GPAT1 Deficiency in Mice Modulates NASH Progression in a Model-Dependent Manner

Cell Mol Gastroenterol Hepatol. 2024;17(2):279-291. doi: 10.1016/j.jcmgh.2023.10.002. Epub 2023 Oct 14.

Abstract

Background & aims: Nonalcoholic fatty liver disease (NAFLD), and its more severe form, nonalcoholic steatohepatitis (NASH), is the leading cause for liver failure and liver cancer. Although the etiology is likely multifactorial, genes involved in regulating lipid metabolism are enriched in human NAFLD genome-wide association studies (GWAS), pointing to dysregulated lipid metabolism as a major pathogenic factor. Glycerol-3-phosphate acyltransferase 1 (GPAT1), encoded by GPAM, converts acyl-CoAs and glycerol-3-phosphate into lysophosphatidic acid and has been shown to regulate lipid accumulation in the liver. However, its role in mediating the progression from NAFLD to NASH has not been explored.

Methods: GPAT1-deficient mice were generated and challenged with diets inducing hepatic steatosis and NASH. Effects of GPAT1 deficiency on lipid and systemic metabolic end points were evaluated.

Results: Ablating GPAT1 globally or specifically in mouse hepatocytes reduced hepatic steatosis in the context of diet-induced or genetic obesity. Interestingly, blunting of progression from NAFLD to NASH in global GPAT1 knockout (KO) mice was model dependent. GPAT1 KO mice were protected from choline deficient, amino acid defined high-fat diet-induced NASH development, but not from the high fat, high carbohydrate, and high cholesterol diet-induced NASH.

Conclusions: Our preclinical data support the notion that lipid metabolism pathways regulated by GPAT1 in hepatocytes play an essential role in NASH progression, albeit in a model-dependent manner.

Keywords: GPAT1; Hepatic Steatosis; Liver Inflammation and Fibrosis; NASH; NASH Mouse Models.

MeSH terms

  • Animals
  • Diet, High-Fat / adverse effects
  • Genome-Wide Association Study
  • Glycerol
  • Humans
  • Lipids
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Phosphates

Substances

  • Glycerol
  • Phosphates
  • Lipids