Treatment of mice with rimonabant (SR), a CB1 receptor antagonist, prevented the development of fatty liver by ethanol. Consistent with. CBD constitutes up to 40% of cannabis extracts with some pharmacological effects without the .. Role of CB2 receptors in the development of fatty liver. This includes liver scarring (cirrhosis) and fatty liver disease (FLD). WHERE DO LIVER DISEASES COME FROM AND WHY DO THEY DEVELOP? . found that CBD is helpful in causing malignant cells found in liver fibrosis.
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Specifically, cannabis use was associated with note: It must be noted that cannabis was most protective in individuals who met the diagnostic criteria for alcohol abuse. Cannabis had less of a protective effect in those who presumably consumed more alcohol and met the criteria for alcohol dependence.
Broadly speaking, alcohol abuse is drinking too much too often, while dependence is the inability to quit. In most cases, those who are dependent end up consuming more alcohol throughout their lives. So it appears that cannabis is only protective against alcoholic liver disease to a point; the more you drink, the less cannabis can help. You can generally think of alcohol abuse as drinking too much too often, while dependence is the inability to quit.
Despite both being classified as an alcohol use disorder, they reflect differences in the way that alcohol affects brain functioning , as well as the changes in the brain that result from long-term consumption. This is therefore a different protective mechanism than halting or killing the cancer directly. The scientists report that cannabis use was associated with a similar reduction in liver cancer in both alcohol abusers and those who were dependent.
Since cannabis was less effective at preventing cirrhosis in those with alcohol dependence, it leaves open the possibility that cannabis directly blocked the development of liver cancer independent of its effects on cirrhosis. Alcohol damages the brain and body by increasing inflammation, and this inflammation contributes to liver disease. The anti-inflammatory properties of the primary cannabinoids, THC and cannabidiol CBD , lead one to predict that cannabis consumption could reduce inflammation caused by alcohol, and therefore help prevent the development of liver disease.
This leads to increased de novo fatty acid synthesis as well as decreased fatty acid oxidation, culminating into the development of fatty liver. High-fat diet, in addition to CB1 receptor activation, appears to activate CB2 receptors that may also contribute to fatty liver. In non-alcoholic fatty liver disease, CB2 receptor activation is associated with the development of fatty liver. Cannabis smoking can increase the severity of fatty liver in hepatitis C patients although the precise mechanism is unknown.
As the mechanisms involved in endocannabinoid receptor signaling are being increasingly well understood and the biosynthetic regulatory elements elucidated, these present good opportunity for the pharmaceutical scientists to design drugs to treat liver diseases, including steatosis, based on the cannabinoids, endocannabinoids, and related templates. Fatty liver steatosis is characterized by an excess accumulation of triglycerides within hepatocytes, which are parenchymal cells of the liver.
It is an initial stage of many liver diseases including alcoholic liver disease, non-alcoholic fatty liver disease NAFLD , and hepatitis C. Excess hepatic fat accumulation could result from the following mechanisms: Steatosis is reversible, and it has been considered as a benign condition for a long time; however, increasing evidence suggests that it is a potentially pathologic condition.
If the causal agent is not eliminated or injury persists, steatosis may progress to inflammation, fibrosis, and even cirrhosis of the liver, especially in the presence of hepatitis C virus, diabetes, and obesity.
Considering potential clinical relevance, researchers were prompted to discern the underlying mechanisms of steatosis. Some of the proposed mechanisms of fatty liver are activation of lipogenic transcription factor sterol regulatory element-binding protein 1c SREBP1c 1 , impaired function of lipolytic transcription factor peroxisome proliferator-activated receptor-alpha 2 , inhibited AMP-activated protein kinase activity 3 , decreased adiponectin levels 4 , sirtuin-1 inhibition 5 , 6 , insulin resistance, interleukin-6 deficiency, increased complement C3 levels, and other factors 7 , 8.
Emerging evidence suggests that cannabinoids play an important role in the modulation of fatty liver. The endocannabinoid system is primarily comprised of three components: Endocannabinoids endogenous cannabinoids are lipid mediators that interact with cannabinoid receptors to produce effects similar to those of delta 9-tetrahydrocannabinol THC , which is the main psychoactive component of cannabis.
The two main endocannabinoids discovered are arachidonoyl ethanolamide anandamide and 2-arachidonoylglycerol 2-AG , and two main cannabinoid receptors identified to date are cannabinoid receptor 1 CB1 and cannabinoid receptor 2 CB2. CB1 receptors are expressed at high levels in the brain, but they are also present in peripheral tissues, though at much lower concentrations in most of the peripheral tissues 9 , On the other hand, CB2 receptors are expressed predominantly in immune and hematopoietic cells 9.
Cannabinoid receptors have also been identified in the liver of rodents 11 — 13 and humans 13 — In addition, liver has been shown to produce endocannabinoids—anandamide 11 and 2-AG Animal studies have shown a link between cannabinoid system and the development of fatty liver associated with various agents such as ethanol 12 , obesity 16 , and high-fat diet 11 , Similarly, recent human studies have also revealed an association between cannabinoids and fatty liver present in patients with hepatitis C 18 and NAFLD This review summarizes the role of the cannabinoid system in the development of fatty liver.
The role of CB1 receptors has been investigated in the development of fatty liver induced by ethanol, high-fat diet, and obesity.
Chronic ethanol consumption is known to induce fatty liver, which is an initial stage of alcoholic liver disease characterized by fatty liver, steatohepatitis, fibrosis, and cirrhosis.
Ethanol exposure of male mice in a low-fat diet induced fatty liver as assessed by histological evaluation and hepatic triglyceride levels. In contrast to ethanol-exposed mice, pair-fed control mice did not develop fatty liver. Ethanol-induced fatty liver was associated with increased hepatic expression of the gene encoding for CB1 receptors. In these mice, ethanol increased hepatic levels of 2-AG but not anandamide , which was selectively produced by hepatic stellate cells.
Treatment of mice with rimonabant SR , a CB1 receptor antagonist, prevented the development of fatty liver by ethanol. Consistent with rimonabant findings, mice with global or hepatocyte-specific CB1 receptor knockout were resistant to ethanol-induced steatosis.
These findings suggest that ethanol induces fatty liver via hepatocyte CB1 receptor activation. Ethanol exposure increased the nuclear level of SREBP-1c in the liver of wild-type mice but not in the liver of global or hepatocyte-specific CB1 receptor knockout mice.
Consistent with this, ethanol increased FAS protein levels in the liver of wild-type mice, but this effect was absent or blunted in both global and hepatocyte-specific CB1 receptor knockout mice. On the other hand, ethanol exposure decreased both hepatic CPT-1 protein level and CPT-1 activity in wild-type mice, but these decreases were not seen in hepatocyte-specific CB1 receptor knockout mice.
In global CB1 receptor knockout mice, although ethanol did not decrease CPT-1 activity, it did decrease CPT-1 protein levels compared to pair-fed control.
Taken together, these results suggest that ethanol-induced increase in 2-AG from stellate cells activates hepatocyte CB1 receptors in a paracrine manner, which leads to steatosis via increasing fatty acid synthesis and decreasing fatty acid oxidation.
Consumption of a high-fat diet is associated with obesity and development of hepatic steatosis. In contrast, global CB1 receptor knockout mice on high-fat diet remained lean, and they did not develop fatty liver despite consuming caloric intake similar to that of wild-type mice on the high-fat diet.
In addition, high-fat diet upregulated hepatic expression of CB1 receptors in wild-type mice and increased hepatic levels of anandamide, but not 2-AG, in both wild-type and CB1 receptor knockout mice. Furthermore, in wild-type mice, high-fat diet increased basal rates of fatty acid synthesis, which was blocked by the CB1 antagonist rimonabant.
Taken together, these results suggest that high-fat diet-induced steatosis resulting from increased fatty acid synthesis is mediated via anandamide-induced CB1 receptor activation. These effects were blocked or prevented by CB1 antagonist. Consistently, treatment with CB1 agonist also increased de novo fatty acid synthesis in the liver or in isolated CB1 receptor-expressing hepatocytes, and this effect was also blocked or prevented by CB1 antagonist, further corroborating the role of CB1 receptor activation in fatty acid synthesis.
In order to discern the specific role of liver CB1 receptors in the development of steatosis, researchers have used liver-specific CB1 knockout mice along with global knockout mice In this study, global CB1 receptor knockout mice were totally resistant to high-fat-induced fatty liver and obesity.
In this study, high-fat diet was also shown to increase CB1 expression in hepatocytes in wild-type mice Furthermore, CB1 receptor agonist HU increased hepatic de novo lipogenesis in wild-type chow-fed mice, but not in global CB1 knockout or liver-specific CB1 knockout mice.
These findings support the contention that high-fat diet induces fatty liver primarily via activation of hepatic CB1 receptors. High-fat diet, compared to chow-fed control, significantly reduced the activity of hepatic CPT-1 in wild-type mice, but not in global or liver-specific CB1 receptor knockout mice. Furthermore, in wild-type chow-fed mice, CB1 receptor agonist HU significantly decreased hepatic CPT-1 activity, whereas rimonabant significantly increased CPT-1 activity and prevented the inhibitory effect of subsequently administered HU Taken together, these results suggest that CB1 activation decreases fatty acid oxidation via decreasing CPT-1 activity, which may contribute, in part, to high-fat diet-induced steatosis.
Obesity is a chronic metabolic disorder characterized by increased body weight and development of adipose tissue with excessive fat storage, and it is invariably associated with fatty liver.
These rats have elevated plasma leptin levels and are resistant to exogenous leptin administration. In addition, they have severe hepatic steatosis characterized by accumulation of fat within hepatocytes. In contrast, in pair-fed rats, which consumed the same amount of food as that consumed by rimonabant-treated rats, steatosis and hepatomegaly were not significantly reduced. This suggests that rimonabant, and not reduced food intake, was responsible for reducing steatosis.
Taken together, these results indicate that in the obese rats, development of fatty liver is mediated via activation of CB1 receptors. Compared with CB1 receptors, the role of CB2 receptors in the development of fatty liver is underinvestigated. CB2 receptors are predominantly expressed in immune cells and hematopoietic cells 9 , and their role in the development of fatty liver is not clear.
The expression of CB2 receptors has been investigated in the liver of patients with NAFLD, which is characterized by fatty liver and steatohepatitis In this study, CB2 receptors were upregulated in all of the liver samples from patients with steatosis and steatohepatitis. Specifically, receptors were localized in hepatocytes, cholangiocytes, and hepatic stellate cells.
In contrast, liver samples obtained from normal subjects did not express CB2 receptors. Expression of CB2 receptors in fatty liver, but not in normal liver, is an indication of CB2 activation in NAFLD, which is associated with obesity, insulin resistance, type 2 diabetes, and hypertriglyceridemia.
In another CB2 receptor study, the role of CB2 receptors was investigated in the development of high-fat diet-induced fatty liver in mice In contrast, hepatic CB2 knockout mice exhibited minimal hepatic steatosis.
Taken together, these findings indicate a mediating role for CB2 receptor activation in high-fat diet-induced fatty liver. Steatosis is a common histologic finding in patients with chronic hepatitis C 20 , In this study, marked steatosis was significantly more frequent in daily cannabis smokers compared with occasional users and nonusers.
Using multivariate logistic regression analysis, it was shown that daily cannabis smoking is an independent predictor of steatosis severity, suggesting a steatogenic role of cannabinoid system. Steatogenic agents such as ethanol and high-fat diet appear to be capable of inducing endocannabinoid production in the liver. For example, ethanol exposure in vivo increased production of 2-AG by cultured mouse HSC 12 , whereas high-fat diet increased anandamide production in the mouse liver Such elevated endocannabinoid levels have been reported in other organs as well.
Ethanol has been shown to increase the levels of 2-AG in rat cerebellar granule neurons 22 and in rat nucleus accumbens Similarly, high-fat diet has been shown to increase the levels of either anandamide, or 2-AG, or both in the skeletal muscle, heart, and kidney of mice
Role of Cannabinoids in the Development of Fatty Liver (Steatosis)
Fatty liver” is the most prevalent form of liver disease in western represents a first step in developing CBD as a preventative therapy for. Non-alcoholic fatty liver disease (NAFLD) is an increasingly common illness that currently has no is always searching for the magic substance to prevent liver fat accumulation. a statistically significant role for cannabis in fatty liver development. . Beverages (Juices/Smoothies) · Bile · Breakfast · CBD Oil · Cholesterol. Herein, we investigated the effects of CBD on liver injury induced by and decreased the alcohol-induced increased liver triglyceride and fat.