Ablation of Hepatic Asah1 Gene Disrupts Hepatic Lipid Homeostasis and Promotes Fibrotic Nonalcoholic Steatohepatitis in Mice

Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of chronic liver conditions, ranging from simple steatosis to nonalcoholic steatohepatitis, which may progress to fibrosis/cirrhosis. Here, the GSE163211 data set was analyzed, and Asah1 (encoding acid ceramidase) was identified as a crucial lysosomal gene that positively correlated with NAFLD stages in obese patients. To evaluate the role of Asah1 in the progression of NAFLD, Asah1'/'/Albcre mice (hepatocyte-specific deletion of Asah1) and Asah1 'oxed (Asah1'/'/wild-type) mice were fed with either a normal diet or a high-fat, high- cholesterol paigen diet (PD) for 20 weeks. Hepatocyte-specific Asah1 ablation markedly aggravated PD- induced hepatic steatosis, hepatitis, and apoptosis, and resulted in marked fibrotic changes. In addition, Asah1 gene ablation exacerbated PD-induced portal venous hemodynamic abnormality. In cultured hepatocytes, Asah1 gene knockdown resulted in increased ceramide and cholesterol levels but did not affect triglyceride level. Knocking down Asah1 gene also exhibited broad impacts on lipid homeostasis pathways, including lipogenesis, fatty acid uptake, fatty acid oxidation, and lipid transport. Furthermore, Asah1 knockdown resulted in increased endoplasmic reticulum stress and lipid droplet biogenesis. Finally, Asah1 gene knockdown impaired chaperone-mediated autophagy. These results suggest that Asah1 functions as an important regulator of hepatic lipid homeostasis, and its deficiency exacerbates hepatocyte lipotoxicity and injury, and promotes the development of fibrotic nonalcoholic steatohepatitis.