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.
Highlights
Enhancing mitochondrial function has been reported to reduce hepatic steatosis caused by diet-induced obesity (DIO)[17]
This study reports a role of obesity related hyperinsulinemia and chronic low-grade inflammation in the development of non-alcoholic steatohepatitis (NASH) and Hepatocellular carcinoma (HCC), independent of diet and carcinogen respectively
This would suggest that obesity alone is not sufficient for the development of NASH and HCC but rather require additional effects of adipose inflammation, hyperinsulinemia and the degree of hepatic inflammation
Summary
Enhancing mitochondrial function has been reported to reduce hepatic steatosis caused by diet-induced obesity (DIO)[17]. A number of molecular mechanisms have been linked to obesity and its associated abnormalities that may facilitate the development of HCC, such as adipose tissue inflammation, hepatic lipotoxicity, and insulin resistance[24,25]. These and other pathological events in obesity have complex interactions while their relative contribution to the development of HCC in various stages of NAFLD progression remains to be determined. In considering the prevailing notion through which obesity may promote NASH and HCC development, we followed the consequence of NAFLD along with insulin resistance and chronic low-grade inflammation on hepatic phenotype in aging Mito-Ob mice. We report that the male Mito-Ob mice spontaneously develop obesity-linked NASH and HCC progressively, independent of diet
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