Oral administration of a new HRI activator as a new strategy to improve high‐fat‐diet‐induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia through FGF21

Abstract

Background and Purpose FGF21 has emerged as a therapeutic strategy for treating type 2 diabetes mellitus due to its antidiabetic effects, and this has led to the development of long‐acting analogues of FGF21. However, these compounds have some limitations, including a need to be administered by s.c. injection and their prolonged pharmacodynamic effect compared with native FGF21, which might be responsible for their reported side effects. Experimental Approach We have previously demonstrated that i.p. administration of haem‐regulated eukaryotic translation initiation factor 2α kinase (HRI) activators increases hepatic and circulating levels of FGF21. In this study, we examined the effects of p.o. administration of a new HRI activator, EPB‐53, on high‐fat diet (HFD)‐induced glucose intolerance, hepatic steatosis, and hypertriglyceridaemia, and compared them with those of metformin. Key Results EPB‐53 administration for the last 2 weeks, to mice fed a HFD for 10 weeks, reduced body weight gain, improved glucose intolerance, and prevented hepatic steatosis and hypertriglyceridaemia, whereas metformin only ameliorated glucose intolerance. Moreover, EPB‐53, similar to the reported effects of FGF21, reduced lipogenesis in cultured human hepatocytes and in the liver of mice fed a HFD. Administration of EPB‐53 to Fgf21‐knockout mice had no effects, demonstrating that its efficacy is dependent on this hormone. Conclusions and Implications Overall, the findings of this study demonstrate that p.o. administration of HRI activators, by increasing FGF21, is a promising strategy for the treatment of type 2 diabetes mellitus and non‐alcoholic fatty liver disease.

Novel Pentafluorosulfanyl-containing Triclocarban Analogs selectively kill Gram-positive bacteria

“…In turn, the intermediate phenyl isocyanates were either commercially available or synthesized in situ from the reaction of the precursor anilines with triphosgene. The analytical data of the compounds fully agreed with the data previously reported (5, 12, 13).…”

“…The eighteen N,N’ -diarylureas evaluated in this work were synthesized following a simple and straightforward procedure consisting of the coupling of phenyl isocyanates with the corresponding anilines, as previously described by some of us reported (5, 12, 13) ( Fig 1 ). In turn, the intermediate phenyl isocyanates were either commercially available or synthesized in situ from the reaction of the precursor anilines with triphosgene.…”

Targeting FGF21 for the Treatment of Nonalcoholic Steatohepatitis

“…Oral administration of HRI activators increases FGF21 levels, ameliorates glucose intolerance and prevents liver steatosis and the increase in serum transaminases in wildtype mice fed an HFD, whereas no changes were observed in FGF21-null mice [71].…”

Polysaccharides isolated from Cordyceps Sinensis contribute to the progression of NASH by modifying the gut microbiota in mice fed a high-fat diet

“…Surprisingly, we found that the TG concentration of CSP-treated mice was notably higher than that of HFD-fed mice (Fig 3D). Accumulating evidence has shown that an abnormally high level of TG is characteristic of NASH [36,37]. Furthermore, we checked the expression of genes related to the de novo synthesis of endogenous fatty acids, including Srebp-1c and FAS [38][39][40].…”