Simultaneous inhibition of peripheral CB1R and iNOS mitigates obesity-related dyslipidemia through distinct mechanisms

Diabetic dyslipidemia (DD), characterized by increased plasma triglycerides (TGs) and decreased high-density lipoprotein cholesterol (HDL) levels, is a major factor contributing to non-alcoholic steatohepatitis (NASH) and cardiovascular risk in type-2 diabetes. Activation of both the cannabinoid-1 receptor (CB1R) and inducible nitric oxide synthase (iNOS) are associated with NASH progression. Here, we tested whether dual-targeting inhibition of hepatic CB1R and iNOS improves DD in diet-induced obese (DIO) mice. DIO mice were treated for 14 days with (S)-MRI-1867, a peripherally-restricted hybrid inhibitor of CB1R and iNOS. (R)-MRI-1867, the CB1R-inactive stereoisomer which retains iNOS inhibitory activity and JD-5037, a peripherally-restricted CB1R antagonist were used to assess the relative contribution of the two targets to the effects of (S)-MRI-1867. (S)-MRI-1867 reduced hepatic steatosis, the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression and reduced the circulating levels of the proprotein convertase subtilisin/kexin type 9 (PCSK9). The decrease in VLDL secretion could be attributed to CB1R blockade while the reduction of PCSK9 levels and the related increase in LDLR resulted from iNOS inhibition via a mTORC1-dependent mechanism. In conclusion, this approach based on the concomitant inhibition of CB1R and iNOS represents a promising therapeutic strategy for the treatment of dyslipidemia.