[HTML][HTML] Prohibitin-induced, obesity-associated insulin resistance and accompanying low-grade inflammation causes NASH and HCC

SR Ande, KH Nguyen, BL Grégoire Nyomba… - Scientific reports, 2016 - nature.com
SR Ande, KH Nguyen, BL Grégoire Nyomba, S Mishra
Scientific reports, 2016nature.com
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 …
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.
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