Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet

• Published in: American journal of physiology: endocrinology and metabolism Vol. 301; no. 6; pp. E1099 - E1107
• Main Authors: van Diepen, Janna A, Vroegrijk, Irene O C M, Berbée, Jimmy F P, Shoelson, Steven E, Romijn, Johannes A, Havekes, Louis M, Rensen, Patrick C N, Voshol, Peter J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.12.2011
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Apolipoprotein C-I - genetics; Aspirin; Aspirin - pharmacology; Aspirin - therapeutic use; Diet, High-Fat - adverse effects; Down-Regulation - drug effects; Drug Evaluation, Preclinical; Gene expression; Hypertriglyceridemia - blood; Hypertriglyceridemia - etiology; Hypertriglyceridemia - metabolism; Hypertriglyceridemia - prevention & control; Lipoproteins, VLDL - blood; Lipoproteins, VLDL - metabolism; Liver - drug effects; Liver - metabolism; Male; Metabolic syndrome; Mice; Mice, Inbred C57BL; Mice, Transgenic; NF-kappa B - metabolism; Plasma; Risk factors; Rodents; Triglycerides - blood; Triglycerides - metabolism
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00185.2011

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.