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

doi:10.1016/j.freeradbiomed.2013.12.026

Free Radical Biology and Medicine

Volume 68, March 2014, Pages 260-267

https://doi.org/10.1016/j.freeradbiomed.2013.12.026 Get rights and content

Highlights

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Cannabidiol protects mouse liver from acute alcohol-induced steatosis through multiple mechanisms.
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Cannabidiol attenuates alcohol-mediated oxidative stress.
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It prevents JNK MAPK activation.
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It increases autophagy.

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. 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.

Section snippets

Materials

CBD was obtained from Tocris Bioscience (Ellisville, MO, USA). Reactive oxygen species (ROS) detection kit was purchased from Enzo Life Sciences (Plymouth Meeting, PA, USA). ATP determination kit was from Molecular Probes (Eugene, OR, USA). Antibodies against phospho-c-Jun N-terminal kinase (pJNK), JNK, microtubule-associated protein 1A/1B light-chain 3 (LC3), pP38 mitogen-activated protein kinase (MAPK), and P38 MAPK were obtained from Cell Signaling (Danvers). Antibody against CYP2E1 was a

CBD decreases ethanol-induced liver injury

To assess the effect of CBD on ethanol-induced hepatotoxicity, we induced liver injury by treating mice with ethanol (30% v/v in saline, 4 g/kg, every 12 h for 5 days). CBD (5 mg/kg, every 12 h) or vehicle was injected ip 30 min before ethanol gavage. Ethanol gavage led to an increase in serum aspartate aminotransferase (AST) that was prevented by CBD (Fig. 1A). Ethanol gavage produced a 60% decrease in hepatic ATP levels (Fig. 1C), suggestive of hepatic bioenergetic injury. This decline in ATP was

Discussion

Acute 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

Acknowledgments

This work was supported by Grants AA-018790 and AA-021362 from the NIAAA (to A.I.C.) and NIH Grant DA 008863 (to L.A.D.).

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¹: These authors contributed equally to this work.

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Published by Elsevier Inc.

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

Highlights

Abstract

Section snippets

Materials

CBD decreases ethanol-induced liver injury

Discussion

Acknowledgments

Free Radic. Biol. Med

Free Radic. Biol. Med.

J. Hepatol.

Biochem. Biophys. Res. Commun.

Free Radic. Biol. Med

Toxicol. Appl. Pharmacol.

Biochim. Biophys. Acta

Gastroenterology

Free Radic. Biol. Med.

FEBS Lett

J. Biol. Chem.

Gastroenterology

Cell Metab.

Cell Metab.

J. Hepatol.

The nonpsychoactive cannabis constituent cannabidiol is an oral anti-arthritic therapeutic in murine collagen-induced arthritis

Proc. Natl. Acad. Sci. USA

Cannabidiol lowers incidence of diabetes in non-obese diabetic mice

Autoimmunity

Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants

Proc. Natl. Acad. Sci. USA

Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma

J. Pharmacol. Exp. Ther.

Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells

Mol. Cancer Ther

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