Extensive deregulation of hepatic cholesterol homeostasis in NAFLD leads to increased hepatic free cholesterol levels 8 these are implicated in hepatic lipotoxicity 9, thereby activating inflammatory recruitment to fatty livers to induce NASH. However, the detailed molecular mechanisms involved in disease progression to NASH remain unclear, in part because of the lack of appropriate animal models.ĭietary cholesterol contributes to the development of steatohepatitis in both animal models and humans, facilitating NASH development by deregulating inflammation and metabolism-associated gene expression 7.
Current evidence suggests that NAFLD exhibits multifactorial pathophysiology 6 with metabolic syndrome, genetic factors, oxidative stress, inflammatory cytokines, endotoxins, and insulin resistance contributing to disease development. NAFLD is frequently associated with obesity, diabetes, dyslipidemia, and hypertension and is considered as the liver manifestation of metabolic syndrome 5. The estimated worldwide prevalence of NAFLD is approximately 25% 3, with 10–30% of cases progressing into NASH 4.
NASH also increases the risk of developing cirrhosis or hepatocellular carcinoma 2. NAFLD progression into the inflammatory state, termed non-alcoholic steatohepatitis (NASH), leads to more serious presentation, including hepatic inflammation, hepatocyte damage, and fibrosis 1. Non-alcoholic fatty liver disease (NAFLD) is a pathological condition characterized by increased lipid accumulation in liver hepatocytes without concomitant alcohol abuse or other liver diseases. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. HCD-fed sB6 albino showed significantly higher mortality rate. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Tyrosinase point-mutated B6 (Cg)- Tyr c-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence.
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