Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice
Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis...
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MDPI AG
2022-07-01
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| Series: | Biomedicines |
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| Online Access: | https://www.mdpi.com/2227-9059/10/7/1667 |
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| author | Zhe Zhang Pan Diao Xuguang Zhang Takero Nakajima Takefumi Kimura Naoki Tanaka |
| author_facet | Zhe Zhang Pan Diao Xuguang Zhang Takero Nakajima Takefumi Kimura Naoki Tanaka |
| author_sort | Zhe Zhang |
| collection | DOAJ |
| description | Pemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting. |
| first_indexed | 2024-03-09T12:11:37Z |
| format | Article |
| id | doaj.art-40c8830a3ccf474f9728eb28cc6d9bd2 |
| institution | Directory Open Access Journal |
| issn | 2227-9059 |
| language | English |
| last_indexed | 2024-03-09T12:11:37Z |
| publishDate | 2022-07-01 |
| publisher | MDPI AG |
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| series | Biomedicines |
| spelling | doaj.art-40c8830a3ccf474f9728eb28cc6d9bd22023-11-30T22:51:06ZengMDPI AGBiomedicines2227-90592022-07-01107166710.3390/biomedicines10071667Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in MiceZhe Zhang0Pan Diao1Xuguang Zhang2Takero Nakajima3Takefumi Kimura4Naoki Tanaka5Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Gastroenterology, Shinshu University School of Medicine, Matsumoto 390-8621, JapanDepartment of Global Medical Research Promotion, Shinshu University Graduate School of Medicine, Matsumoto 390-8621, JapanPemafibrate (PEM) is a novel lipid-lowering drug classified as a selective peroxisome proliferator-activated receptor α (PPARα) modulator whose binding efficiency to PPARα is superior to that of fibrates. This agent is also useful for non-alcoholic fatty liver disease and primary biliary cholangitis with dyslipidemia. The dose of PEM used in some previous mouse experiments is often much higher than the clinical dose in humans; however, the precise mechanism of reduced serum triglyceride (TG) for the clinical dose of PEM has not been fully evaluated. To address this issue, PEM at a clinically relevant dose (0.1 mg/kg/day) or relatively high dose (0.3 mg/kg/day) was administered to male C57BL/6J mice for 14 days. Clinical dose PEM sufficiently lowered circulating TG levels without apparent hepatotoxicity in mice, likely due to hepatic PPARα stimulation and the enhancement of fatty acid uptake and β-oxidation. Interestingly, PPARα was activated only in the liver by PEM and not in other tissues. The clinical dose of PEM also increased serum/hepatic fibroblast growth factor 21 (FGF21) without enhancing hepatic lipid peroxide 4-hydroxynonenal or inflammatory signaling. In conclusion, a clinically relevant dose of PEM in mice efficiently and safely reduced serum TG and increased FGF21 targeting hepatic PPARα. These findings may help explain the multiple beneficial effects of PEM observed in the clinical setting.https://www.mdpi.com/2227-9059/10/7/1667β-oxidationpemafibratePPARαtriglyceridesliverFGF21 |
| spellingShingle | Zhe Zhang Pan Diao Xuguang Zhang Takero Nakajima Takefumi Kimura Naoki Tanaka Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice Biomedicines β-oxidation pemafibrate PPARα triglycerides liver FGF21 |
| title | Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice |
| title_full | Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice |
| title_fullStr | Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice |
| title_full_unstemmed | Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice |
| title_short | Clinically Relevant Dose of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα), Lowers Serum Triglyceride Levels by Targeting Hepatic PPARα in Mice |
| title_sort | clinically relevant dose of pemafibrate a novel selective peroxisome proliferator activated receptor α modulator spparmα lowers serum triglyceride levels by targeting hepatic pparα in mice |
| topic | β-oxidation pemafibrate PPARα triglycerides liver FGF21 |
| url | https://www.mdpi.com/2227-9059/10/7/1667 |
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