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Pathophysiology

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

  1. Célia Roger1,
  2. Chloé Buch1,
  3. Tania Muller1,
  4. Julia Leemput1,
  5. Laurent Demizieux1,
  6. Patricia Passilly-Degrace1,
  7. Resat Cinar2,
  8. Malliga R. Iyer2,
  9. George Kunos2,
  10. Bruno Vergès1,
  11. Pascal Degrace1 and
  12. Tony Jourdan1⇑
  1. 1INSERM Lipids, Nutrition, Cancer (LNC) UMR1231, Team PADYS, University of Burgundy and Franche-Comté, Dijon, France
  2. 2Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
  1. Corresponding author: Tony Jourdan, tony.jourdan{at}u-bourgogne.fr
Diabetes 2020 Oct; 69(10): 2120-2132. https://doi.org/10.2337/db20-0078
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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 iNOS inhibition via an mTOR complex 1–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.

Footnotes

  • See accompanying article, p. 2061.

  • This article contains supplementary material online at https://doi.org/10.2337/figshare.12620075.

  • Received January 21, 2020.
  • Accepted July 5, 2020.
  • © 2020 by the American Diabetes Association
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Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms
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
Diabetes Oct 2020, 69 (10) 2120-2132; DOI: 10.2337/db20-0078

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Simultaneous Inhibition of Peripheral CB1R and iNOS Mitigates Obesity-Related Dyslipidemia Through Distinct Mechanisms
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
Diabetes Oct 2020, 69 (10) 2120-2132; DOI: 10.2337/db20-0078
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