Cardiovascular Prevention and Pharmacotherapy

Original Article

Glucagon-like peptide-1 receptor agonists improve cholesterol metabolism by inhibiting SREBP-2 via SIRT6-AMPK pathway in HepG2 cells treated with palmitic acid: Jinmi Lee, Eun-Jung Rhee, Yu-Mi Lim, Seok-Woo Hong, Won-Young Lee; Cardiovasc Prev Pharmacother. 2025;7(3):61-72. Published online July 24, 2025; DOI: https://doi.org/10.36011/cpp.2025.7.e11

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Abstract PDF Supplementary Material: Background
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exhibit not only hypoglycemic effects but also protective effects against nonalcoholic fatty liver disease and cardiovascular diseases, conditions that are associated with dyslipidemia.
Methods
To evaluate the beneficial effects of GLP-1RAs on hepatic cholesterol metabolism, HepG2 cells were exposed to palmitic acid (PA) and subsequently treated with or without the GLP-1RAs, exendin-4 and liraglutide. Cholesterol levels and the expression of cholesterol metabolism-related factors were measured.
Results
Exendin-4 and liraglutide reduced cholesterol levels in both cell lysates and culture media of PA-treated HepG2 cells. They also decreased the expression of genes involved in cholesterol synthesis (ACAT1, SREBP-2, HMGCR, and SQLE), bile acid synthesis (LXRα and CYP7A1), and PCSK9, while increasing the expression of genes involved in the reverse cholesterol transport pathway (ABCA1 and SR-B1) and low-density lipoprotein cholesterol uptake (LDLR). SREBP-2 inhibition by small interfering RNA in GLP-1RAs treated cells amplified the reduction in the expression of HMGCR, SQLE, LXRα, CYP7A1, and PCSK9 genes and HMGCR protein, as well as the increase in expression of the LDLR gene. However, inhibition of SIRT6 and AMPK, which were increased by GLP-1RAs, reversed the suppression of SREBP-2 and its downstream factor genes and amplified the increase in expression of the LDLR gene in PA-treated HepG2 cells.
Conclusions
These findings demonstrate that GLP-1RAs improve cholesterol metabolism through activation of the SIRT6-AMPK pathway, resulting in the inhibition of SREBP-2 in PA-treated HepG2 cells. Moreover, the upregulation of LDLR gene expression in cells treated with GLP-1RAs occurs through both SREBP-2-dependent and SREBP-2-independent pathways.

Review Article

Paradigm shift from glucocentric to organ protection for the management of hyperglycemia in patients with type 2 diabetes: Jie-Eun Lee, Jong Chul Won; Cardiovasc Prev Pharmacother. 2024;6(4):116-122. Published online October 31, 2024; DOI: https://doi.org/10.36011/cpp.2024.6.e15

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The UK Prospective Diabetes Study was the first study to investigate the effectiveness of glycemic control in patients with type 2 diabetes. Since then, many studies have evaluated the impact of intensive glycemic control on diabetes-related morbidities and mortality. The results of these studies were intended to change the paradigm for controlling glycated hemoglobin and preventing diabetes-related complications, but the beneficial outcomes were limited to microvascular diseases rather than diabetes-related cardiorenal diseases and deaths. This has emphasized the need for comprehensive management of other risk factors (hypertension, dyslipidemia, renal failure, etc.) in addition to hyperglycemia to prevent atherosclerotic cardiovascular diseases and end-stage renal disease in type 2 diabetes. Since 2008, clinical trials to demonstrate cardiovascular safety have shown a beneficial effect of sodium-glucose transporter 2 inhibitors or glucagon-like peptide-1 receptor agonists on macrovascular or renal complications in patients with type 2 diabetes. Recently, major societies around the world including the Korean Diabetes Association, have shifted the goals of diabetes management from the typical glucocentric view to cardiorenal outcome-oriented (organ protection) care, which has been widely accepted and is gradually applied to primary care.

Citations

Citations to this article as recorded by

Type 2 diabetes mellitus: Isn’t it time to update the terminology?
Arkiath Veettil Raveendran
World Journal of Diabetes.2025;[Epub] CrossRef

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