title: Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet.
abstract: Systemic inflammation is strongly involved in the pathophysiology of the metabolic syndrome, a cluster of metabolic risk factors that includes hypertriglyceridemia. Aspirin treatment lowers inflammation via inhibition of NF-κB activity but also reduces hypertriglyceridemia in humans. The aim of this study was to investigate the mechanism by which aspirin improves hypertriglyceridemia. Human apolipoprotein CI (apoCI)-expressing mice (APOC1 mice), an animal model with elevated plasma triglyceride (TG) levels, as well as normolipidemic wild-type (WT) mice were fed a high-fat diet (HFD) and treated with aspirin. Aspirin treatment reduced hepatic NF-κB activity in HFD-fed APOC1 and WT mice, and in addition, aspirin decreased plasma TG levels (-32%, P < 0.05) in hypertriglyceridemic APOC1 mice. This TG-lowering effect could not be explained by enhanced VLDL-TG clearance, but aspirin selectively reduced hepatic production of VLDL-TG in both APOC1 (-28%, P < 0.05) and WT mice (-33%, P < 0.05) without affecting VLDL-apoB production. Aspirin did not alter hepatic expression of genes involved in FA oxidation, lipogenesis, and VLDL production but decreased the incorporation of plasma-derived FA by the liver into VLDL-TG (-24%, P < 0.05), which was independent of hepatic expression of genes involved in FA uptake and transport. We conclude that aspirin improves hypertriglyceridemia by decreasing VLDL-TG production without affecting VLDL particle production. Therefore, the inhibition of inflammatory pathways by aspirin could be an interesting target for the treatment of hypertriglyceridemia.
authors.affiliation: Department of General Internal Medicine, Endocrinology, and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands. J.A.van_Diepen@lumc.nl
authors.forename: Janna A
authors.initials: JA
authors.lastname: van Diepen
authors.forename: Irene O C M
authors.initials: IO
authors.lastname: Vroegrijk
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.forename: Steven E
authors.initials: SE
authors.lastname: Shoelson
authors.forename: Johannes A
authors.initials: JA
authors.lastname: Romijn
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Voshol
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology / Q000627:therapeutic use; D053302:Apolipoprotein C-I / Q000235:genetics; D001241:Aspirin / Q000494:pharmacology* / Q000627:therapeutic use; D059305:Diet, High-Fat / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D015228:Hypertriglyceridemia / Q000097:blood / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008079:Lipoproteins, VLDL / Q000097:blood / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D053302:Apolipoprotein C-I; D008079:Lipoproteins, VLDL; D016328:NF-kappa B; D014280:Triglycerides; C030106:very low density lipoprotein triglyceride; D001241:Aspirin