effects in primary hepatocytes or high-fat diet (HFD)-fed mice. Treatment with palmitic acid (PA) or HFD significantly increased the expression of miR-33a in hepatocytes or liver tissues. In primary hepatocytes, miR-33a mimic decreased mitochondrial function, including reduction of ATP production and oxygen consumption, whereas miR-33a inhibition protected PA-induced mitochondrial dysfunction. Interestingly, miR-33a selectively suppressed mitochondrial complex I activity and protein expression, but not other complexes. Through bioinformatics prediction, we found miR-33a directly targeted on the 3'-UTR of NDUFA5. Dual-luciferase reporter analysis further confirmed the direct suppression of miR-33a on NDUFA5 expression. More importantly, administration of miR-33a antisense could effectively restore HFD-induced mitochondrial dysfunction through up-regulation of NDUFA5 levels. Mice treated with miR-33a antisense also exhibited improved liver function and structural disorders under obese status. Taken together, miR-33a was an important mediator of hepatocyte mitochondrial function, and the therapeutic benefits implied miR-33a antisense had the potential clinical application in combating the fatty liver disease.

Keywords: NDUFA5; hepatocyte; lipid; liver; microRNA-33a; mitochondria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / genetics
  • Animals
  • Diet, High-Fat
  • Disease Models, Animal
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Gene Expression Regulation / genetics
  • Hepatocytes / metabolism
  • Hepatocytes / pathology
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Mice
  • MicroRNAs / genetics*
  • Mitochondria, Liver / genetics*
  • Mitochondria, Liver / metabolism
  • Mitochondria, Liver / pathology
  • NADH Dehydrogenase / genetics*
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Oxygen Consumption / genetics
  • Palmitic Acid / metabolism
  • Primary Cell Culture


  • MIRN33a microRNA, human
  • MicroRNAs
  • NDUFA5 protein, human
  • Palmitic Acid
  • Adenosine Triphosphate
  • NADH Dehydrogenase