Deletion of steroid receptor coactivator-3 gene ameliorates hepatic steatosis

J Hepatol. 2011 Aug;55(2):445-52. doi: 10.1016/j.jhep.2010.11.022. Epub 2010 Dec 22.


Background & aims: Excess dietary fat can cause hepatic steatosis, which can progress into severe liver disorders including steatohepatitis and cirrhosis. Steroid receptor coactivator-3 (SRC-3), a member of the p160 coactivator family, is reported as a key regulator of adipogenesis and energy homeostasis. We sought to determine the influence of SRC-3 on hepatic steatosis and the mechanism beneath.

Methods: The influence of siRNA-mediated SRC-3 silencing on hepatic lipid accumulation was assessed in HepG2 cells. The molecular mechanism of SRC-3 regulation of hepatic lipid metabolism was also studied. Moreover, the effect of SRC-3 ablation on hepatic steatosis was examined in SRC-3 deficient mice.

Results: In this study, we report that SRC-3 ablation reduces palmitic acid-induced lipid accumulation in HepG2 cells. Moreover, deletion of SRC-3 ameliorates hepatic steatosis and inflammation response in mice fed a high fat diet (HFD). These metabolic improvements can presumably be explained by the reduction in chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) expression and the subsequent elevation in peroxisome proliferator-activated receptor α (PPARα) level. At the molecular level, SRC-3 interacts with retinoic receptor α (RARα) to activate COUP-TFII expression under all-trans retinoic acid (ARTA) treatment.

Conclusions: These findings indicate a crucial role for SRC-3 in regulating hepatic lipid metabolism and provide the possible novel inner mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COUP Transcription Factor II / genetics
  • COUP Transcription Factor II / metabolism
  • Dietary Fats / administration & dosage
  • Disease Models, Animal
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fatty Liver / prevention & control
  • Gene Knockdown Techniques
  • Hep G2 Cells
  • Humans
  • Immunohistochemistry
  • Lipid Metabolism
  • Liver Cirrhosis, Experimental / genetics
  • Liver Cirrhosis, Experimental / metabolism
  • Liver Cirrhosis, Experimental / pathology
  • Liver Cirrhosis, Experimental / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease
  • Nuclear Receptor Coactivator 3 / antagonists & inhibitors*
  • Nuclear Receptor Coactivator 3 / deficiency
  • Nuclear Receptor Coactivator 3 / genetics*
  • Nuclear Receptor Coactivator 3 / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • Promoter Regions, Genetic
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Retinoic Acid / genetics
  • Receptors, Retinoic Acid / metabolism
  • Retinoic Acid Receptor alpha
  • Tretinoin / pharmacology


  • COUP Transcription Factor II
  • Dietary Fats
  • PPAR alpha
  • RARA protein, human
  • RNA, Small Interfering
  • Rara protein, mouse
  • Receptors, Retinoic Acid
  • Retinoic Acid Receptor alpha
  • Tretinoin
  • NCOA3 protein, human
  • Ncoa3 protein, mouse
  • Nuclear Receptor Coactivator 3