Low-density Lipoprotein Receptor Deficiency Increases Susceptibility to Diet-induced Non-alcoholic Fatty Liver Disease in Mice

Non-alcoholic steatohepatitis (NASH) is a progressive liver disease characterized by hepatic inflammation, fibrosis and, potentially, cirrhosis. Lipid dysregulation plays a significant role in the exacerbation of liver fibrosis. This study investigated the impact of a fructose, palmitate, cholesterol, and trans-fat (FPC) diet on hepatic fibrosis in Ldlrknockout (Ldlr KO) mice, a model with impaired cholesterol metabolism and elevated oxidized low-density lipoprotein. Ldlr KO mice on the FPC diet exhibited significantly slower increases in body weight and elevated serum ALT levels as compared to wild-type (WT) mice. Along with decreased high density lipoprotein cholesterol (HDL) levels, Ldlr KO mice also showed elevated serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and triglyceride (TG) levels, reflecting impaired cholesterol metabolism. Histopathological analysis revealed pronounced hepatocyte swelling, lipid accumulation, and more extensive fibrosis in Ldlr KO mice. TGF-β signaling pathway was notably activated in FPC-fed Ldlr KO mice, with increased levels of Smad2/3 and Smad4 proteins. Furthermore, α-SMA expression was elevated, reflecting active hepatic stellate cell activation and collagen deposition. As evidenced by elevated serum TC, LDL, and TG levels, the FPC diet significantly amplifies hepatic fibrosis in Ldlr KO mice by promoting lipid metabolism imbalance. Along with increased inflammatory responses and activation of the TGF-β signaling pathway, this lipid overload leads to enhanced collagen deposition and fibrosis. These findings highlight the critical role of cholesterol dysregulation and lipid imbalance in the progression of liver fibrosis, reinforcing the utility of Ldlr KO mice as a model for investigating NASH pathogenesis and developing potential therapeutic interventions.