Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5

Fenofibrate and other fibrates are peroxisome proliferator-activated receptor alpha agonists that are used to lower plasma triglyceride (TG) levels. Although fibrates are effective in decreasing TG, their ability to reduce adverse cardiovascular events and cardiovascular mortality in clinical trials has been disappointing. Peroxisome proliferator-activated receptor alpha agonists influence the expression of dozens of genes, but the mechanisms by which they lower TG levels are incompletely understood. Apolipoprotein A5 (APOA5) and angiopoietin-like proteins 3, 4, and 8 (ANGPTL3/4/8) are important regulators of intravascular TG metabolism. To explore if their regulation might explain the TG-lowering effect of fibrates, we examined the impact of fenofibrate on the expression of APOA5 and the ANGPTL3/4/8 proteins in mice and humans. In WT mice, fenofibrate reduced plasma TG levels, increased Angptl4 and Angptl3 transcripts in the liver, and reduced Angptl8 and Apoa5 transcripts. Fenofibrate also decreased plasma APOA5 levels and increased levels of ANGPTL3, ANGPTL3/8, ANGPTL4/8, and the C-terminal domain of ANGPTL4 (CD-ANGPTL4). These changes would be predicted to increase rather than decrease TG levels. The TG reduction by fenofibrate was maintained in Apoa5-deficient mice, further indicating that APOA5 is not involved in TG lowering by fenofibrate. In humans, fenofibrate reduced TG without increasing APOA5 levels or reducing ANGPTL3/8 levels. In addition, fenofibrate treatment increased levels of ANGPTL3, ANGPTL4/8, and CD-ANGPTL4. The collective human and mouse data suggest that APOA5 and ANGPTL3/4/8 proteins do not mediate fenofibrate-induced TG lowering. Our findings are noteworthy because elevated levels of ANGPTL3, ANGPTL4/8, and CD-ANGPTL4 are associated with increased cardiovascular mortality.