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

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posted on 24.08.2020 by Ada Admin, Célia Roger, Chloé Buch, Tania Muller, Julia Leemput, Laurent Demizieux, Patricia Passilly-Degrace, Resat Cinar, Malliga R Iyer, George Kunos, Bruno Vergès, Pascal Degrace, Tony Jourdan
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.

Funding

This work was supported by the INSERM (Institut National de la Santé et de la Recherche Médicale, the University of Bourgogne-Franche Comté, by a French Government grant managed by the French National Research Agency (ANR) under the program “Investissements d’Avenir” with the reference ANR-11-LABX-0021-01-LipSTIC LabEx and a grant (2019-Y-10658) from the “Région Bourgogne-Franche-Comté” to TJ.

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