38 The stimulation of HDL-C uptake by SR141716 is in contrast with human and rodent in vivo studies reporting that CB1R blockade was associated with increased HDL-C levels.6, 9, 10 Nevertheless, plasma HDL-C also depends on cholesterol efflux from cells and tissues, and recent works have indicated that CB1R antagonism might increase cholesterol efflux39 and thereby HDL-C. Taken together, these
data suggest that CB1R blockade may improve reverse-cholesterol transport, Deforolimus molecular weight inducing both cholesterol efflux and removal. Importantly, it also emerged from the present study that the ECS has a major role in the regulation of liver FA oxidation. Indeed, when experimental conditions were set to force the utilization of FA as a substrate, CB1R antagonism led to an increase in oxygen consumption, likely resulting from a stimulation of FA oxidation. This assumption is supported by the current selleck chemicals llc findings that the selective inactivation of CB1R by SR141716 increased palmitic acid ß-oxidation, decreased cytosolic malonyl-CoA content, and increased CPT-I gene expression in liver explants. Because malonyl-CoA is a strong inhibitor
of CPT-I activity,40, 41 it could be assumed that the penetration of FA into mitochondria is facilitated. The regulation process likely involves the phosphorylation and inactivation of ACC, which catalyzes the transformation of acetyl-CoA to malonyl-CoA, as suggested by the stimulatory effect of SR141716 on p-AMPK.42 Our results are consistent with others showing that treatment with a CB1R antagonist stimulates CPT-I activity
in the liver of mice fed a standard diet,16 and with those of Watanabe et al., in which CB1R antagonism results in the phosphorylation of AMPK in ob/ob adipo−/− click here mice.43 Of particular note is the finding that antagonism of liver CB1R stimulates fat oxidation when carbohydrate utilization is limited. Such conditions are encountered in vivo in the fasting state and, particularly, in type II diabetes that is associated with excessive rise in plasma free FA.44 In line with this, direct evidence for an improvement of FA catabolism by CB1R blockade in the steatotic liver is provided by the present findings showing an increase in ß-oxidation activity in livers of diabetic ob/ob mice. Data relative to ß-oxidation activity also give information regarding the pharmacological action of SR141716. In liver slices from lean mice, endogenous EC production should be very low,27, 45 supporting the possibility that per se effect of SR141716 on ß-oxidation activity may be the result of inhibition of constitutive CB1R activity and/or to the inverse agonist action of the compound.