Role of Cannabinoids in the Development of Fatty Liver (Steatosis)

Abstract

Abstract. Emerging evidence suggests that cannabinoids play an important role in the modulation of fatty liver, which appears to be mediated via activation of cannabinoid receptors. Steatogenic agents such as ethanol and high-fat diet can upregulate the activity of cannabinoid 1 (CB1) receptors via increasing synthesis of endocannabinoids, 2-arachidonoylglycerol, and anandamide. CB1 receptors can also be upregulated by obesity. CB1 receptor activation results in upregulation of lipogenic transcription factor, sterol regulatory element-binding protein 1c and its target enzymes, acetyl-CoA carboxylase-1, and fatty acid synthase and concomitantly, downregulation of carnitine palmitoyltransferase-1. 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.

Action of the chemical agent fipronil (active ingredient of acaricide Frontline®) on the liver of mice: An ultrastructural analysis

“…However, in this study, the effects of the accumulation of lipid in the hepatocytes of individuals from treated groups led to cytoplasm disorganization, which caused structural and physiological alterations in the organ, once in the cellular metabolism all the enzymatic synthesis activity seems to have been concentrated on the attempt to produce enzymes to metabolize the molecules of fipronil to eliminate them from the system. Purohit et al 2010 found similar results studying the receptors of cannabinoids (cannabinoid 1 receptor-CB1; e cannabinoid 2 receptor-CB2) and the relation between these receptors and the agents, which are considered factors in the steatosis etiopathogenesis, such as ethanol and high-fat diet. These authors observed that, once these agents activate CB1, there would be an increase in the synthesis of fatty acids and a decrease in their oxidation, resulting in an accumulation of lipid in the liver.…”

Exercise without dietary changes alleviates nonalcoholic fatty liver disease without weight loss benefits

“…Cannabinoid-1 receptor (CB1), which responds to cannabinoids that increase fat intake, regulates the activity of these lipogenic and lipolytic transcription factors [6, 7], and the intake of ethanol and high-fat diet induce upregulation of CB1 activity through increased synthesis of endocannabinoids, 2-AG, and anandamide [1]. Because CB1 is also upregulated in obesity, CB1 is a potential therapeutic target for obesity and NAFLD [8].…”

Δ9-Tetrahydrocannabinol induces endocannabinoid accumulation in mouse hepatocytes: antagonism by Fabp1 gene ablation

“…-THC treatment promote steatosis and are associated with development of NAFLD (14,15). Similarly, activation of the endogenous EC system to increase AEA, 2-AG, and CB1 is linked to NAFLD (8)(9)(10).…”

“…The mechanism whereby CB1 induces hepatic lipid accumulation involves downstream upregulation of sterol regulatory element binding protein 1c (SREBP1c) which in turn induces transcription of de novo lipogenic enzymes (8,14). However, it is not known if Δ…”