Collagen VI-Derived Endotrophin Promotes Hepatic Apoptosis, Inflammation, and Fibrosis in Chronic Liver Disease

Type VI collagen alpha3 chain (Col6a3) is a biomarker for hepatic fibrosis and poor prognosis of hepatocellular carcinoma (HCC), but its function in liver pathology remains unknown. Analysis of human HCC patients revealed that elevated mRNA levels of COL6A3 in tumor-proximal liver regions were associated with poor prognosis in HCC patients. Here, we show that endotrophin (ETP), a cleaved Col6a3 fragment, significantly augmented hepatocyte apoptosis, inflammation, and fibrosis in chemically induced chronic liver disease models by utilizing either CCl4 or DEN in the background of hepatocyte-specific ETP transgenic mice, nevertheless ETP per se showed a limited phenotypic changes in liver tissues. Notably, both hepatocytes and non-parenchymal cells in liver tissues were responsible for an increase of ETP levels in chronic liver injuries, and inhibition of ETP with neutralizing antibodies (10B6) ameliorated hepatic apoptosis, inflammation, and fibrosis in these cells. Our results mechanistically implicate ETP as a necessary component for sustained JNK activation in early stage of chronic liver diseases; thus, ETP-JNK axis could be a promising therapeutic target, particularly in individuals with high local levels of COL6A3 in chronic liver disease. Disclosure M. Kim: None. J. Park: None.