非酒精性脂肪性肝病 (NAFLD) 及其更严重的非酒精性脂肪性肝炎 (NASH) 是导致肝衰竭和肝癌的主要原因。尽管病因可能是多因素的，但人类 NAFLD 全基因组关联研究 (GWAS) 中富含参与调节脂质代谢的基因，表明脂质代谢失调是主要致病因素。 3-磷酸​​甘油酰基转移酶 1 (GPAT1) 由 GPAM 编码，可将酰基辅酶 A 和 3-磷酸甘油转化为溶血磷脂酸 (LPA)，并已被证明可以调节肝脏中的脂质积累。然而，其在介导 NAFLD 进展为 NASH 中的作用尚未被探索。 生成了 GPAT1 缺陷小鼠，并用诱导肝脂肪变性和 NASH 的饮食进行挑战。评估了 GPAT1 缺乏对脂质和全身代谢终点的影响。在饮食诱导或遗传性肥胖的情况下，全局或特定地在小鼠肝细胞中消除 GPAT1 可减少肝脂肪变性。有趣的是，在全局 GPAT1 敲除 (KO) 小鼠中，从 NAFLD 到 NASH 的进展的减缓是模型依赖性的：GPAT1 KO 小鼠可以免受胆碱缺乏、氨基酸限定的高脂肪饮食 (CDAHFD) 诱导的 NASH 发展，但不能免受高脂肪的影响、高碳水化合物和高胆固醇 (GAN) 饮食诱发的 NASH。我们的临床前数据支持这样的观点，即肝细胞中 GPAT1 调节的脂质代谢途径在 NASH 进展中发挥着重要作用，尽管是以模型依赖的方式。版权所有 © 2023作者。由爱思唯尔公司出版。保留所有权利。

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 (LPA) 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.GPAT1-deficient mice were generated and challenged with diets inducing hepatic steatosis and NASH. Effects of GPAT1-deficiency on lipid and systemic metabolic endpoints were evaluated.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 (CDAHFD) induced NASH development, but not from the high fat, high carbohydrate, and high cholesterol (GAN) diet-induced NASH.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.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.