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.
Highlights
Cardiovascular diseases are the major cause of morbidity and mortality in patients with type 2 diabetes (T2D)
Taking advantage of the cannabinoid-1 receptor (CB1R)-inactive stereoisomer (R)-MRI-1867, which retains the inducible nitric oxide synthase (iNOS) inhibitory activity, and JD-5037, a peripherally restricted CB1R antagonist, we further demonstrate that underlying mechanisms involve a CB1R-dependent reduction in VLDL assembly and an iNOS-dependent reduction of proprotein convertase subtilisin kexin 9 (PCSK9) activity associated with a restoration in hepatic LDL receptor (LDLR) levels
Dyslipidemia in patients with T2D significantly increases the risk of cardiovascular diseases, and T2D prevalence has increased by 31% worldwide from 2005 to 2015, rendering this disease and its metabolic sequelae an important public health issue [33]
Summary
Animal Experimentation Official French regulations for the use and care of laboratory animals were followed throughout the experiments. This was in agreement with earlier findings [21] indicating that HFD-induced increase in hepatic glucose production is due to a CB1R-mediated increase in glycogenolysis, resulting in reduced hepatic glycogen content These differences were associated with lower levels of the hepatic injury markers ALT and AST (Supplementary Fig. 1D), suggesting that (S)-MRI-1867 reverses obesity-induced hepatocyte injury. Compared with vehicle-treated controls, (S)-MRI-1867–treated mice had higher levels of plasma free fatty acids and similar plasma TGs and lower total cholesterol concentration (Fig. 1E)—indicators of altered plasma lipoprotein profile. This was further associated with a marked decrease in the plasma levels of apoB100, the primary apolipoprotein present in lipoproteins, in (S)-MRI-1867–treated mice (Fig. 1F). LDL was strongly reduced, while HDL was only slightly modified, leading to a much higher HDL–to–LDL cholesterol ratio in the (S)-MRI-1867–treated group compared with the vehicle-treated group (Fig. 1F)
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