Hepatocyte lipoapoptosis as a mechanism of chronic liver injury in obese mice model: a close link with fetuin-A

Abstract

Obesity is a major risk factor for type 2 diabetes, cardiovascular diseases, hypertension, dyslipidemia, non-alcoholic fatty liver disease and several cancers. Liver, a vital metabolic organ and a primary insulin target, is vulnerable to high dietary fat. In conditions of obesity, the hepatic secretory profile of hepatokines is altered. One of the major hepatokines, fetuin-A (FetA) is over-secreted in obesity-induced diabetes and promotes insulin resistance and inflammation. The present study was undertaken to examine hepatocyte lipoapoptosis in obesity and the potential involvement of fetuin-A in such lipotoxicity. We used obese diabetic mice models by feeding high fat diet for different durations, short-term D1 (4-week), moderate-term D2 (16-week) and prolonged-term D3 (32-week). For understanding FetA effect, in vivo and in vitro experiments were carried out. Blood parameters, whole-body glucose tolerance, hepatocyte lipid and ROS accumulation, TUNEL assay, and immunoblotting analyses were performed. ROS induced apoptosis progressively in lipid-laden hepatocytes of obese diabetic mice. In FetA-treated mice, hepatic oxidative stress and histopathological alterations were observed. Hepatocyte apoptotic markers were elevated by FetA in vivo and in vitro. Taken together, the data implied pivotal role of FetA in mediating hepatocyte lipoapoptosis and thereby, exacerbating liver damage associated with obesity and type 2 diabetes.