Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and can lead to multiple complications, including non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular carcinoma. The fibrotic liver is characterized by the pathological accumulation of extracellular matrix (ECM) proteins. Type VI collagen alpha3 (Col6a3) is a biomarker of hepatic fibrosis, and its cleaved form, endotrophin (ETP), plays a critical role in adipose tissue dysfunction, insulin resistance, and breast cancer development. Here, we studied the effects of the Col6a3-derived peptide ETP on the progression of chronic liver diseases, such as NASH and liver cancer. We used a doxycycline (Dox)-inducible liver-specific ETP-overexpressing mouse model on a NAFLD-prone (liver-specific SREBP1a transgenic) background. For this, we evaluated the consequences of local ETP expression in the liver and its effect on hepatic inflammation, fibrosis, and insulin resistance. Accumulation of ETP in the liver induced hepatic inflammation and the development of fibrosis with associated insulin resistance. Surprisingly, ETP overexpression also led to the emergence of liver cancer within 10 months in the SREBP1a transgenic background. Our data revealed that ETP can act as a “second hit” during the progression of NAFLD and can play an important role in the development of NASH and hepatocellular carcinoma (HCC). These observations firmly link elevated levels of ETP to chronic liver disease.
Highlights
On average, 25% of the population suffers from nonalcoholic fatty liver disease (NAFLD), which is one of the most common liver diseases and is associated with insulin resistance and metabolic syndrome[1]
COL6A3 expression in adipose tissue was associated with insulin resistance in humans[8], and human adipocyte-specific COL6A3 knockdown resulted in the development of a unique state of inflammatory resistance via the suppression of MCP1 induction[9]
To subsequently induce non-alcoholic steatohepatitis (NASH) in the presence of ETP, we used steatosis as the starting point for this set of experiments. This condition in the mouse is similar to the progression of human chronic liver disease and is based on our hypothesis that ETP contributes to the progression from simple steatosis to NASH
Summary
25% of the population suffers from nonalcoholic fatty liver disease (NAFLD), which is one of the most common liver diseases and is associated with insulin resistance and metabolic syndrome[1]. Early-stage NAFLD usually does not cause any symptoms, but sustained liver damage induced by NAFLD can lead to serious liver disease, including non-alcoholic steatohepatitis (NASH), cirrhosis, and HCC. NASH is characterized by inflammation, immune cell infiltration, and hepatocellular damage in the presence of NAFLD. This disease state is a known factor that can lead to hepatic fibrosis and liver cancer. Col[6] levels are positively associated with the degree of liver fibrosis in NASH6,7. Col6a3 is associated with metabolic disease and several cancers. COL6A3 has been proposed to be an important marker of colorectal cancer and to serve as a predictive marker of poor prognosis[10]
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