title: Hepatocyte-specific Ptpn6 deletion promotes hepatic lipid accretion, but reduces NAFLD in diet-induced obesity: potential role of PPARγ.
abstract: Hepatocyte-specific Shp1 knockout mice (Ptpn6(H-KO)) are protected from hepatic insulin resistance evoked by high-fat diet (HFD) feeding for 8 weeks. Unexpectedly, we report herein that Ptpn6(H-KO) mice fed an HFD for up to 16 weeks are still protected from insulin resistance, but are more prone to hepatic steatosis, as compared with their HFD-fed Ptpn6(f/f) counterparts. The livers from HFD-fed Ptpn6(H-KO) mice displayed 1) augmented lipogenesis, marked by increased expression of several hepatic genes involved in fatty acid biosynthesis, 2) elevated postprandial fatty acid uptake, and 3) significantly reduced lipid export with enhanced degradation of apolipoprotein B (ApoB). Despite more extensive hepatic steatosis, the inflammatory profile of the HFD-fed Ptpn6(H-KO) liver was similar (8 weeks) or even improved (16 weeks) as compared to their HFD-fed Ptpn6(f/f) littermates, along with reduced hepatocellular damage as revealed by serum levels of hepatic enzymes. Interestingly, comparative microarray analysis revealed a significant up-regulation of peroxisome proliferator-activated receptor gamma (PPARγ) gene expression, confirmed by quantitative polymerase chain reaction. Elevated PPARγ nuclear activity also was observed and found to be directly regulated by Shp1 in a cell-autonomous manner.
  
  
  CONCLUSIONS
  These findings highlight a novel role for hepatocyte Shp1 in the regulation of PPARγ and hepatic lipid metabolism. Shp1 deficiency prevents the development of severe hepatic inflammation and hepatocellular damage in steatotic livers, presenting hepatocyte Shp1 as a potential novel mediator of nonalcoholic fatty liver diseases in obesity.
authors: Department of Medicine, Cardiology Axis of the Institut Universitaire de Cardiologie et de Pneumologie de Québec (Hôpital Laval), Ste-Foy, Québec, Canada.
authors: Elaine
authors: E
authors: Xu
authors: Marie-Pier
authors: MP
authors: Forest
authors: Michael
authors: M
authors: Schwab
authors: Rita Kohen
authors: RK
authors: Avramoglu
authors: Emmanuelle
authors: E
authors: St-Amand
authors: Annabelle Z
authors: AZ
authors: Caron
authors: Kerstin
authors: K
authors: Bellmann
authors: Michaël
authors: M
authors: Shum
authors: Gregory
authors: G
authors: Voisin
authors: Marilene
authors: M
authors: Paquet
authors: Alain
authors: A
authors: Montoudis
authors: Emile
authors: E
authors: Lévy
authors: Katherine A
authors: KA
authors: Siminovitch
authors: Benjamin G
authors: BG
authors: Neel
authors: Nicole
authors: N
authors: Beauchemin
authors: André
authors: A
authors: Marette
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology*; D007333:Insulin Resistance; D050155:Lipogenesis; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease; D009765:Obesity / Q000150:complications*; D047495:PPAR gamma / Q000502:physiology*; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology*
chemical_list: D005227:Fatty Acids; D047495:PPAR gamma; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse