期刊
JOURNAL OF ATHEROSCLEROSIS AND THROMBOSIS
卷 30, 期 1, 页码 74-86出版社
JAPAN ATHEROSCLEROSIS SOC
DOI: 10.5551/jat.60921
关键词
GLP-1 receptor agonist; VLDL-cholesterol; LDL-cholesterol; Cholesterol absorption; Ldlr-deficient mice; SREBP2
We investigated the effect of GLP-1 receptor agonist exendin-4 on serum LDL-C levels and its mechanism in Ldlr-/- and C57BL/6J mice. The treatment decreased serum VLDL-C and LDL-C levels in both mouse strains, independent of LDLR.
Aims: 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.Methods: 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.Results: 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.Conclusions: 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.
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