It is also remarkable that, under conditions promoting FA utiliza

It is also remarkable that, under conditions promoting FA utilization, SR141716 tended to strengthen FA catabolism (Fig. 2, black column 3). Taken together, these data suggested that CB1R blockade improved carbohydrate and FA catabolism, according to the operating metabolic pathway. The stimulatory effect of SR141716 on carbohydrate metabolism revealed by respiration measurements was associated with an increased expression of glucokinase (GLCK), which catalyzes glucose phosphorylation and controls glycolytic flux26 (Fig. 3A). These findings were associated with a slight overexpression of sterol regulatory element-binding protein (SREBP-1) and with a concomitant increase in cellular triacylglycerol (TG) content, whereas the expression

of the two isoforms of acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) remained unchanged (Fig. 3A,B). Sorafenib price Besides, fatty acid translocase (FAT/CD36)

mRNA levels were increased by SR141716, suggesting that TG accumulation could result from FA uptake, rather from de novo lipogenesis. Interestingly, hyperactivation of ECS by AEA treatment induced both a strong increase in SREBP-1 expression and in genes related to lipogenesis (e.g., ACC, FAS, and GLCK) that was suppressed by the presence of SR141716 (Fig. 3A). To address the role of CB1R antagonism on cholesterol de novo synthesis, we tested the effects of SR141716 in the presence of atorvastatin as a potent inhibitor of hydroxymethylglutaryl-coenzyme A reductase (HMG-CoA red), Fulvestrant order the enzyme responsible for the first step of cholesterol MCE公司 synthesis. Cholesterol content was increased by SR141716, whereas treatment with atorvastatin tended to decrease it (P < 0.185) (Fig. 4A. It is noteworthy that SR141716 failed to increase cholesterol hepatocyte content in the presence of atorvastatin. Because another possible source of cholesterol for hepatocytes could be HDL, we also measured the effect of CB1R blockade on HDL-CE uptake. We showed that HDL-CE uptake was significantly increased in explants treated with SR141716 (Fig. 4B). Concomitantly, variations of intracellular cholesterol contents induced by SR141716

were associated with an increased expression of HMG-CoA red, whereas scavenger receptor class B type 1 (SR-B1) and hepatic lipase (HL) mRNA levels were reduced (Fig. 4C). All together, these biochemical and molecular data suggested the existence of interrelations between cholesterol metabolism and CB1R signaling. In line with an improvement of FA catabolism by SR141716 (Fig. 2), we observed that CB1R blockade increased the capacity of liver explants to ß-oxidize palmitic acid (Fig. 5A). On the other hand, when explants were treated with AEA to hyperactivate ECS and, therefore, approach the physiological conditions encountered in the liver of obese subjects, palmitic acid oxidation was decreased by 30%, compared to control, whereas cotreatment of liver explants with AEA and SR141716 normalized oxidation rates (Fig. 5A).

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