Related Experiment Video
Updated: Sep 29, 2025
Quantification of Atherosclerosis in Mice
Published on: June 12, 2019
Acute Cholesterol-Lowering Effect of Exendin-4 in Ldlr-/- and C57BL/6J Mice
Mika Hori1,2,3, Yukiko Hasegawa1,4, Yoshitaka Hayashi2,3
1Department of Molecular Innovation in Lipidology, National Cerebral and Cardiovascular Center Research Institute.
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.
Insights
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like exendin-4 lower cholesterol by reducing liver cholesterol synthesis, independent of LDL receptors. This study investigates the mechanisms in mice lacking LDL receptors.
Area of Science:
- Metabolic Research
- Endocrinology
- Cardiovascular Science
Background:
- Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown potential in reducing low-density lipoprotein cholesterol (LDL-C) in type 2 diabetes patients.
- The precise contribution of LDL receptor (LDLR) expression to this LDL-C-lowering effect remains unclear.
Purpose of the Study:
- To investigate the effect of exendin-4, a GLP-1RA, on serum LDL-C levels and its underlying mechanisms.
- To compare these effects in mice with and without functional LDLR.
Main Methods:
- Exendin-4 or saline was administered to Ldlr knockout and wild-type C57BL/6J mice for 5 days.
- Serum and hepatic lipid profiles, cholesterol metabolism gene/protein expression, and fecal bile acid composition were analyzed.
Main Results:
- Exendin-4 decreased serum VLDL-C and LDL-C levels in both mouse models.
- Hepatic SREBP2 levels were reduced, while Insig1/2 mRNA expression increased.
- In Ldlr knockout mice, exendin-4 reduced hepatic cholesterol, fecal bile acid excretion, and hepatic Cyp7a1 mRNA, while increasing intestinal Fgf15 mRNA.
- In wild-type mice, exendin-4 reduced intestinal NPC1L1 levels.
Conclusions:
- Exendin-4 lowers serum VLDL-C and LDL-C independently of LDLR.
- The cholesterol-lowering effect may involve reduced hepatic SREBP2 levels and altered cholesterol absorption.
- Distinct mechanisms for cholesterol absorption may be employed by exendin-4 in different mouse models.
Related Concept Videos
01:20Lipid-Lowering Drugs: Statins and Miscellaneous Agents
01:29Cholesterol: Significance and Regulation
Considering cholesterol and...