Journal of Atherosclerosis and Thrombosis
Online ISSN : 1880-3873
Print ISSN : 1340-3478
A Novel Selective PPARα Modulator (SPPARMα), K-877 (Pemafibrate), Attenuates Postprandial Hypertriglyceridemia in Mice
Masami SairyoTakuya KobayashiDaisaku MasudaKoutaro KannoYinghong ZhuTakeshi OkadaMasahiro KosekiTohru OhamaMakoto NishidaYasushi SakataShizuya Yamashita
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JOURNALS FREE ACCESS Advance online publication

Article ID: 39693

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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.

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