Role of endotrophin in chronic liver disease

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including nonalcoholic steatohepatitis (NASH), cirrhosis, liver cancer, hypertension, and atherosclerosis. Fibrotic liver is characterized by pathological accumulation of Extracullar matrix (ECM) proteins. Type VI collagen alpha3 chain (Col6a3) is one of biomarker for hepatic fibrosis and its cleaved form, endotropohin (ETP), plays critical roles in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of Col6a3-derived peptides ETP, on chronic liver disease progression such as NASH and liver cancer. By utilizing a doxycycline (Dox)-inducible liver-specific ETP overexpressing mouse model under the NAFLD model (SREBP1a transgenic) background, we investigated the role of ETP on hepatic inflammation, fibrosis and insulin resistance. The accumulation of ETP induces hepatic inflammation, and fibrosis development with insulin resistance. Surprisingly, ETP overexpression can induce liver cancer after treatment of Dox for 10 months. Our data reveal that ETP can act as a “second hit” on NAFLD condition and induce progression of NASH. We provide new evidences for understanding the relationship between ETP and chronic liver disease.