The very low-density lipoprotein receptor (VLDLR) plays an important role in the development of hepatic steatosis. In this study, we investigated the role of Peroxisome Proliferator-Activated Receptor (PPAR)β/δ and fibroblast growth factor 21 (FGF21) in hepatic VLDLR regulation. Studies were conducted in wild-type and Pparβ/δ-null mice, primary mouse hepatocytes, human Huh-7 hepatocytes, and liver biopsies from control subjects and patients with moderate and severe hepatic steatosis. Increased VLDLR levels were observed in liver of Pparβ/δ-null mice and in Pparβ/δ-knocked down mouse primary hepatocytes through mechanisms involving the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI), activating transcription factor (ATF) 4 and the oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathways. Moreover, by using a neutralizing antibody against FGF21, Fgf21-null mice and by treating mice with recombinant FGF21, we show that FGF21 may protect against hepatic steatosis by attenuating endoplasmic reticulum (ER) stress-induced VLDLR upregulation. Finally, in liver biopsies from patients with moderate and severe hepatic steatosis, we observed an increase in VLDLR levels that was accompanied by a reduction in PPARβ/δ mRNA abundance and DNA-binding activity compared with control subjects. Overall, these findings provide new mechanisms by which PPARβ/δ and FGF21 regulate VLDLR levels and influence hepatic steatosis development.

Fibroblast growth factor 21 (FGF21), a peptide hormone with pleiotropic effects on carbohydrate and lipid metabolism, is considered a target for the treatment of diabetes. We investigated the role of peroxisome proliferator–activated receptor (PPAR) β/δ deficiency in hepatic FGF21 regulation. Increased Fgf21 expression was observed in the livers of PPARβ/δ-null mice and in mouse primary hepatocytes when this receptor was knocked down by small interfering RNA (siRNA). Increased Fgf21 was associated with enhanced protein levels in the heme-regulated eukaryotic translation initiation factor 2α (eIF2α) kinase (HRI). This increase caused enhanced levels of phosphorylated eIF2α and activating transcription factor (ATF) 4, which is essential for Fgf21-induced expression. siRNA analysis demonstrated that HRI regulates Fgf21 expression in primary hepatocytes. Enhanced Fgf21 expression attenuated tunicamycin-induced endoplasmic reticulum stress, as demonstrated by using a neutralizing antibody against FGF21. Of note, increased Fgf21 expression in mice fed a high-fat diet or hepatocytes exposed to palmitate was accompanied by reduced PPARβ/δ and activation of the HRI-eIF2α-ATF4 pathway. Moreover, pharmacological activation of HRI increased Fgf21 expression and reduced lipid-induced hepatic steatosis and glucose intolerance, but these effects were not observed in Fgf21-null mice. Overall, these findings suggest that HRI is a potential target for regulating hepatic FGF21 levels.

Concerns have been raised about the long-term accumulating effects of triclocarban, a polychlorinated diarylurea widely used as an antibacterial soap additive, in the environment and in human beings. Indeed, the Food and Drug Administration has recently banned it from personal care products. Herein, we report the synthesis, antibacterial activity and cytotoxicity of novel N,N′-diarylureas as triclocarban analogs, designed by reducing one or more chlorine atoms of the former and/or replacing them by the novel pentafluorosulfanyl group, a new bioisostere of the trifluoromethyl group, with growing importance in drug discovery. Interestingly, some of these pentafluorosulfanyl-bearing ureas exhibited high potency, broad spectrum of antimicrobial activity against Gram-positive bacterial pathogens, and high selectivity index, while displaying a lower spontaneous mutation frequency than triclocarban. Some lines of evidence suggest a bactericidal mode of action for this family of compounds.

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.

In recent years, N,N’ -diarylureas have emerged as a promising chemotype for the treatment of schistosomiasis, a parasite-caused disease that poses a considerable health burden to millions of people worldwide. Here, we report a novel series of N,N’ -diarylureas featuring the scarcely explored pentafluorosulfanyl group (SF ₅ ).