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Introduction/Overview

Cannabinoid receptor type 1 (CB₁ receptors) are present in a wide array of peripheral tissues including those involved in lipogenesis (liver and adipose tissue).^1-6 The CB₁ receptor is expressed in mouse hepatocytes and in primary cultures of human hepatic stellate cells.^{7, 8} Importantly, CB₁ receptor activation has been shown to enhance de novo lipogenesis in hepatocytes.^{7, 9} Both levels of the endocannabinoid anandamide and the density of CB₁ receptors are increased in the livers of diet-induced obese mice.⁷

Energy Balance and Metabolic Regulation

Peripheral Metabolic Regulation: Role of the ECS

Activation of the endocannabinoid system (ECS) in the liver appears to be an early step in the development of diet-induced obesity. This was shown in experiments in which wild-type and CB₁ receptor knockout mice were fed a high-fat diet.⁷ After 3 weeks, before obesity was detectable, hepatic anandamide levels were significantly elevated in both wild-type and CB₁ receptor knockout mice exposed to the high-fat diet as compared with mice receiving a standard diet. However, the increase was much smaller in the CB₁ receptor knockout mice.⁷ In addition to the increase in the levels of CB₁ receptor ligands, the expression of hepatic CB₁ receptor mRNA was increased.⁷ Other experiments by the same investigators showed that basal rates of hepatic fatty-acid synthesis were significantly increased in wild-type animals fed a high-fat diet for 3 weeks but not in CB₁ knockout mice receiving the same diet, and that this effect was blunted in wild-type mice, but not knockout mice, treated with a CB₁ receptor antagonist.⁷

In additional experiments, injection of mice with the CB₁ receptor agonist HU210 was associated with increased hepatic gene expression of the lipogenic transcription factor sterol regulatory element-binding protein (SREBP)-1c and its target enzymes acetyl coenzyme-A carboxylase-1 (ACC-1) and fatty acid synthase (FAS).⁷ These effects were blocked by pretreating the mice with the CB₁ receptor antagonist SR141716. Taken together, the results of these experiments indicate that, in the diet-induced obesity, activation of the ECS stimulates hepatic lipogenesis and suggests a role of the ECS in the regulation of fat metabolism.

Implications

The finding that an early, ECS-mediated increase in hepatic lipogenesis may be involved in the induction of dietary obesity suggests that CB₁ receptor antagonists may have therapeutic utility as antiobesity agents.⁷

Dyslipidemia

Lipid Metabolism: Role of the ECS

Data from studies conducted in rodent models demonstrate that the ECS acts directly in the liver to regulate hepatic lipogenesis.² First, activation of hepatic CB₁ receptors increases de novo fatty acid synthesis.⁷ One of the main molecular pathways for hepatic lipogenesis involves activation of the transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) and its associated enzymes, acetyl-CoA carboxylase-1 (ACC1) and fatty acid synthase (FAS).¹⁰ The role of the ECS in this pathway was demonstrated by Osei-Hyiaman and colleagues by using rodent models of diet-induced obesity and CB₁ receptor knockout mice.⁷ Activation of the CB₁ receptor with a potent receptor agonist (HU210) increased hepatic expression of SREBP-1c and its target enzymes, ACC1 and FAS, in wild-type mice fed standard chow (Figure 1).⁷ Second, the ECS can affect the activity of hepatic adenosine 5’-monophosphate-activated protein kinase (AMPK), which stimulates fatty acid oxidation.^{11, 12} Kola and colleagues demonstrated cannabinoid-induced inhibition of AMPK activity in rat liver, although in this case the involvement of cannabinoid CB₁ receptors was not demonstrated. In summary, these data suggest that ECS is an important regulator of hepatic fat metabolism and that ECS activation inhibits fatty acid oxidation and stimulates de novo lipogenesis in the liver.

Activation of these lipogenic enzymes was associated with a 2-fold increase in the rate of fatty acid synthesis.⁷ The role of the CB₁ receptor in mediating this effect was suggested because no increase was observed in CB₁ receptor knockout mice or in mice pretreated with the CB₁ receptor antagonist SR141716.⁷ Other studies have demonstrated that in the hypothalamus, where FAS inhibitors elicit anorexia, SREBP-1c and FAS expression were similarly affected by CB₁ receptor ligands.^{7, 13-15} These combined data suggest that the same molecular pathway is involved in the central ECS feeding effects and the peripheral ECS metabolic effects. Hepatic CB₁ receptor stimulation in vivo contributes to activation of the FAS lipogenic pathway, while CB₁ receptor blockade inhibits this effect.⁷

A high-fat diet also increased de novo hepatic fatty acid synthesis through activation of CB₁ receptors (Figure 2). The rate of incorporation of tritium (a radioactive isotope of hydrogen) to fatty acids in the liver was assayed in wild-type mice 15 minutes after placebo or 3 mg/kg SR141716. Animals were on normal or high-fat diets for 3 weeks prior to testing. The marked increase in hepatic fatty acid synthesis in wild-type mice was inhibited in the presence of SR141716 and was absent in CB₁ receptor knockout mice, further evidence that CB₁ receptors mediate this effect.⁷ Moreover, wild-type mice, but not CB₁ receptor knockout mice, on the high-fat diet became obese when exposed to a high-fat diet and developed fatty liver, despite similar levels of caloric intake between the two groups of mice.⁷

Implications

Nonalcoholic fatty liver disease is an important complication of obesity, because it can lead to severe liver disease and is associated with dyslipidemia (increased serum triglycerides and decreased serum high-density lipoprotein cholesterol concentration). Data from preclinical studies indicate that the CB₁ receptor is an important regulator of hepatic fat metabolism; ECS activation simultaneously inhibits fatty-acid oxidation and stimulates de novo lipogenesis in the liver. Therefore, the ECS may play an important role in the metabolic mechanisms responsible for obesity-induced nonalcoholic fatty liver disease and dyslipidemia (Figure 3).

Glucose Homeostasis

Glucose Metabolism and the Role of the ECS

The liver is the major source of endogenous glucose production,¹⁶ and insulin suppresses hepatic glucose output.¹⁷ Visceral adiposity contributes to an increased flux of free fatty acids (FFA) to the liver, which results in hepatic insulin resistance and, consequently, a failure of insulin to properly suppress glucose output.¹⁷ In addition, increased levels of circulating FFAs are correlated with reduced insulin sensitivity in muscle and adipose tissue.¹⁸

Implications

FFA release from adipose tissue is increased in the presence of obesity, type 2 diabetes, and other insulin-resistant states.¹⁹ Visceral adiposity contributes to an increased flux of FFA to the liver, reducing insulin sensitivity.¹⁷ Thus, portal FFA flux to the liver may contribute to the relationship between visceral adiposity and hepatic insulin resistance.¹⁷ Additional studies are needed to determine the involvement of increased CB₁ receptor density and the clinical effects of CB₁ receptor blockade on hepatic insulin clearance and glucose production.

Figures

Figure 1. The CB1 receptor modulates expression of lipogenic enzymes in the liver. ACC1, acetyl CoA carboxylase; FAS, fatty acid synthase; SREBP, sterol regulatory element-binding protein. *P <0.05 vs control. Reprinted from Osei-Hyiaman D, DePetrillo M, Pacher P et al.⁷

Figure 2. De novo hepatic fatty acid synthesis is increased by high-fat diet and is attenuated by CB1 receptor blockade. ACC1, acetyl CoA carboxylase; FAS, fatty acid synthase; SREBP, sterol regulatory element-binding protein. *P <0.05 vs control. Reprinted from Osei-Hyiaman D, DePetrillo M, Pacher P et al.⁷

Figure 3. Model for the role of ECS activation on dyslipidemia. FFA, free fatty acids, ACC, acetyl CoA carboxylase; FA, fatty acid; FAS, fatty acid synthase; SREBP, sterol regulatory element-binding protein. Adapted from Lichtman AH, Cravatt BF.¹⁰

References

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