Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms.

Diabetes
Célia RogerTony Jourdan

Abstract

Diabetic dyslipidemia, characterized by increased plasma triglycerides and decreased HDL cholesterol levels, is a major factor contributing to nonalcoholic steatohepatitis and cardiovascular risk in type 2 diabetes. Activation of the cannabinoid-1 receptor (CB1R) and activation of inducible nitric oxide synthase (iNOS) are associated with nonalcoholic steatohepatitis progression. Here, we tested whether dual-targeting inhibition of hepatic CB1R and iNOS improves diabetic dyslipidemia in mice with diet-induced obesity (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 that 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 and the rate of hepatic VLDL secretion, upregulated hepatic LDLR expression, and reduced the circulating levels of 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 ...Continue Reading

References

May 6, 2003·Nature Genetics·Marianne AbifadelCatherine Boileau
Jun 11, 2005·Arteriosclerosis, Thrombosis, and Vascular Biology·Martin AdielsMarja-Riitta Taskinen
Jul 5, 2005·Journal of Lipid Research·John S MillarJeffrey T Billheimer
Jul 20, 2006·American Journal of Physiology. Endocrinology and Metabolism·Marion A M den BoerLouis M Havekes
Sep 14, 2006·Pharmacological Reviews·Pál PacherGeorge Kunos
Apr 9, 2008·Oncogene·D N GrossM J Birnbaum
May 24, 2008·The Journal of Clinical Investigation·Adama KamagateH Henry Dong
Oct 12, 2011·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Tony JourdanPascal Degrace
Mar 20, 2012·The Journal of Clinical Investigation·Ding AiAlan R Tall
Jun 26, 2013·The New England Journal of Medicine·Rena R WingSusan Z Yanovski
Jul 25, 2013·Journal of Lipid Research·Rongya TaoX Charlie Dong
May 28, 2014·BioMed Research International·Yu WangDana T Graves
Mar 3, 2015·Diabetologia·Bruno Vergès
Dec 1, 2015·The Journal of Clinical Investigation·Pierre-Damien DenechaudLluis Fajas
Mar 15, 2016·Cell·Lynne ChantranupongDavid M Sabatini
Mar 26, 2016·Cell·James E Hughes Hallett, Brendan D Manning
Aug 4, 2016·Nature·Robert A SaxtonDavid M Sabatini
Sep 7, 2016·The Journal of Clinical Investigation·Donna M ConlonHenry N Ginsberg
Feb 9, 2017·Clinical Research in Cardiology Supplements·Rainer Schulz, Klaus-Dieter Schlüter
Mar 23, 2017·American Journal of Physiology. Endocrinology and Metabolism·Tania MullerPascal Degrace
Jun 27, 2017·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Maggie LindAnthony Zulli
Jul 29, 2017·Methods in Molecular Biology·Marcela Aparicio-VergaraMyriam Aouadi
Dec 1, 2017·Journal of Endocrinological Investigation·M G RadaelliG Perseghin
Nov 8, 2018·The New England Journal of Medicine·Gregory G SchwartzUNKNOWN ODYSSEY OUTCOMES Committees and Investigators
Dec 5, 2019·Nature Biotechnology·Cormac Sheridan
Jan 12, 2020·Pharmacology & Therapeutics·Resat CinarGeorge Kunos

❮ Previous
Next ❯

Citations

Sep 23, 2020·Diabetes·Vishal Kothari, Karin E Bornfeldt
Jul 27, 2021·Frontiers in Endocrinology·Myriam Dao, Helene François
Jul 30, 2021·Clinical and Translational Medicine·Resat CinarMay Christine V Malicdan
Aug 28, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Luis Santos-MolinaGrzegorz Godlewski

❮ Previous
Next ❯

Related Concepts

Related Feeds

American Diabetes Association Journals

Discover the latest diabetes research published by the journals from the American Diabetes Association.