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Dyslipidemia—Basic Science

ECSN Faculty

H. Bryan Brewer, Jr, MD
Director, Lipoprotein and Atherosclerosis Research
Cardiovascular Research Institute
Washington Hospital Center
Washington, DC

Henry N. Ginsberg, MD
Irving Professor of Medicine
College of Physicians and Surgeons of Columbia University
Director, Irving Center for Clinical Research
NewYork-Presbyterian Hospital
New York, New York

Samuel Klein, MD
Professor of Medicine
Washington University School of Medicine
Director, Washington University Center for Human Nutrition
Associate Program Director, General Clinical Research Center
Medical Director, Barnes-Jewish Hospital Nutrition Support Service
St. Louis, Missouri

Kenneth Mackie, MD
Professor of Psychology
Department of Psychological and Brain Sciences
Indiana University
Bloomington, Indiana

Overview to Dyslipidemia

Cardiovascular disease is the leading cause of mortality in the United States today.1 Approximately 75% of all deaths because of cardiovascular disease result from heart attack or stroke caused by atherosclerosis.1 One of the most prevalent modifiable risk factors for atherosclerosis is dyslipidemia, abnormalities in serum lipids.2 Dyslipidemia includes elevated total cholesterol, low-density lipoprotein cholesterol (LDL-C), lipoprotein (a), and triglycerides (TGs); low levels of high-density lipoprotein cholesterol (HDL-C); and small, dense LDL particles.2 These lipid abnormalities can be present individually or in combination.

Dr Brewer’s video clip on the ECS and dyslipidemia.
Click play for Dr Brewer’s comment on the ECS and dyslipidemia.

Approximately 50% of the adults in the United States have elevated total cholesterol levels, at least 200 mg/dL.1 Because early recognition and treatment of lipid abnormalities reduces the risk for cardiovascular disease, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recommends routine lipid analysis for all adults 20 years old or older.2 Obesity, particularly obesity with excess abdominal fat distribution, is associated with a lipoprotein profile that is characterized by increased TGs, low levels of HDL-C, and alterations in LDL-C composition and concentration, which accelerates atherogenesis. 3-5

Studies conducted in animal models suggest that obesity leads to chronic stimulation of the endocannabinoid system (ECS) and persistent activation of cannabinoid type 1 (CB1) receptors.6, 7 In addition to being present in several areas of the brain, CB1 receptors are also present in peripheral organs and tissues, including those involved in energy balance (adipose tissue), glucose homeostasis (pancreas and skeletal tissue), and lipogenesis (liver and adipose tissue).7-12 Notably, CB1 receptor activation has been shown to enhance de novo lipogenesis in hepatocytes.6, 13

Lipid Metabolism

Liver

Role of the ECS

Figure 1
Click to Enlarge Figure 1

Studies conducted in rodent models have demonstrated that the ECS acts directly in the liver to regulate hepatic lipogenesis, affecting fatty acid synthesis and oxidation. Activation of hepatic CB1 receptors increases de novo fatty acid synthesis6 and a primary molecular pathway 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).14 Osei-Hyiaman and colleagues demonstrated the role of the ECS in this pathway using rodent models of diet-induced obesity and CB1 receptor knockout mice.6 Activation of the CB1 receptor with a potent receptor agonist (HU210) increased hepatic mRNA expression of SREBP-1c and its target enzymes, ACC1 and FAS, in genetically normal (wild-type) mice fed standard chow (Figure 1).6

The ECS also affects the activity of hepatic adenosine 5’-monophosphate-activated protein kinase (AMPK), which stimulates fatty acid oxidation.15, 16 Kola and colleagues demonstrated cannabinoid-induced inhibition of AMPK activity in rat liver, although the involvement of cannabinoid CB1 receptors was not demonstrated. 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 lipogenic enzymes was associated with a 2-fold increase in the rate of fatty acid synthesis in the liver.6 The role of the CB1 receptor in mediating this effect was proposed because no increase in fatty acid synthesis was seen in CB1 receptor knockout mice or in mice pretreated with the CB1 receptor antagonist SR141716.6 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.6, 17-19 Combined, these data suggest involvement of the same molecular pathway 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.6

In this same study, a high-fat diet also increased de novo hepatic fatty acid synthesis through activation of CB1 receptors. 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 administration of placebo or SR141716 3 mg/kg. Before testing, animals were on normal or high-fat diets for 3 weeks. 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.6 Moreover, wild-type mice, but not CB1 receptor knockout mice, became obese when they were fed a high-fat diet and developed fatty liver, despite similar levels of caloric intake between the two groups of mice.6

The Effect of ECS Blockade on Lipid Abnormalities Associated with Diet-Induced Obesity

Figure 2
Click to Enlarge Figure 2

In other animal studies, investigators have examined whether blocking the CB1 receptor reverses the lipid abnormalities associated with diet-induced obesity. Poirier and colleagues investigated the effects of chronic treatment with SR141716 10 mg/kg per day orally for 10 weeks in mice with obesity produced by 5 months of a high-fat diet. Diet-induced obesity in mice led to abnormal serum lipid profiles (Figure 2). Treatment with SR141716 significantly reduced TGs and LDL-C levels and notably increased the HDL-C/LDL-C ratio (12.4 vs 7.9 in the high-fat control group, P <0.001).20 However, the body weight of mice treated with SR141716 was significantly lower than the body weight of mice in the high-fat control group. Additional studies are needed to determine the weight-loss-dependent and weight-loss-independent effects of SR141716 on serum lipid profiles.

Implications

Nonalcoholic fatty liver disease is a important complication of obesity, because it can lead to severe liver disease and is associated with dyslipidemia, specifically increased serum TG and decreased serum HDL-C concentration. Data from preclinical studies indicate that the CB1 receptor is an important component in the regulation 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. Additional studies are needed to determine whether the ECS specifically affects hepatic lipoprotein production.

Adipocyte

Role of the ECS

Figure 3
Click to Enlarge Figure 3

The ECS is active in adipose tissue-the body’s major site for energy storage and an important endocrine organ.13 CB1 receptors and fatty acid amide hydrolase, which is the enzyme that metabolizes some endocannabinoids, are expressed in human adipocytes.21 Obesity is associated with increased CB1 receptor expression in rodent adipocytes and increased endocannabinoid levels in both rodent and human visceral adipose tissue.2, 12 In the setting of obesity, lipoprotein lipase activity in adipose tissue, but not skeletal muscle, is increased.22 One of the consequences of this shift may be the shunting of dietary fat into adipose tissue for storage, rather than use in muscle tissue. Furthermore, CB1 receptor stimulation in mouse 3T3 adipocytes accelerated adipocyte differentiation, as assessed by PPAR-gamma expression, and lipogenesis (Figure 3).12

As other studies have shown, CB1 receptor blockade in adipose tissue inhibits ECS-induced lipogenesis. While stimulation of mouse 3T3F44 adipocytes with the CB1 receptor-agonist HU-210 increased adipocyte differentiation and lipogenesis, co-incubation with the CB1 receptor-selective antagonist SR141716A blocked both of these effects.12 In another study, pre-incubation with SR141716A blocked the increase in heparin-releasable lipoprotein lipase activity observed when primary adipocytes from the epididymal fat pads of male mice were stimulated with the CB1 receptor-agonist WIN-55,212.8 Such findings support a CB1 receptor-mediated effect on lipogenesis and indicate that adipose tissue is an important target in the ECS.

Adiponectin, the most abundant protein secreted by adipocytes, has several important regulatory roles in glucose and lipid metabolism, is.20 Adiponectin increases fatty-acid oxidation in skeletal muscle and may protect against excess accumulation of TGs in the tissues of obese mice. Injection of recombinant adiponectin in mice fed a high-fat and high-sucrose meal significantly decreased the levels of free fatty acids and TGs in plasma compared with saline-injected mice.23 Stimulation of the ECS decreases adiponectin secretion from adipocytes,12 while CB1 receptor blockade by SR141617 is associated with an increase in serum adiponectin levels.24 Effects of the ESC on lipid metabolism may also involve the role of this system in modulating adiponectin secretion from adipocytes.

Implications

Serum adiponectin concentration is positively correlated with HDL-C levels and is negatively correlated with total cholesterol, LDL-C, and TG.25 Thus, evidence from studies in rodents and in cultured cells suggests that CB1 receptor blockade might lead to an improved lipid profile by increasing adiponectin levels.

Summary

Dr. Brewer’s video clip on the ECS and dyslipidemia.
Click play for Dr. Brewer’s comment on the ECS and dyslipidemia.

Role of ECS—Interrelated integrated pathways

Figure 4
Click to Enlarge Figure 4

The ECS regulates fat metabolism through central and peripheral pathways (Figure 4).14 Activation of CB1 receptors in adipocytes increases lipoprotein lipase activity and decreases adiponectin secretion. Additional studies are needed to determine whether there is a causal relationship between ECS stimulation, obesity, and atherogenic dyslipidemia in humans.

Implications

Evidence from studies in rodents as well as cultured cells suggests that selective pharmacologic antagonism of the ECS improves the lipid abnormalities associated with obesity and diabetes. Additional studies are needed to determine the weight loss-dependent (central mechanism) and weight-loss-independent (peripheral mechanism) effects of CB1 receptor blockade on adipose tissue metabolism and dyslipidemia.

Figures

Figure 1. The CB1 receptor modulates expression of lipogenic enzymes in the liver. ACC1, acetyl-CoA carboxylase-1; FAS, fatty acid synthase; SREBP-1c, sterol regulatory element-binding protein-1c. * P <0.05 vs control. Reprinted from Osei-Hyiaman D, DePetrillo M, Pacher P, et al.6

The CB1 receptor modulates expression of lipogenic enzymes in the liver

Figure 2. CB1 receptor blockade attenuates dyslipidemia in mice fed a high-fat diet. STD, standard diet; HFD, high-fat diet; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides. * P <0.001 vs other groups; † P <0.05 vs STD-control group. Adapted from Poirier B, Bidouard J-P, Cadrouvele C, et al.20

CB1 receptor blockade attenuates dyslipidemia in mice fed a high-fat diet

Figure 3. Stimulation of mouse 3T3F44 adipocyte differentiation and lipogenesis with the CB1/CB2 receptor-agonist HU-210. (A) Effect of chronic treatment with HU-210 (100 nM), with or without co-incubation with SR141716 on lipid droplet formation in differentiated adipocytes, as revealed by Oil Red-O staining and microscopic observation (day 8). (B) Effect on PPARg and adiponectin expression, in differentiated and mature adipocytes, respectively, of chronic treatment with HU-210, SR141716, and HU-210 + SR141716. Expression was measured by real-time RT-PCR and is expressed as fold enhancement over control (vehicle). Error bars are not shown and they were always ≤ 10%. SD values for cycle threshold were always < 1%. ** P <0.01, *** 0.005 vs vehicle, respectively; ##, P <0.01 vs HU-210. From Matias I, et al.12

Figure 4. Model for the role of ECS activation on dyslipidemia. In adipose tissue, ECS activation increases activity of the enzyme lipoprotein lipase, which promotes the storage of triglyceride in adipocytes. As adipocytes enlarge, there is increased free fatty acids flux to the liver. In the liver, ECS activation simultaneously inhibits FA oxidation and stimulates de novo FA synthesis. This latter effect occurs through activation of transcription factor SREBP-1c and its associated enzymes ACC and FAS. With a net increase in hepatic lipogenesis, dyslipidemia may arise from potential increases in the synthesis of very-low-density lipoproteins and release of triglycerides into the circulation. 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 and Cravatt BF.14

Model for the role of ECS activation on dyslipidemia

References

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