Dipeptidyl Peptidase-4 Inhibitor Sitagliptin Phosphate Accelerates Cellular Cholesterol Efflux in THP-1 Cells

Area of Science:

• Cardiovascular Biology
• Metabolic Disease Research
• Pharmacology

Background:

• High-density lipoproteins (HDLs) are crucial for cholesterol efflux, a key atheroprotective mechanism, particularly in Type 2 diabetes.
• Dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin phosphate increase glucagon-like peptide-1 (GLP-1) and are used to manage Type 2 diabetes.
• GLP-1R is expressed in human monocytes and THP-1 cells, suggesting a potential role in immune cell function.

Purpose of the Study:

• To investigate the direct impact of GLP-1 and DPP-4 inhibition on HDL-mediated cholesterol efflux.
• To determine if sitagliptin enhances cholesterol efflux independently of its glucose-lowering effects.
• To elucidate the mechanisms underlying sitagliptin's influence on cholesterol metabolism in macrophages.

Main Methods:

• Cholesterol efflux was measured in cultured THP-1 cells labeled with 3H-cholesterol and stimulated with LXR/RXR agonists.
• Sitagliptin and GLP-1 effects on apolipoprotein (apo)A1-mediated cholesterol efflux were assessed.
• Adenosine triphosphate-binding cassette transporter A1 (ABCA1) mRNA and protein expression were analyzed in different cellular fractions.

Main Results:

• Sitagliptin, in combination with GLP-1, significantly increased apoA1-mediated cholesterol efflux in a dose-dependent manner.
• This sitagliptin-induced increase in cholesterol efflux was dependent on the presence of GLP-1.
• Sitagliptin enhanced ABCA1 protein expression in the membrane fraction, but not total cellular expression, and the effect was mediated via GLP-1R signaling.

Conclusions:

• Sitagliptin directly enhances cholesterol efflux in cultivated macrophages, suggesting potential anti-atherosclerotic effects.
• These beneficial effects on HDL function appear to be independent of improvements in glucose metabolism.
• Sitagliptin may promote de novo HDL synthesis by facilitating cholesterol efflux, offering a novel therapeutic avenue for cardiovascular risk reduction.