title: Sitagliptin promotes macrophage-to-faeces reverse cholesterol transport through reduced intestinal cholesterol absorption in obese insulin resistant CETP-apoB100 transgenic mice.
abstract: Dipeptidyl peptidase-4 inhibitors (DPP-4i) improve glycaemic control in type 2 diabetes, but their benefits on reverse cholesterol transport (RCT) remain unknown. We evaluated the effects of DPP-4i sitagliptin 500 mg/kg/day on RCT in obese insulin-resistant CETP-apoB100 transgenic mice. Metformin 300 mg/kg/day orally was used as a reference compound. Both metformin and sitagliptin showed the expected effects on glucose parameters. Although no significant effect was observed on total cholesterol and high-density lipoprotein (HDL) cholesterol levels, sitagliptin, but not metformin, increased faecal cholesterol mass excretion by 132% (p < 0.001 vs. vehicle), suggesting a potent effect on cholesterol metabolism. Mice were then injected i.p. with (3) H-cholesterol labelled macrophages to measure RCT over 48 h. Compared with vehicle, sitagliptin significantly increased macrophage-derived (3) H-cholesterol faecal excretion by 39%. Administration of (14) C-cholesterol labelled olive oil orally showed a significant reduction of (14) C-tracer plasma appearance over time with sitagliptin, indicating that this drug promotes RCT through reduced intestinal cholesterol absorption.
authors.affiliation: Physiogenex SAS, Prologue Biotech, Rue Pierre et Marie Curie, Rue Pierre et Marie Curie, Labège-Innopole, France. f.briand@physiogenex.com
authors.forename: F
authors.initials: F
authors.lastname: Briand
authors.forename: Q
authors.initials: Q
authors.lastname: Thieblemont
authors.forename: R
authors.initials: R
authors.lastname: Burcelin
authors.forename: T
authors.initials: T
authors.lastname: Sulpice
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007408:Intestinal Absorption / Q000187:drug effects; D008075:Lipoproteins, HDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D011719:Pyrazines / Q000494:pharmacology*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D053299:Apolipoprotein B-100; D015415:Biomarkers; D001786:Blood Glucose; D053480:Cholesterol Ester Transfer Proteins; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D008075:Lipoproteins, HDL; D011719:Pyrazines; D014230:Triazoles; D008687:Metformin; D002784:Cholesterol; D000068900:Sitagliptin Phosphate