Cannabinoids May Protect Liver From Alcohol Related Damage

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A new study published in the journal Free Radical Biology and Medicine has found that cannabidiol, a compound found in cannabis, can prevent damage to the liver caused by alcohol consumption. budcannabis

According to the study’s abstract; “Acute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis.”

It continues; “We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prei-love-marijuana-vs-alcoholvent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol.”

Researchers conclude that these results “show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.”

The study was conducted by researchers at the School of Public Health at Sun Yat-sen University in China, the Mount Sinai School of Medicine in New York, and the State Key Laboratory of Oncology at the Sun Yatsen University Cancer Center in China.

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STUDY

Cannabidiol protects liver from binge alcohol-induced steatosis by mechanisms including inhibition of oxidative stress and increase in autophagy


Abstract

imagesAcute alcohol drinking induces steatosis, and effective prevention of steatosis can protect liver from progressive damage caused by alcohol. Increased oxidative stress has been reported as one mechanism underlying alcohol-induced steatosis. We evaluated whether cannabidiol, which has been reported to function as an antioxidant, can protect the liver from alcohol-generated oxidative stress-induced steatosis. Cannabidiol can prevent acute alcohol-induced liver steatosis in mice, possibly by preventing the increase in oxidative stress and the activation of the JNK MAPK pathway. Cannabidiol per se can increase autophagy both in CYP2E1-expressing HepG2 cells and in mouse liver. Importantly, cannabidiol can prevent the decrease in autophagy induced by alcohol. In conclusion, these results show that cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms including attenuation of alcohol-mediated oxidative stress, prevention of JNK MAPK activation, and increasing autophagy.

Alcoholic-liver-diseaseBoth acute and chronic alcohol drinking induces hepatosteatosis [1,2]. Although steatosis is a reversible injury to liver, its progression can develop into more severe liver problems such as hepatitis and cirrhosis. Recent research showed that oxidative stress is an important factor contributing to mechanisms that induce steatosis [24]. Although exact pathways for this have not been clearly identified or studied in detail, possible mechanisms may include reactive oxygen activation of lipogenic transcription factors, e.g., SREBP, or decline in lipolytic factors, e.g., PPARα, or mitochondrial dysfunction and decline in fatty acid oxidation, or activation of the unfolded protein response and endoplasmic reticulum stress. CYP2E1, a cytochrome P450 enzyme, has been shown to play a major role in alcohol-induced oxidative stress and fat accumulation as well as non-alcohol-induced steatosis [14]. Studies with CYP2E1-knockout mice showed little or no oxidative stress produced by alcohol compared to CYP2E1-overexpressing mice [1]. Increased oxidative stress was also found in CYP2E1-overexpressing HepG2 cells compared to HepG2 cells lacking CYP2E1 expression [4,5]. These data indicate that oxidative stress is important for the induction of steatosis by alcohol and suggest that compounds that could effectively prevent the induction of oxidative stress represent potential drugs for the prevention of liver steatosis caused by alcohol drinking.

cannabidiolCannabidiol (CBD) is a nonpsychoactive molecule from the cannabis plant that exhibits unique pharmacological and biological activities. In recent years, CBD has been shown to act as an anti-inflammatory molecule, to be able to block the progression of arthritis [6] and type 1 diabetes [7], to have antioxidant actions [8], and to act as an antiproliferative compound inducing a loss in viability in various tumor cell lines [911]. However, the molecular mechanisms mediating the biological effects of CBD are not well understood.

Given the antioxidant properties of CBD, we hypothesized that this compound could exhibit therapeutic properties in the context of alcohol-induced liver injury, by alleviating oxidative stress-induced hepatocellular injury and fat accumulation.

doi:10.1016/j.tips.2009.07.006Cannabinoid compounds have also been shown to induce autophagy [12,13]. This is of particular interest in the context of liver injury, as autophagy has recently emerged as a major regulator of lipid homeostasis in the liver [1418]. Autophagy, especially macroautophagy, is a mechanism by which hepatocytes break down lipids (a mechanism called lipophagy). Inhibition of macroautophagy causes lipid droplets to increase in size and number and to accumulate in hepatocytes. A decreased rate of lipolysis leads to an increase in cellular triglyceride (TG) content, a feature observed in steatosis. In some studies, acute alcohol was shown to decrease autophagy in the liver, leading to steatosis [2,19]. However, other studies showed that acute and chronic alcohol increased autophagy, possibly to protect against alcohol-induced fat accumulation [20,22]. In line with these observations and the proautophagic properties of cannabinoids, we determined whether CBD can protect against alcohol-induced liver steatosis through induction of autophagy.

About Author manuscripts Submit a manuscript NIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;

Full  Study can be found at:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112960/

Discussion

supplement-manual-mass-57-638Acute alcohol drinking induces liver steatosis [2,19,27,29]. The induction of liver steatosis is promoted by CYP2E1, as wild-type mice with CYP2E1 expression displayed steatosis, but CYP2E1-knockout mice exhibit strongly decreased steatosis after acute alcohol treatment [1,2,19]. In the current study, lipid accumulation was found in CYP2E1-expressing HepG2 cells after ethanol treatment, and liver steatosis was observed in mice treated with acute alcohol. Mechanisms by which CYP2E1 promotes ethanol induction of steatosis include elevated ROS, activation of MAPKs such as JNK, inhibition of autophagy, and decreases in levels of PPARα, a major regulator of fatty acid oxidation [1,2]. Oxidative stress has been reported to be one major cause of liver steatosis by alcohol. Antioxidants such as N-acetylcysteine attenuate acute alcohol-induced steatosis [2,30]. We previously found that a JNK inhibitor partially blocked acute ethanol-induced steatosis [2]. CBD is a nonpsychotic cannabinoid, which has been shown to have anti-inflammatory and antioxidant properties. CBD has also been reported to function as an antioxidant in preventing glutamate toxicity and preventing neurotoxicity by acute alcohol [31]. Consistent with reports that CBD has antioxidant activity, we found that CBD can reduce ROS production in HepG2 cells expressing CYP2E1 and that CBD inhibited the increase in ROS induced by alcohol treatment. CBD protected liver from acute alcohol-induced steatosis and lowered 4-HNE levels via its antioxidant property. CBD did not alter CYP2E1 levels or catalytic activity; therefore the CBD prevention of alcohol-induced steatosis and oxidant stress is not due to effects on CYP2E1.

How activation of CYP2E1 by alcohol consumption, in addition to oxidative stress, promotes steatosis requires further mechanistic evaluation. The JNK MAPK pathway is a major signaling pathway, which initiates apoptosis and cell death [32,33]. Recent reports also showed that activation of the JNK MAPK pathway by alcohol may be a key factor regulating the increase in liver steatosis, because inhibition of JNK activation prevented acute alcohol-induced steatosis [2]. We found that CBD can inhibit the increase in JNK MAPK phosphorylation by acute alcohol, which may be due to its antioxidant actions. Inhibition of JNK activation may contribute to CBD’s anti-steatosis effects.

While a basal level of autophagy is required for the survival of cells or organisms, prolonged activation of autophagy may have adverse effects. In mammalian systems, autophagy is stimulated by nutrient starvation or deprivation of growth factors [3438]. Although it is not clear yet whether alcohol increases or decreases autophagy under different conditions, it is consistent that autophagy is a protective mechanism against alcohol-induced liver injury [2,19,27,29]. Increasing autophagy can protect cells from injury by various stimuli, as inhibition of autophagy increases toxicity to cells. Genetically enhancing autophagy by overexpressing Atg7 could alleviate hepatic steatosis induced by a high-fat diet [39]. Carbamazepine, an FDA-approved antiepileptic drug, can alleviate fatty liver by inducing autophagy [40]. In contrast, loss of autophagy in vitro or in vivo increases lipid accumulation in cells and in liver [2,4,19]. We found that CBD can stimulate autophagy in HepG2 cells that express CYP2E1. The increased flux from LC3-I to LC3-II was confirmed by treating cells with a lysosome inhibitor. Because the LC3-II/LC3-I ratio is used to assay autophagy, the increased flux from LC3-I to LC3-II indicates increases in autophagy. CBD-mediated increase in autophagy may be important for the prevention of alcohol-induced steatosis by CBD.

In conclusion, this is the first report demonstrating that CBD can alleviate lipid accumulation in both an in vitro HepG2 cell model and an in vivo binge alcohol treatment model by multiple mechanisms. These mechanisms may involve activation of autophagy, inhibition of the JNK MAPK pathway, and inhibition of oxidative stress, and all three mechanisms could be important for alleviating steatosis.

Study found at:  http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4112960/