Low-density lipoprotein receptor–related protein-1 dysfunction synergizes with dietary cholesterol to accelerate steatohepatitis progression

Reduced low-density lipoprotein receptor–related protein-1 (LRP1) expression in the liver is associated with poor prognosis of liver cirrhosis and hepatocellular carcinoma. Previous studies have shown that hepatic LRP1 deficiency exacerbates palmitate-induced steatosis and toxicity in vitro and also promotes high-fat diet–induced hepatic insulin resistance and hepatic steatosis in vivo. The current study examined the impact of liver-specific LRP1 deficiency on disease progression to steatohepatitis. hLrp1/ mice with normal LRP1 expression and hLrp1/ mice with hepatocyte-specific LRP1 inactivation were fed a high-fat, high-cholesterol (HFHC) diet for 16 weeks. Plasma lipid levels and body weights were similar between both groups. However, the hLrp1/ mice displayed significant increases in liver steatosis, inflammation, and fibrosis compared with the hLrp1/ mice. Hepatocyte cell size, liver weight, and cell death, as measured by serum alanine aminotransferase levels, were also significantly increased in hLrp1/ mice. The accelerated liver pathology observed in HFHC-fed hLrp1/ mice was associated with reduced expression of cholesterol excretion and bile acid synthesis genes, leading to elevated immune cell infiltration and inflammation. Additional in vitro studies revealed that cholesterol loading induced significantly higher expression of genes responsible for hepatic stellate cell activation and fibrosis in hLrp1/ hepatocytes than in hLrp1/ hepatocytes. These results indicate that hepatic LRP1 deficiency accelerates liver disease progression by increasing hepatocyte death, thereby causing inflammation and increasing sensitivity to cholesterol-induced pro-fibrotic gene expression to promote steatohepatitis. Thus, LRP1 may be a genetic variable that dictates individual susceptibility to the effects of dietary cholesterol on liver diseases.