Ande Sudharsana R, Nguyen K Hoa, Grégoire Nyomba B L, Mishra Suresh
Department of Internal Medicine, University of Manitoba, Winnipeg, Canada.
Department of Physiology &Pathophysiology, University of Manitoba, Winnipeg, Canada.
Sci Rep. 2016 Mar 23;6:23608. doi: 10.1038/srep23608.
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.
肥胖会增加非酒精性脂肪性肝炎（NASH）和肝癌发生的风险。然而，疾病过程中涉及的潜在机制仍不清楚。最近，我们通过在脂肪细胞中由抑制素介导的线粒体重塑，开发了一种转基因肥胖小鼠模型（Mito-Ob）。Mito-Ob小鼠以性别中性的方式发生肥胖，但以雄性特异性的方式出现与肥胖相关的脂肪炎症和代谢失调。在此我们报告，随着年龄增长，雄性Mito-Ob小鼠会自发发生与肥胖相关的NASH和肝细胞癌（HCC）。相比之下，雌性Mito-Ob小鼠维持正常的血糖和胰岛素水平，未发生NASH和HCC。与各自的对照小鼠相比，抗炎肽胃饥饿素在雌性小鼠中显著上调，在雄性小鼠中下调。此外，在发生NASH/HCC的雄性Mito-Ob小鼠肝脏中，发现线粒体含量和功能的标志物减少。我们发现，在Mito-Ob小鼠的肿瘤中，ERK1/2信号显著上调，而STAT3信号显著下调。这些数据提供了一个概念验证，即脂肪组织的代谢和炎症状态及其在全身和肝脏水平的相互作用在肥胖相关的NASH和HCC发病机制中起核心作用。
