| Abstract|| |
Non alcoholic steatohepatitis (NASH) has gained a lot of attention recently due to the increased prevalence of diabetes, obesity, and hyperlipedemia. The endogenous compounds, endocannabinoids (ECBs), bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. Recently, two G-proteins coupled, and specific receptors, to cannabinoids, CB1 & CB2, which act via adenylate cyclase and calcium channels, were described. In this brief review, we shed light on the possible relation between NASH and these proteins. It has been hypothesized that ECBs regulate peripheral lipogenesis. Some studies suggest that in CB1-deficient mice there is complete resistance to the development of dietinduced hepatic steatosis, while wild-type mice showed remarkable hepatic steatosis after 3 and 14 weeks of high-fat diet. Based on these results and others, the hepatic ECB system may be a target for the treatment of NASH. The CB1 antagonist, Rimonabant, will shortly be approved for the treatment of obesity and may thus reduce the necessity for bariatric surgery.
|How to cite this article:|
Helmy A. Endocannabinoids and non-alcoholic steatohepatitis. Saudi J Gastroenterol 2006;12:36-7
The endogenous compounds, endocannabinoids (ECBs), bind to the same receptors as tetrahydrocannabinol, the active component in marijuana and hashish. Cannabis has been used for psychoactive and recreational purposes as well as in traditional medicine, long before the advent of modern medicine and scientific research. , In addition, the appetite stimulating effects of Cannabis sativa ingredients have been known since ancient times.  Tetra-hydro-cannabinol, the active component of cannabis, was discovered in 1964 . This finding led to the discovery of two G-proteins coupled, and specific receptors, to cannabinoids, CB1 & CB2, which act via adenylate cyclase and calcium channels. The CB1 receptor was discovered initially in the brain and subsequently in the gut and vascular endothelium, ,,, while the CB2 receptor was isolated primarily in the immune system.  Anandamide, the first endogenous ligand for these receptors was found in 1992.  Over the last decade, ECBs were closely linked to the pathogenesis of many liver diseases [Table 1]. This was reviewed elsewhere. 
| ECBs and Hepatic Lipogenesis & Steatosis:|| |
The liver plays a major role in de novo lipogenesis. Based on this fact, a recent study in CB1 deficient mice, by Osei-Hyaiman et al, investigated the role of hepatic CB1 receptors in diet-induced obesity . One of the most remarkable findings of this study is that CB1-deficient mice were completely resistant to the development of diet-induced hepatic steatosis, while wild-type mice showed remarkable hepatic steatosis after 3 and 14 weeks of high-fat diet. In addition, CB1-deficient mice showed no significant increase in body weight or levels of triglycerides, insulin, and leptin, as well as no significant decrease of adiponectin.What further strengthens the hypothesis that ECBs regulate peripheral lipogenesis is that the development of hepatic steatosis in wild-type mice was not due to higher food intake. In comparison to CB1-deficient mice, wild-type mice showed an approximate 3-fold induction of hepatic fatty acid synthesis, >3-fold upregulated hepatic levels of anandamide, These elevations were not caused by an increased synthesis of anandamide, but by a decrease in anandamide degradation by the enzyme fatty acid amide hydrolase. The authors provided further evidence for the role of hepatic CB1 receptors in hepatic steatosis by stimulating wild-type mice with a specific CB1 agonist, HU210. This stimulation lead to increased hepatic and hypothalamic expression of the genes of the key regulators of fat metabolism, namely the transcription factor SREBP-1c and its targets, acetyl coenzyme-A carboxylase, and fatty acid synthase. In addition, CB1 stimulation produced a 2-fold increase in hepatic fat synthesis. The figure illustrates the current understanding of role of ECB system in hepatic lipogenesis, and provides two potential sites of interrupting this pathway as a potential future therapy of hepatic steatosis; 1) via inhibiting the CB1 receptor; and 2) via stimulating the fatty acid amid hydrolase enzyme.
| The future|| |
Based on the results of the study by Osei-Hyaiman et al , the hepatic ECB system may be a target for the treatment of nonalcoholic steatohepatitis (NASH). The CB1 antagonist, Rimonabant, will shortly be approved for the treatment of obesity and may thus reduce the necessity for bariatric surgery. Rimonabant may also provide a second pharmacotherapeutic option for NASH, in addition to the thiazolidinediones, and thus prevents NASH complications. However, the role of the ECB system in the normal and injured liver warrants further human investigations to judge the safety and potential adverse effects of blocking or stimulating the CB1 receptors. Synthetic, non-psychotropic ECBs will be more socially and legally accepted and better tolerated. Future studies on humans assessing the expression of ECB agonists in humans with steatohepatitis, and therapeutic role of ECB antagonism in these patients are awaited.
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Department of Liver Transplantation, Hepatobiliary & Pancreatic Surgery, King Faisal Specialist Hospital & Research Center (KFSH&RC), MBC: 72, PO Box: 3354, Riyadh 11211
Source of Support: None, Conflict of Interest: None
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