Turofexorate Isopropyl

Hepatic steatosis, also known as fatty liver disease, occurs due to abnormal lipid accumulation in the liver. It has been known that gut absorption also plays an important role in the mechanism underlying hepatic steatosis. Conventional in vitro cell culture models have limitations in recapitulating the mechanisms of hepatic steatosis because it does not include the gut absorption process. Previously, we reported development of a microfluidic gut–liver chip that can recapitulate the gut absorption of fatty acids and subsequent lipid accumulation in liver cells. In this study, we performed a series of experiments to verify that our gut–liver chip reproduces various aspects of hepatic steatosis. The absorption of fatty acids was evaluated under various culture conditions. The anti‐steatotic effect of turofexorate isopropyl (XL‐335) and metformin was tested, and both drugs showed different action mechanisms. In addition, the oxidative stress induced by lipid absorption was evaluated. Our results demonstrate the potential of the gut–liver chip for use as a novel, physiologically realistic in vitro model to study fatty liver disease.

The nuclear receptor (FXR) plays essential roles in maintaining bile acid and lipid homeostasis by regulating diverse target genes. And its agonists were promising agents for treating various liver diseases. Nevertheless, the potential side effect of chronic FXR activation by specific agonists is not fully understood. In this study, we investigated the mechanism of FXR agonist WAY-362450 induced liver enlargement during treating liver diseases. We demonstrated that chronic ingestion of WAY-362450 induced liver hypertrophy instead of hyperplasia in mouse. Global transcriptional pattern was also examined in mouse livers after treatment with WAY-362450 by RNA-seq assay. Through GO and KEGG enrichment analyses, we demonstrated that the expression of Cyclin D1 (Ccnd1) among the cell cycle-regulating genes was notably increased in WAY-362450-treated mouse liver. Activation of FXR-induced Ccnd1 expression in hepatocyte in a time-dependent manner in vivo and in vitro. Through bioinformatics analysis and ChIP assay, we identified FXR as a direct transcriptional activator of Ccnd1 through binding to a potential enhancer, which was specifically active in livers. We also found active histone acetylation was essential for Ccnd1 induction by FXR. Thus, our study indicated that activation of FXR-induced harmless liver hypertrophy with spatiotemporal modulation of Ccnd1. With a better understanding of the mechanism of tissue-specific gene regulation by FXR, it is beneficial for development and appropriate application of its specific agonist in preventing hepatic diseases.