Fenofibrate Increases Very Low Density Lipoprotein Triglyceride Production Despite Reducing Plasma Triglyceride Levels in APOE*3-Leiden.CETP Mice

Abstract

The peroxisome proliferator-activated receptor alpha (PPAR␣) activator fenofibrate efficiently decreases plasma triglycerides (TG), which is generally attributed to enhanced very low density lipoprotein (VLDL)-TG clearance and decreased VLDL-TG production. However, because data on the effect of fenofibrate on VLDL production are controversial, we aimed to investigate in (more) detail the mechanism underlying the TG-lowering effect by studying VLDL-TG production and clearance using APOE*3-Leiden.CETP mice, a unique mouse model for human-like lipoprotein metabolism. Male mice were fed a Western-type diet for 4 weeks, followed by the same diet without or with fenofibrate (30 mg/kg bodyweight/day) for 4 weeks. Fenofibrate strongly lowered plasma cholesterol (؊38%) and TG (؊60%) caused by reduction of VLDL. Fenofibrate markedly accelerated VLDL-TG clearance, as judged from a reduced plasma halflife of glycerol tri[ 3 H]oleate-labeled VLDL-like emulsion particles (؊68%). This was associated with an increased postheparin lipoprotein lipase (LPL) activity (؉110%) and an increased uptake of VLDL-derived fatty acids by skeletal muscle, white adipose tissue, and liver. Concomitantly, fenofibrate markedly increased the VLDL-TG production rate (؉73%) but not the VLDL-apolipoprotein B (apoB) production rate. Kinetic studies using [ 3 H]palmitic acid showed that fenofibrate increased VLDL-TG production by equally increasing incorporation of re-esterified plasma fatty acids and liver TG into VLDL, which was supported by hepatic gene expression profiling data. We conclude that fenofibrate decreases plasma TG by enhancing LPL-mediated VLDL-TG clearance, which results in a compensatory increase in VLDL-TG production by the liver.The lipid-lowering agent fenofibrate reduces plasma triglyceride (TG) 2 levels and increases high density lipoprotein-cholesterol (HDL-C) levels, which generates a less atherogenic lipid phenotype (1, 2). Fenofibrate acts through activation of peroxisome proliferator-activated receptor alpha (PPAR␣) thereby altering the expression of genes involved in lipid metabolism (3, 4, 5). Several mechanisms of action have been proposed through which fenofibrate lowers TG levels, including increased very low density lipoprotein (VLDL)-TG clearance and decreased hepatic TG production (5).VLDL-TG clearance is governed by lipoprotein lipase (LPL), of which the expression is potently induced by PPAR␣ (6). In addition, it has been shown that PPAR␣ agonists down-regulate the expression of the LPL inhibitor apolipoprotein CIII (apoCIII) and up-regulate the expression of the LPL activator apoAV (7). Altogether this results in an increase in LPL-mediated lipolysis and clearance of VLDL. Indeed, two human studies show that fenofibrate increases the fractional catabolic rate (FCR) of VLDL-apoB in patients with hypertriglyceridemia without or with type 2 diabetes (8, 9), which is associated with increased LPL activity (9).Hepatic VLDL production is dependent on the availability of fatty acids (FA) which is determined by de novo ...

Metformin Lowers Plasma Triglycerides by Promoting VLDL-Triglyceride Clearance by Brown Adipose Tissue in Mice

“…CETP (E3L.CETP) transgenic mice, a well-established model of human-like lipoprotein metabolism (19) that also responds to lipid-lowering pharmacological interventions (20)(21)(22)(23). Collectively, our data show that treatment of E3L.CETP mice with metformin is able to recapitulate the lipid-lowering effect of the drug evidenced in humans, i.e., causing a reduction in plasma VLDL-TG associated with a parallel mild increase in HDL cholesterol.…”

“…Additional blood samples were taken at t = 15, 30, 60, and 90 min after tyloxapol injection and used for determination of plasma TG concentration. After 90 min, the animals were killed and blood was collected by orbital bleeding for isolation of VLDL by density-gradient ultracentrifugation, as previously described (19)(20)(21)(22)(23). 35 S-apoB was measured in the VLDL fraction, and VLDL-apoB production rate was calculated as dpm/h, as previously reported (19)(20)(21)(22)(23).…”

“…Liver lipids were extracted as previously described (20). In brief, small liver pieces were homogenized in ice-cold methanol.…”

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

“…Taken together, these results suggest that PPARα or fatty acid oxidation disorders may also participate in the development of human NAFLD. In addition, some studies have demonstrated that PPARα agonist improved liver steatosis in several obese mice models (57)(58)(59). However, the effect of PPARα agonists on improving human NAFLD is still controversial, although some studies have shown positive effects (60,61).…”

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

“…Fenofibrate lowers serum triacylglycerol levels through several mechanisms, including increasing VLDL-triacylglycerol clearance and decreasing hepatic triacylglycerol production [12]. Hepatic VLDL production depends on the availability of FA, which is determined by de novo FA synthesis and β-oxidation of FA in the liver [13]. Fenofibrate interferes with FA synthesis and stimulates hepatic fatty acid oxidation, thereby reducing the amount of FA available to the liver for triacylglycerol synthesis [14][15][16].…”