Institute of Medical Research, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea.
Endocrinol Metab (Seoul). 2022 Feb;37(1):74-83. doi: 10.3803/EnM.2021.1293. Epub 2022 Feb 9.
Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA).
HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting.
Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9-39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation.
These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.
长效胰高血糖素样肽-1 受体激动剂（GLP-1RA）度拉糖肽已被证明可降低 2 型糖尿病患者的体重和肝脂肪含量。家族性与序列相似性 3 成员 A（FAM3A）在调节葡萄糖和脂质代谢中起着至关重要的作用。本研究旨在确定度拉糖肽通过何种机制在棕榈酸（PA）处理的 HepG2 细胞中防止肝脂肪变性。
用 400μM PA 预处理 HepG2 细胞 24 小时，然后用或不用 100 nM 度拉糖肽处理 24 小时。用油红 O 染色和甘油三酯（TG）测定法测定肝脂质积聚，并用定量实时聚合酶链反应和 Western blot 分析脂质代谢相关因子的表达。
度拉糖肽显著降低了 PA 处理的 HepG2 细胞中的肝脂质积聚，并降低了与脂滴结合蛋白、从头合成和 TG 合成相关的基因的表达。度拉糖肽还增加了 PA 处理细胞中与脂肪分解和脂肪酸氧化相关的蛋白质和 FAM3A 的表达。然而，GLP-1R 拮抗剂 exendin-(9-39) 逆转了 FAM3A 的表达，并且由于度拉糖肽的作用，脂肪酸氧化相关因子增加。此外，siRNA 抑制 FAM3A 减弱了度拉糖肽降低 TG 含量的作用及其增加调节脂肪酸氧化的作用。
这些结果表明，度拉糖肽可用于治疗非酒精性脂肪性肝病，其作用部分可通过 GLP-1R 依赖性途径上调 FAM3A 表达来介导。
