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

Autor: George Kunos, Pascal Degrace, Resat Cinar, Patricia Passilly-Degrace, Malliga R. Iyer, Tania Muller, Bruno Vergès, Julia Leemput, Chloé Buch, Célia Roger, Laurent Demizieux, Tony Jourdan
Přispěvatelé: Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, National Institute on Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health [Bethesda] (NIH), Jourdan, Tony
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Male
Very low-density lipoprotein
Endocrinology
Diabetes and Metabolism
Nitric Oxide Synthase Type II
[SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
[SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
Mice
0302 clinical medicine
Receptor
Cannabinoid
CB1
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
Receptor
[SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Cells
Cultured
[SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
biology
[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biomolecules [q-bio.BM]
Nitric oxide synthase
Liver
[SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Kexin
lipids (amino acids
peptides
and proteins)
medicine.medical_specialty
[SDV.OT]Life Sciences [q-bio]/Other [q-bio.OT]
Lipoproteins
Immunoblotting
030209 endocrinology & metabolism
Real-Time Polymerase Chain Reaction
03 medical and health sciences
Internal medicine
Commentaries
Internal Medicine
medicine
Animals
Obesity
[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Biochemistry [q-bio.BM]
Dyslipidemias
business.industry
[SDV.OT] Life Sciences [q-bio]/Other [q-bio.OT]
PCSK9
nutritional and metabolic diseases
[SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry
Molecular Biology/Molecular biology
medicine.disease
Lipid Metabolism
[SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology
Mice
Inbred C57BL
030104 developmental biology
Endocrinology
Glucose
LDL receptor
biology.protein
Hepatocytes
[SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology
Steatosis
business
Dyslipidemia
Zdroj: Diabetes
Diabetes, American Diabetes Association, 2020, pp.db200078. ⟨10.2337/db20-0078⟩
ISSN: 0012-1797
1939-327X
DOI: 10.2337/db20-0078⟩
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: