title: Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC.
abstract: Obesity increases the risk for nonalcoholic steatohepatitis (NASH) and hepatocarcinogenesis. However, the underlying mechanisms involved in the disease process remain unclear. Recently, we have developed a transgenic obese mouse model (Mito-Ob) by prohibitin mediated mitochondrial remodeling in adipocytes. The Mito-Ob mice develop obesity in a sex-neutral manner, but obesity-associated adipose inflammation and metabolic dysregulation in a male sex-specific manner. Here we report that with aging, the male Mito-Ob mice spontaneously develop obesity-linked NASH and hepatocellular carcinoma (HCC). In contrast, the female Mito-Ob mice maintained normal glucose and insulin levels and did not develop NASH and HCC. The anti-inflammatory peptide ghrelin was significantly upregulated in the female mice and down regulated in the male mice compared with respective control mice. In addition, a reduction in the markers of mitochondrial content and function was found in the liver of male Mito-Ob mice with NASH/HCC development. We found that ERK1/2 signaling was significantly upregulated whereas STAT3 signaling was significantly down regulated in the tumors from Mito-Ob mice. These data provide a proof-of-concept that the metabolic and inflammatory status of the adipose tissue and their interplay at the systemic and hepatic level play a central role in the pathogenesis of obesity-linked NASH and HCC.
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: Sudharsana R
authors.initials: SR
authors.lastname: Ande
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: K Hoa
authors.initials: KH
authors.lastname: Nguyen
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
authors.forename: B L
authors.initials: BL
authors.lastname: Grégoire Nyomba
authors.affiliation: Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.|Department of Physiology &Pathophysiology, University of Manitoba, Winnipeg, Canada.
authors.forename: Suresh
authors.initials: S
authors.lastname: Mishra
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000209:etiology*; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D007333:Insulin Resistance; D008113:Liver Neoplasms / Q000209:etiology*; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008820:Mice, Obese; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology*; D009765:Obesity / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D000091402:Prohibitins; D012097:Repressor Proteins / Q000172:deficiency*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D012727:Sex Characteristics
chemical_list: D000091402:Prohibitins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse