Abstract
Liver fibrosis is a critical complication of obesity-induced fatty liver disease. Wnt1 inducible signaling pathway protein 1 (WISP1/CCN4), a novel adipokine associated with visceral obesity and insulin resistance, also contributes to lung and kidney fibrosis. The aim of the present study was to investigate the role of CCN4 in liver fibrosis in severe obesity. For this, human liver biopsies were collected from 35 severely obese humans (BMI 42.5 ± 0.7 kg/m2, age 46.7 ± 1.8 y, 25.7% males) during bariatric surgery and examined for the expression of CCN4, fibrosis, and inflammation markers. Hepatic stellate LX-2 cells were treated with human recombinant CCN4 alone or in combination with LPS or transforming growth factor beta (TGF-β) and examined for fibrosis and inflammation markers. CCN4 mRNA expression in the liver positively correlated with BMI and expression of fibrosis markers COL1A1, COL3A1, COL6A1, αSMA, TGFB1, extracellular matrix turnover enzymes TIMP1 and MMP9, and the inflammatory marker ITGAX/CD11c. In LX-2 cells, the exposure to recombinant CCN4 caused dose-dependent induction of MMP9 and MCP1. CCN4 potentiated the TGF-β-mediated induction of COL3A1, TIMP1, and MCP1 but showed no interaction with LPS treatment. Our results suggest a potential contribution of CCN4 to the early pathogenesis of obesity-associated liver fibrosis.
Highlights
Liver fibrosis is a critical complication of non-alcoholic fatty liver disease (NAFLD), which is associated with obesity, metabolic syndrome, and type 2 diabetes
CCN4 can be secreted in the circulation and was recently described to play a role in the pathogenesis of obesity [15], we further investigated the association of its circulating levels with anthropometric and biochemical parameters as well as markers of hepatic function
Our study provided the first piece of evidence that the novel adipokine WISP1/CCN4, Our study provided the first piece of evidence that the novel adipokine which is increased in visceral obesity, might contribute to the early development of obesityWISP1/CCN4, which is increased in visceral obesity, might contribute to the early develassociated fibrosis even before marked cirrhotic changes occur
Summary
Liver fibrosis is a critical complication of non-alcoholic fatty liver disease (NAFLD), which is associated with obesity, metabolic syndrome, and type 2 diabetes. NAFLD is defined by excessive triglyceride accumulation in hepatocytes and represents an increasingly prevalent and common liver disease affecting 20–30% of Western countries [1]. In about 25% of subjects with NAFLD, the disease can progress to non-alcoholic steatohepatitis (NASH) that is histologically characterized by hepatocyte ballooning, apoptosis, and chronic inflammation. Hepatic fibrosis is an important component of the progression of NAFLD and NASH to cirrhosis and strongly contributes to the disturbance of liver functions. Besides metabolically-induced fibrosis, other chronic liver diseases caused by viral, inflammatory, or toxic liver injury are accompanied by liver fibrosis [3]
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