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  • Writer's pictureTravis Cesarone

How anandamide helps regrow liver cells, NIH study

The liver, like the skin, is a unique organ. The liver spends its lifespan filtering toxins, so regeneration is critical. After a surgeon cuts away a piece from a living human, it will grow back over time. Every cell in the body, including the liver, relies on a network of receptors and ligands known as the endocannabinoid system. And a new National Institute of Health (NIH) study discusses how one transmitter in the ECS — anandamide — helps maintain balance and regrow liver cells.


41,743 deaths occurred in 2017 in America due to over 4 million cases of chronic liver disease. To help prevent casualties, Bani Mukhopadhyay, Ph.D., an NIH staff scientist, led a project with Dr. George Kunos. The latter, an NIH lab chief, previously coauthored studies detailing connections between metabolic energy regulation and the endocannabinoid system (ECS). Authoring their explanation of anandamide’s ability to regrow liver cells with Dr. David Goldman, Drs. Kunos and Mukhopadhyay conducted experiments with six other colleges. (1)


How does anandamide regrow cells in the liver?

Published in Nature’s Cell Death Discovery, the new study analyzed hepatocytes — which are mature cells (cytes) comprising the liver (hepato). And HPCs are premature hepatic cells. To learn how the ECS helps HPCs mature, researchers used CRISPR to delete a specific process from lab mice.


NIH scientists silenced a protein involved in a genetic process known as transcription. DNA uses transcription to spell pieces of biological code (RNA) and make new cellular tissue. But transcription can also silence a biological function. According to the study, anandamide induces a protein and its associated gene that shuts off cellular death in premature liver cells, which helps regrow hepatic tissue. The researchers suggested that,


During liver regeneration, endocannabinoids not only promote cell cycle progression but also stimulate the maturation of HPCs.

Anandamide helps regrow liver cells
Anandamide (AEA) activates CB1 receptor-related genes (CNR1), which promotes the proliferative Axin2-catenin pathway. The effect occurs in premature cells known as hepatic progenitor cells (HPCs), which form mature liver cells. Image courtesy of NIH.

Receptors downstream of anandamide

By shutting down cannabinoid receptors with the drug, rimonabant, NIH researchers confirmed that anandamide relies on CB1 receptors to protect premature liver cells from the immune system. CB1 receptor agonists boost the protein (beta-catenin) involved in liver regeneration. More importantly, though, the cannabinoid receptor directly expresses with a gene that silences cell death (Axin2). And beyond its direct involvement, anandamide affects five genes that work to proliferate liver cells.


Mechanisms that regrow healthy tissue can inadvertently boost levels of cancer cells, too. However, anandamide regulates specific factors of oxidative stress. This means that endocannabinoids regrow healthy liver cells with a relatively low risk of cancer progression.


Anandamide and alcohol consumption

An earlier experiment calibrated a PET imaging scan to detect FAAH, an enzyme that eats up anandamide and spits out an inflammatory byproduct. But the study focused on a person’s brain and behavior rather than the adverse effects of alcohol. (2) Furthermore, anandamide is minimally expressed in the brain compared to the liver.


The new NIH study helps confirm that decreased FAAH levels in the brain only correlate with increased alcohol consumption. Rather, heightened levels of anandamide in the liver likely prevent negative symptoms caused by alcohol metabolism. This means that anandamide-supportive diets, such as Omega-3-rich foods, might regenerate liver cells during chronic disease or even reduce damage after a night of drinking.


If you suffer from chronic liver disease, let us know in the comments if and how diet helps you maintain your ailment.


Author’s note

Dr. Mukhopadhyay dedicated the research, supported by intramural funds from the National Institute on Alcohol Abuse and Alcoholism, to the memory of her late father, Mr. Sridhar Mukherjee.


Sources

  1. Mukhopadhyay, B., Holovac, K., Schuebel, K. et al. The endocannabinoid system promotes hepatocyte progenitor cell proliferation and maturation by modulating cellular energetics. Cell Death Discov. 9, 104 (2023).

  2. Best, L. M., Hendershot, C. S., Buckman, J. F., Jagasar, S., McPhee, M. D., Muzumdar, N., Tyndale, R. F., Houle, S., Logan, R., Sanches, M., Kish, S. J., Le Foll, B., & Boileau, I. (2022). Association Between Fatty Acid Amide Hydrolase and Alcohol Response Phenotypes: A Positron Emission Tomography Imaging Study With [11C]CURB in Heavy-Drinking Youth. Biological psychiatry, S0006-3223(22)Advanced. Advance online publication.

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