A Novel Selective PPARα Modulator (SPPARMα), K-877 (Pemafibrate), Attenuates Postprandial Hypertriglyceridemia in Mice

Abstract

Aims: Fasting and postprandial hypertriglyceridemia (PHTG) are caused by the accumulation of triglyceride (TG)-rich lipoproteins and their remnants, which have atherogenic effects. Fibrates can improve fasting and PHTG; however, reduction of remnants is clinically needed to improve health outcomes. In the current study, we investigated the effects of a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), K-877 (Pemafibrate), on PHTG and remnant metabolism.

Methods: Male C57BL/6J mice were fed a high-fat diet (HFD) only, or an HFD containing 0.0005% K-877 or 0.05% fenofibrate, from 8 to 12 weeks of age. After 4 weeks of feeding, we measured plasma levels of TG, free fatty acids (FFA), total cholesterol (TC), HDL-C, and apolipoprotein (apo) B-48/B-100 during fasting and after oral fat loading (OFL). Plasma lipoprotein profiles after OFL, which were assessed by high performance liquid chromatography (HPLC), and fasting lipoprotein lipase (LPL) activity were compared among the groups.

Results: Both K-877 and fenofibrate suppressed body weight gain and fasting and postprandial TG levels and enhanced LPL activity in mice fed an HFD. As determined by HPLC, K-877 and fenofibrate significantly decreased the abundance of TG-rich lipoproteins, including remnants, in postprandial plasma. Both K-877 and fenofibrate decreased intestinal mRNA expression of ApoB and Npc1l1; however, hepatic expression of Srebp1c and Mttp was increased by fenofibrate but not by K-877.Hepatic mRNA expression of apoC-3 was decreased by K-877 but not by fenofibrate.

Conclusion: K-877 may attenuate PHTG by suppressing the postprandial increase of chylomicrons and the accumulation of chylomicron remnants more effectively than fenofibrate.

Keywords: Chylomicron remnants; Fenofibrate; K-877 (Pemafibrate); Postprandial hypertriglyceridemia; SPPARMα.

Fig. 1.

Body weight gain and food intake in mice fed after treatment with K-877 and fenofibrate. Mice (n = 10, male, C57B6/J) were fed a normal chow diet up to 8 weeks of age, and they were then fed with a HFD only, an HFD containing 0.0005% K-877, or an HFD containing 0.05% fenofibrate for 4 weeks (A). Body weight gain from the baseline level (g) (B) and food intake (g/day) (C) were observed in these groups from 8 to 12 weeks of age. *: p < 0.05, **: p < 0.01 compared to HFD only.

Fig. 2.

Oral fat loading test after treatment with K-877 and fenofibrate. At twelve weeks of age, the OFL test was performed using olive oil by gavage (17 µL/g body weight) after an overnight fast. Blood (50 µL) was drawn from an orbital vein, and plasma levels of TGs (A, B), FFA (C, D), TC (E,F) and HDL-cholesterol (HDL-C) (G) were measured, and these levels were compared on the basis of incremental AUC. Lipoprotein lipase (LPL) activities were compared among the three groups during the fasting state. *: p < 0.05, **: p < 0.01 compared with HFD only.

Fig. 3.

Lipoprotein profile and apolipoprotein B-48/B-100 relative mass of plasma after the oral fat load Lipoprotein profiles were analyzed and compared among the 3 groups by measurement of TG and cholesterol concentrations of every sub-fractionated sample 4 hours after OFL by using HPLC. Increases in apoB-48 and apoB-100 concentrations after OFL were compared by western blot using a rabbit polyclonal anti-apoB antibody. *: p < 0.05, **: p < 0.01 compared with HFD only.

Fig. 4.

Fasting and postprandial messenger RNA expressions of genes related to lipoprotein metabolism after treatment with K-877 and fenofibrate. Gene expression in the intestinal epithelial cells and hepatocytes was measured with qRT-PCR. Intestinal mRNA expressions of Apob(A), Npc1l1(B), Srebp1c(C) and Mttp(D) were compared among the 3 groups, and hepatic mRNA expressions of ApoB(E) and ApoC3(F) were compared in the same manner. The relative gene expression values were normalized to those of GAPDH gene expression. *: p < 0.05, **: p < 0.01 compared with HFD only, ^#: p < 0.05, ^##: p < 0.01 compared with HFD containing fenofibrate.