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Download fileSimultaneous inhibition of peripheral CB1R and iNOS mitigates obesity-related dyslipidemia through distinct mechanisms
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posted on 2020-08-24, 16:43 authored by Ada AdminAda 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 JourdanDiabetic
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.