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Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.

ABSTRACT: The efficacy of peroxisome proliferator-activated receptor ?-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor ? modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH.

SUBMITTER: Honda Y

PROVIDER: S-EPMC5307366 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.

Honda Yasushi Y Kessoku Takaomi T Ogawa Yuji Y Tomeno Wataru W Imajo Kento K Fujita Koji K Yoneda Masato M Takizawa Toshiaki T Saito Satoru S Nagashima Yoji Y Nakajima Atsushi A

Scientific reports 20170214

The efficacy of peroxisome proliferator-activated receptor α-agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptor α modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the pres ...[more]

PMID: 28195199

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Project description:CHS-131 is a selective peroxisome proliferator-activated receptor gamma modulator with antidiabetic effects and less fluid retention and weight gain compared to thiazolidinediones in phase II clinical trials. We investigated the effects of CHS-131 on metabolic parameters and liver histopathology in a diet-induced obese (DIO) and biopsy-confirmed mouse model of nonalcoholic steatohepatitis (NASH). Male C57BL/6JRj mice were fed the amylin liver NASH diet (40% fat with trans-fat, 20% fructose, and 2% cholesterol). After 36 weeks, only animals with biopsy-confirmed steatosis and fibrosis were included and stratified into treatment groups (n = 12-13) to receive for the next 12 weeks (1) low-dose CHS-131 (10 mg/kg), (2) high-dose CHS-131 (30 mg/kg), or (3) vehicle. Metabolic parameters, liver pathology, metabolomics/lipidomics, markers of liver function and liver, and subcutaneous and visceral adipose tissue gene expression profiles were assessed. CHS-131 did not affect body weight, fat mass, lean mass, water mass, or food intake in DIO-NASH mice with fibrosis. CHS-131 improved fasting insulin levels and insulin sensitivity as assessed by the intraperitoneal insulin tolerance test. CHS-131 improved total plasma cholesterol, triglycerides, alanine aminotransferase, and aspartate aminotransferase and increased plasma adiponectin levels. CHS-131 (high dose) improved liver histology and markers of hepatic fibrosis. DIO-NASH mice treated with CHS-131 demonstrated a hepatic shift to diacylglycerols and triacylglycerols with a lower number of carbons, increased expression of genes stimulating fatty acid oxidation and browning, and decreased expression of genes promoting fatty acid synthesis, triglyceride synthesis, and inflammation in adipose tissue. Conclusion: CHS-131 improves liver histology in a DIO and biopsy-confirmed mouse model of NASH by altering the hepatic lipidome, reducing insulin resistance, and improving lipid metabolism and inflammation in adipose tissue.

Dataset Information

Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.

Publications

Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis.

Similar Datasets

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