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

Targets for rescue from fatty acid-induced lipotoxicity in pancreatic beta cells: Seok-Woo Hong, Won-Young Lee; Cardiovasc Prev Pharmacother. 2022;4(2):57-62. Published online April 26, 2022; DOI: https://doi.org/10.36011/cpp.2022.4.e9

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1 Citations

A persistent intake of excess calories increases plasma levels of free fatty acids, particularly the saturated form that has been shown to exert toxic effects on pancreatic beta cells by inducing dysfunction and apoptosis (i.e., lipotoxicity). An insufficient supply of insulin due to beta cell failure is a major factor in the onset and progression of type 2 diabetes; therefore, it is crucial to understand the cellular mechanisms of lipotoxicity to prevent beta cell failure. Many studies on the effects of lipotoxicity have demonstrated the various factors responsible for beta cell impairment, but the mechanisms of dysfunction and apoptosis resulting from lipotoxicity have not been fully described. This review discusses lipotoxicity-induced alterations of cellular mechanisms, and assesses drugs such as incretin mimetics, thiazolidinedione, and clusterin. Understanding the molecular mechanisms of lipotoxicity-induced beta cell failure is useful in guiding the development of new therapeutic targets for diabetes treatment.

Citations

Citations to this article as recorded by

ВПЛИВ ПОЛІВІТАМІННОГО КОМПЛЕКСУ НА СТАН ПІДШЛУНКОВОЇ ЗАЛОЗИ ХОМ’ЯКІВ ЗА УМОВ ЕКСПЕРИМЕНТАЛЬНОГО МЕТАБОЛІЧНОГО СИНДРОМУ
Н. Ю. Духніч, К. О. Калько, О. Я. Міщенко
Medical and Clinical Chemistry.2023; (3): 72. CrossRef

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