Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Bátkai S, Marsicano G, Lutz B, Buettner C, Kunos G. Hepatic CB 1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 2008;118:3160–3169. (Reprinted with permission.)
Diet-induced obesity is associated with fatty liver, insulin resistance, leptin resistance, and changes in plasma lipid profile. Endocannabinoids have been implicated in the development of these associated phenotypes, because mice deficient for the cannabinoid receptor CB(1) (CB1(−/−)) do not display these changes in association with diet-induced obesity. The target tissues that mediate these effects, however, remain unknown. We therefore investigated the relative role of hepatic versus extrahepatic CB(1) receptors in the metabolic consequences of a high-fat diet, using liver-specific CB(1) knockout (LCB1(−/−)) mice. LCB1(−/−) mice fed a high-fat diet developed a similar degree of obesity as that of wild-type mice, but, similar to CB1(−/−) mice, had less steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance than did wild-type mice fed a high-fat diet. CB(1) agonist-induced increase in de novo hepatic lipogenesis and decrease in the activity of carnitine palmitoyltransferase-1 and total energy expenditure were absent in both CB1(−/−) and LCB1(−/−) mice. We conclude that endocannabinoid activation of hepatic CB(1) receptors contributes to the diet-induced steatosis and associated hormonal and metabolic changes, but not to the increase in adiposity, observed with high-fat diet feeding. Theses studies suggest that peripheral CB(1) receptors could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia in order to minimize the neuropsychiatric side effects of nonselective CB(1) blockade during treatment of obesity-associated conditions.
Liver steatosis in patients without significant alcohol consumption (nonalcoholic fatty liver disease [NAFLD]) is the leading cause of elevated liver enzymes worldwide and is associated with greatly increased health care use and costs.1 The clinical spectrum of NAFLD ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) with inflammatory cell infiltration, eventually resulting in liver cirrhosis in a significant proportion of patients. Histologically, NAFLD is characterized by the accumulation of triglycerides within hepatocytes.2 In most patients, liver steatosis is associated with obesity, insulin resistance, and hypertension (i.e., features of the so-called metabolic syndrome). Therefore, NAFLD has been widely considered as the hepatic manifestation of the metabolic syndrome.
Although much work has been performed to better define the pathophysiological events leading to liver steatosis, the important role of the endocannabinoid system in NAFLD and other liver diseases has only recently been appreciated. Endocannabinoids are endogenous ligands of cannabinoid receptors in numerous mammalian tissues. The best-characterized cannabinoid receptors are the CB1 and CB2 receptors, which differ in their tissue distribution. These receptors are faintly or not expressed in normal human liver but are substantially up-regulated in parenchymal and nonparenchymal cells upon liver injury of different etiologies. Accordingly, endocannabinoids have been convincingly implicated in liver diseases, including inflammation, fibrogenesis, vascular complications, and neurologic dysfunctions.3
The hepatic CB1 receptor has now been functionally associated with hepatic steatosis. It has already been shown that CB1 knockout mice are resistant to diet-induced obesity even though their caloric intake is similar to that of wild-type mice, suggesting that endocannabinoids also regulate fat metabolism.4 Furthermore, activation of CB1 increases intrahepatic gene expression of the lipogenic transcription factor SREBP-1c and its targets acetyl-CoA carboxylase-1 and fatty acid synthase in mice. A high-fat diet, commonly used to induce obesity and steatosis in mice, increases the hepatic levels of the endocannabinoid anandamide, the CB1 expression in the liver, and the basal rates of fatty acid synthesis.5 However, it is not yet clear whether the effects of endocannabinoids on hepatic steatosis and obesity are regulated by hepatic or extrahepatic endocannabinoid receptors. This important question has now been elegantly addressed by generating hepatocyte-specific CB1 (CB1Δhepa) knockout mice.6 Kunos and colleagues have used the Cre recombinase driven by the mouse albumin promoter to generate mice with a hepatocyte-specific knockout of the CB1 receptor (CB1Δhepa). These mice express normal levels of CB1 receptor in all tissues except the liver. The main results of the study are that CB1Δhepa mice fed a high-fat diet develop a similar degree of obesity as wild-type mice, but have less liver steatosis, hyperglycemia, dyslipidemia, and insulin and leptin resistance. Functionally, a CB1 agonist induced an increase in hepatic lipogenesis and a decrease in the activity of carnitine palmitoyltransferase-1 and total energy expenditure in wild-type mice. These effects were absent in CB1−/− and CB1Δhepa mice.6 Of note, the same group has recently demonstrated that hepatic CB1 receptors are also needed for ethanol-induced steatosis. After ethanol feeding, hepatic stellate cells, a resident liver fibrogenic cell type, generated steatosis through production of the endocannabinoid 2-arachidonoylglycerol with paracrine stimulation of hepatocyte CB1 receptors7 (Fig. 1). This liver phenotype of CB1Δhepa mice perfectly fits with the current knowledge that enndocannabinoids act on their receptors only locally, possibly because of their high lipophilicity, and are immediately inactivated under physiological conditions.8 Therefore, the effects of endocannabinoids on liver steatosis indeed seem to be primarily located within hepatocytes.
What might be the clinical perspectives of these intriguing new findings? The endocannabinoid system has gained a lot of interest in recent years as selective antagonists of CB1 receptors (rimonabant, taranabant) are actively evaluated for treatment of obesity-related organ damage. However, the usefulness of these drugs is limited due to neurological and psychiatric side effects due to antagonism of neuronal CB1 receptors.9 Therefore, the development of CB1 antagonists with high tissue specificity would be an important step forward to circumvent these limitations. The current animal studies further enforce this fascinating concept. Nevertheless, it should be taken into account that with respect to the progression of liver disease, hepatic steatosis alone seems to be less important than the development of NASH.10 In epidemiological studies, only patients with NASH and progressive liver disease have increased overall and liver-related mortality and would therefore be primary candidates of antisteatotic treatment.11 However, although rimonabant has been shown to be effective in ameliorating diet-induced NASH in an aminal model12 and is effective in reducing toxically induced liver fibrosis,13 the importance of the local liver-related endocannabinoid system for NASH has not yet been formally proven in vivo. This seems especially important, because the CB2 receptor is more abundant in immune cells, which play an important role in the development of NASH.14
In conclusion, the study by Osei-Hyiaman and colleagues represents an important step forward in our understanding of liver steatosis and the role of endocannabinoid in its pathophysiology. As liver steatosis is the most common liver disease worldwide with increasing prevalence, this new information will help to better define specific molecular targets to treat this condition and prevent its potential complications.