In fact, the regulation of hepatic endocannabinoids by circulating leptin is still unclear. In the hypothalamus, it has been observed that, in contrast to an inhibition of food intake by leptin, CB1 cannabinoid receptors and endocannabinoids stimulate food intake.25 In other words, endocannabinoids appear to be under negative control by leptin in hypothalamus.25 Pembrolizumab mw Interestingly, we found that acute intraportal infusion of leptin significantly increases hepatic endocannabinoid production and IHR in NASH cirrhotic rat livers. Furthermore, inactivation of Kupffer cells by pretreatment with GdCl3 attenuated the leptin-related increase

in hepatic endocannabinoid levels and IHR in HF/MCD-Zucker and HF/MCD+leptin-lean rats with NASH cirrhotic livers. Our study is the first to report the occurrence of the leptin-induced activation of endocannabinoids in rat livers. Hepatic microsomal cytochrome P450 (CYP2E1) can be activated by hyperleptinemia and the HF/MCD diet in rats with steatohepatitis.18-20 A recent study reported a link between cytochrome P450 enzyme and the endocannabinoid system.20 GdCl3 has an inhibitory effect on hepatic cytochrome P450, which mediates liver endocannabinoid metabolism.20, 26 In

our study we tried to clarify whether pretreatment with GdCl3 is able to simultaneously modulate hepatic endocannabinoids and the cytochrome P450 system. Pretreatment with GdCl3 significantly

attenuated the leptin-induced increase in endocannabinoid production without modification of CYP2E1 activity and protein expression Buparlisib supplier in our Zucker rat livers. In fact, it has been reported that hepatic CYP3A, rather than CYP2E1, is involved in the interaction between cytochrome P450 and the endocannabinoids system.20 Specifically, the role of cytochrome P450 in leptin-induced endocannabinoid production needs to be clarified by measuring another subfamily of cytochrome P450 such as CYP3A. Taken together, the leptin-induced increase in endocannabinoid production was found STK38 to be independent of the overexpression of hepatic microsomal CYP2E1 in our NASH rats. We found in the present study that there was a concomitant increases in leptin, TGF-β1, and endothelin-1 in NASH cirrhotic rat livers (both in HF/MCD-Zucker and HF/MCD+leptin-lean rat livers). In adipocytes, hepatic stellate, and endothelial cells, leptin and TGF-β1 have been found to strongly increase endothelin-1 mRNA and protein expression.27-29 Moreover, obesity-induced up-regulation of myocardial endothelin-1 expression is also mediated by leptin.30 In other words, a positive feedback amplification loop between endothelin-1 and leptin secretion is already known to exist.28, 29 As was found in our study, an increase in hepatic endothelin-1 production is one of the important characteristics of cirrhotic rats with hyperleptinemia.