Controversies surrounding peripheral cannabinoid receptor 1 in fatty liver disease
Beste Mutlu, Pere Puigserver
Beste Mutlu, Pere Puigserver
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e154147. https://doi.org/10.1172/JCI154147.
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Commentary

Controversies surrounding peripheral cannabinoid receptor 1 in fatty liver disease

Abstract

Cannabinoid receptor 1 (CB-1) antagonists are potential candidates for treating obesity and metabolic complications. Despite clear metabolic benefits, unwanted side effects in the brain pose issues for patients. With the hope of overcoming this obstacle, CB-1 in peripheral tissues has become a potential drug target. Previous studies had suggested that liver CB-1 would be an excellent target to prevent development of nonalcoholic steatohepatitis (NAFLD). However, in this issue of the JCI, Wang et al. showed that CB-1 was barely detectable in the liver and deletion of CB-1 in hepatocytes provided no metabolic benefits against NAFLD. These contradictory results raise substantial concerns about the potential benefits of peripheral CB-1 blockers against NAFLD.

Authors

Beste Mutlu, Pere Puigserver

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Figure 1

Source of liver fats during NAFLD and the role of CB-1 signaling in liver and adipose tissue.

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Source of liver fats during NAFLD and the role of CB-1 signaling in live...
Free fatty acids (FFAs) produced by lipolysis in adipose tissue, de novo lipogenesis (DNL) in the liver, and dietary lipids are major sources (approximately 47%, 38%, and 15%, respectively) of FAs that comprise triglycerides (TG) in the liver. Activation of cannabinoid receptor 1 (CB-1) signaling by agonists in the liver was previously shown to increase DNL (14). Wang et al. (17) dispute the presence of CB-1 in the liver and downstream metabolic effects. However, it is possible that blockade of CB-1 signaling in adipose tissue may decrease lipolysis and FFA release, thereby protecting against NAFLD.