What is the clinical evidence from this study?

Study design: Other. Intervention: Fenofibrate. Primary outcome: Expression of APOA5 and ANGPTL3/4/8 proteins.

What question did this study set out to answer?

This research investigates the role of fenofibrate in regulating ANGPTL3, ANGPTL4, ANGPTL8, and APOA5 in triglyceride metabolism.

April 30, 2026Journal of Lipid Research1 citationsOpen Access

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

YYYe Yang SSSydney A. Smith YCYan Q. Chen

Key Result

Fenofibrate reduced triglyceride levels in mice and humans but increased levels of ANGPTL3, ANGPTL4/8, and CD-ANGPTL4, suggesting these proteins do not mediate its triglyceride-lowering effect.

Key Points

This research investigates the role of fenofibrate in regulating ANGPTL3, ANGPTL4, ANGPTL8, and APOA5 in triglyceride metabolism.
Examined fenofibrate's effects on gene expression in wild-type mice and humans.
Measured plasma triglyceride levels and protein expression using molecular techniques.
Performed a comparative analysis in Apoa5-deficient mice.
Fenofibrate reduced plasma triglycerides in both mice and humans.
Increased levels of ANGPTL3 and ANGPTL4/8 while decreasing APOA5 levels in plasma.
Findings indicate that APOA5 and ANGPTL3/4/8 proteins do not mediate triglyceride lowering by fenofibrate.

Structured PICO

Does fenofibrate alter the expression of APOA5 and ANGPTL3/4/8 proteins to lower triglyceride levels in mice and obese humans?

Population

Wild-type and Apoa5-/- mice, and 20 obese Caucasian adults (BMI > 27 kg/m2, 10 men, 10 women).

Intervention

Fenofibrate (0.2% diet in mice for 4 weeks; 200 mg/day oral in humans for 6 weeks).

Comparator

Standard chow diet in mice; matching placebo in humans.

Outcome

Plasma levels of APOA5, ANGPTL3, ANGPTL3/8, ANGPTL4/8, CD-ANGPTL4, and triglycerides.surrogate

Fenofibrate lowers triglycerides without increasing APOA5 or decreasing ANGPTL3/8, but paradoxically increases ANGPTL3, ANGPTL4/8, and CD-ANGPTL4, which are associated with increased cardiovascular mortality.

Abstract

Fenofibrate and other fibrates are peroxisome proliferator-activated receptor alpha (PPAR) 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.PPAR 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 wild-type 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.

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