Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute.
Department of Endocrinology, Research Institute of Environmental Medicine, Nagoya University.
J Atheroscler Thromb. 2023 Jan 1;30(1):74-86. doi: 10.5551/jat.60921. Epub 2022 Mar 19.
We previously reported that glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduced serum low-density lipoprotein cholesterol (LDL-C) levels in patients with type 2 diabetes mellitus receiving statins, which increased LDL receptor (LDLR) expression. Nevertheless, it remains unclear how much LDLR expression contributes to the LDL-C-lowering effect of GLP-1RAs. We examined the effect of a GLP-1RA, namely, exendin-4, on serum LDL-C levels and its mechanism in Ldlr and C57BL/6J mice.
Ten-week-old Ldlr and C57BL/6J mice received exendin-4 or saline for 5 days, and serum lipid profiles and hepatic lipid levels were examined. Cholesterol metabolism-related gene expression and protein levels in the liver and ileum and the fecal bile acid (BA) composition were also examined.
Exendin-4 treatment significantly decreased serum very-low-density lipoprotein cholesterol (VLDL-C) and LDL-C levels and mature hepatic SREBP2 levels and increased hepatic Insig1/2 mRNA expression in both mouse strains. In Ldlr mice, exendin-4 treatment also significantly decreased hepatic cholesterol levels and fecal BA excretion, decreased hepatic Cyp7a1 mRNA expression, and increased small intestinal Fgf15 mRNA expression. In C57BL/6J mice, exendin-4 treatment significantly decreased small intestinal NPC1L1 levels.
Our findings demonstrate that exendin-4 treatment decreased serum VLDL-C and LDL-C levels in a manner that was independent of LDLR. Exendin-4 treatment might decrease serum cholesterol levels by lowering hepatic SREBP2 levels and cholesterol absorption in Ldlr and C57BL/6J mice. Exendin-4 treatment might decrease cholesterol absorption by different mechanisms in Ldlr and C57BL/6J mice.
我们之前报道过，胰高血糖素样肽-1 受体激动剂（GLP-1RAs）可降低接受他汀类药物治疗的 2 型糖尿病患者的血清低密度脂蛋白胆固醇（LDL-C）水平，从而增加 LDL 受体（LDLR）的表达。然而，GLP-1RAs 降低 LDL-C 的作用有多少归因于 LDLR 的表达仍不清楚。我们研究了 GLP-1RA，即 exendin-4，对 LDLr 和 C57BL/6J 小鼠的血清 LDL-C 水平及其机制的影响。
10 周龄的 LDLr 和 C57BL/6J 小鼠接受 exendin-4 或生理盐水治疗 5 天，检测血清脂质谱和肝内脂质水平。还检测了肝脏和回肠中胆固醇代谢相关基因的表达和蛋白水平以及粪便胆汁酸（BA）组成。
exendin-4 处理显著降低了两种小鼠血清极低密度脂蛋白胆固醇（VLDL-C）和 LDL-C 水平以及成熟肝 SREBP2 水平，并增加了肝 Insig1/2 mRNA 的表达。在 LDLr 小鼠中，exendin-4 处理还显著降低了肝内胆固醇水平和粪便 BA 排泄，降低了肝 Cyp7a1 mRNA 表达，增加了小肠 Fgf15 mRNA 表达。在 C57BL/6J 小鼠中，exendin-4 处理显著降低了小肠 NPC1L1 水平。
我们的研究结果表明，exendin-4 处理以 LDLR 独立的方式降低了血清 VLDL-C 和 LDL-C 水平。Exendin-4 处理可能通过降低 LDLr 和 C57BL/6J 小鼠的肝 SREBP2 水平和胆固醇吸收来降低血清胆固醇水平。Exendin-4 处理可能通过不同的机制降低 LDLr 和 C57BL/6J 小鼠的胆固醇吸收。
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