title: All-trans-retinoic acid ameliorates hepatic steatosis in mice by a novel transcriptional cascade.
abstract: 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.
authors.affiliation: Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH.
authors.forename: Seong Chul
authors.initials: SC
authors.lastname: Kim
authors.forename: Chun-Ki
authors.initials: CK
authors.lastname: Kim
authors.forename: David
authors.initials: D
authors.lastname: Axe
authors.forename: Aaron
authors.initials: A
authors.lastname: Cook
authors.forename: Mikang
authors.initials: M
authors.lastname: Lee
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
authors.forename: Nicole
authors.initials: N
authors.lastname: Smallwood
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
authors.forename: James P
authors.initials: JP
authors.lastname: Hardwick
authors.forename: David D
authors.initials: DD
authors.lastname: Moore
authors.forename: Yoon Kwang
authors.initials: YK
authors.lastname: Lee
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D005234:Fatty Liver / Q000188:drug therapy* / Q000378:metabolism; D005786:Gene Expression Regulation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D047495:PPAR gamma / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D014158:Transcription, Genetic; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D047495:PPAR gamma; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C411859:HES6 protein, human; C000607071:RARA protein, human; C000607072:Rara protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2
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