K-877 regulates hepatic gene expression as a selective PPARα modulator, upregulating fatty acid β-oxidative genes and clinically beneficial targets like VLDLR, FGF21, and ABCA1 in human hepatocytes.
Does K-877 regulate hepatic gene expression differently than fenofibrate in human hepatocytes and mouse liver?
K-877 is a highly potent and selective PPARα modulator that enhances hepatic fatty acid catabolism and beneficial metabolic gene expression without inducing peroxisome proliferation in human cells, suggesting a favorable efficacy and safety profile for treating dyslipidemia.
AIM: Selective PPARα modulators (SPPARMα) are under development for use as next-generation lipid lowering drugs. In the current study, to predict the pharmacological and toxicological effects of a novel SPPARMα K-877, comprehensive transcriptome analyses of K-877-treated primary human hepatocytes and mouse liver tissue were carried out. METHODS: Total RNA was extracted from the K-877 treated primary human hepatocytes and mouse liver and adopted to the transcriptome analysis. Using a cluster analysis, commonly and species specifically regulated genes were identified. Also, the profile of genes regulated by K-877 and fenofibrate were compared to examine the influence of different SPPARMα on the liver gene expression. RESULTS: Consequently, a cell-based transactivation assay showed that K-877 activates PPARα with much greater potency and selectivity than fenofibric acid, the active metabolite of clinically used fenofibrate. K-877 upregulates the expression of several fatty acid β-oxidative genes in human hepatocytes and the mouse liver. Almost all genes up- or downregulated by K-877 treatment in the mouse liver were also regulated by fenofibrate treatment. In contrast, the K-877-regulated genes in the mouse liver were not affected by K-877 treatment in the Ppara-null mouse liver. Depending on the species, the peroxisomal biogenesis-related gene expression was robustly induced in the K-877-treated mouse liver, but not human hepatocytes, thus suggesting that the clinical dose of K-877 may not induce peroxisome proliferation or liver toxicity in humans. Notably, K-877 significantly induces the expression of clinically beneficial target genes (VLDLR, FGF21, ABCA1, MBL2, ENPEP) in human hepatocytes. CONCLUSION: These results indicate that changes in the gene expression induced by K-877 treatment are mainly mediated through PPARα activation. K-877 regulates the hepatic gene expression as a SPPARMα and thus may improve dyslipidemia as well as metabolic disorders, such as metabolic syndrome and type 2 diabetes, without untoward side effects.
Raza-Iqbal et al. (Thu,) conducted a other in Dyslipidemia (Preclinical model). K-877 vs. Vehicle / DMSO / Fenofibrate was evaluated on Hepatic gene expression changes (transcriptome analysis). K-877 regulates hepatic gene expression as a selective PPARα modulator, upregulating fatty acid β-oxidative genes and clinically beneficial targets like VLDLR, FGF21, and ABCA1 in human hepatocytes.