All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade

Hepatology. 2014 May;59(5):1750-60. doi: 10.1002/hep.26699. Epub 2014 Mar 26.


Mice deficient in small heterodimer partner (SHP) are protected from diet-induced hepatic steatosis resulting from increased fatty acid oxidation and decreased lipogenesis. The decreased lipogenesis appears to be a direct consequence of very low expression of peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2), a potent lipogenic transcription factor, in the SHP(-/-) liver. The current study focused on the identification of a SHP-dependent regulatory cascade that controls PPAR-γ2 gene expression, thereby regulating hepatic fat accumulation. Illumina BeadChip array (Illumina, Inc., San Diego, CA) and real-time polymerase chain reaction were used to identify genes responsible for the linkage between SHP and PPAR-γ2 using hepatic RNAs isolated from SHP(-/-) and SHP-overexpressing mice. The initial efforts identify that hairy and enhancer of split 6 (Hes6), a novel transcriptional repressor, is an important mediator of the regulation of PPAR-γ2 transcription by SHP. The Hes6 promoter is specifically activated by the retinoic acid receptor (RAR) in response to its natural agonist ligand, all-trans retinoic acid (atRA), and is repressed by SHP. Hes6 subsequently represses hepatocyte nuclear factor 4 alpha (HNF-4α)-activated PPAR-γ2 gene expression by direct inhibition of HNF-4α transcriptional activity. Furthermore, we provide evidences that atRA treatment or adenovirus-mediated RAR-α overexpression significantly reduced hepatic fat accumulation in obese mouse models, as observed in earlier studies, and the beneficial effect is achieved by the proposed transcriptional cascade.

Conclusions: Our study describes a novel transcriptional regulatory cascade controlling hepatic lipid metabolism that identifies retinoic acid signaling as a new therapeutic approach to nonalcoholic fatty liver diseases.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Blood Glucose / analysis
  • Fatty Liver / drug therapy*
  • Fatty Liver / metabolism
  • Gene Expression Regulation
  • Lipid Metabolism
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Non-alcoholic Fatty Liver Disease
  • PPAR gamma / genetics*
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Retinoic Acid / physiology
  • Repressor Proteins / genetics
  • Retinoic Acid Receptor alpha
  • Transcription, Genetic
  • Tretinoin / pharmacology
  • Tretinoin / therapeutic use*


  • Basic Helix-Loop-Helix Transcription Factors
  • Blood Glucose
  • HES6 protein, human
  • PPAR gamma
  • RARA protein, human
  • Rara protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Retinoic Acid Receptor alpha
  • nuclear receptor subfamily 0, group B, member 2
  • Tretinoin