Transcriptome Analysis of K-877 (a Novel Selective PPARα Modulator (SPPARMα))-Regulated Genes in Primary Human Hepatocytes and the Mouse Liver

Abstract

Aim: Selective PPAR modulators (SPPARM ) 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 SPPARM 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 SPPARM on the liver gene expression. Results: Consequently, a cell-based transactivation assay showed that K-877 activates PPAR 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 -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

Selective peroxisome proliferator‐activated receptor‐α modulator K‐877 efficiently activates the peroxisome proliferator‐activated receptor‐α pathway and improves lipid metabolism in mice

“…Based on a previous report, 8‐week‐old male WT mice were fed a moderate‐fat (MF) diet containing 0.2% (w/w) Feno or 0.001% (w/w) K‐877 for 6 days. Although the dose of K‐877 was 200‐fold lower than that of Feno, compared with no treatment, K‐877 and Feno significantly reduced plasma TG levels, and tended to reduce TC and NEFA levels (Figure a), and the effects of both agonists were blunted in Ppara −/− mice (Figure a).…”

“…Therefore, a potent and selective PPARα agonist is required for patients with metabolic syndrome. K‐877 is a novel selective PPARα modulator (SPPARMα) that enhances PPARα activity; it also elicits higher PPARα activation than other fibrates, with lower EC 50 values and higher PPAR subtype selectivity.…”

In vivo interactions between α7 nicotinic acetylcholine receptor and nuclear peroxisome proliferator-activated receptor-α: Implication for nicotine dependence

“…SPPARMS are thought to interact with the large binding pocket of PPARα to induce a different co-factor recruitment, resulting in higher potency and fewer adverse side effects than the original fibrate compounds (Fruchart, 2013). LY518674 and K-877 are currently in phase II trials with promising results in treating dyslipidemia (Ishibashi et al, 2016; Raza-Iqbal et al, 2015). These compounds may prove to be more efficacious candidates for smoking cessation therapy; however, preclinical studies are imperative to investigate this hypothesis.…”

PPARs and Mitochondrial Metabolism: From NAFLD to HCC

“…K-877 is a SPPAR α M currently being tested in dyslipidemic patients that exhibits higher lipid lowering activity than fibrates and has a favorable risk profile [206, 207]. INT-131, SPPAR γ M, has potent glucose lowering effects not associated with TZD side-effects [208].…”