Hepatic lipotoxicity and Fibrogenesis are attenuated by the hepatotrophic factor ALR

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and its spectrum ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH has been thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis. Hepatic stellate cells, which are activated under conditions of liver injury, are mainly responsible for fibrogenesis. The protein ALR (augmenter of liver regeneration) was previously shown to have hepatoprotective properties against liver toxins. The aim of our study was to investigate the potential protective role of ALR under conditions of NASH. Primary human hepatocytes and hepatoma cells (HepG2, Huh-7) were treated with free fatty acids and showed dose and time depended accumulation of fat vacuoles and triglyceride levels. To elucidate the role of ALR under conditions leading to NASH we generated stable-transfected HepG2 cells expressing human ALR protein. We cultured wt-HepG2 and HepG2-ALR cells with FFAs and after 24h we observed a significant lower lipid-induced cell toxicity and caspase activity in HepG2-ALR cells compared to wildtype. Further, lipotoxicity of wt-HepG2 could be reduced to levels of HepG2-ALR after treatment with recombinant human ALR. In addition, intracellular triglyceride content was significantly decreased in HepG2-ALR cells compared to wt-HepG2 cells. Additional, we analyzed the effect of ALR on the expression of profibrogenic genes in hepatic stellate cells. Treatment of these cells with ALR revealed a significantly reduced expression of col-I and sma-α. This data indicates that ALR reduces hepatic steatosis, diminish cellular lipid accumulation and decreases the expression of fibrogenic factors. In conclusion, we demonstrate that hepatotrophic factor ALR, besides its beneficial effect in liver regeneration, exhibit anti-fibrogenic properties in fibrosis related liver diseases.