Abstract
Bile acids concentration in liver is tightly regulated to prevent cell damage. Previous studies have demonstrated that deregulation of bile acid homeostasis can lead to cholestatic liver disease. Recently, we have shown that ER-bound transcription factor Crebh is a downstream effector of hepatic Cb1r signaling pathway. In this study, we have investigated the effect of alcohol exposure on hepatic bile acid homeostasis and elucidated the mediatory roles of Cb1r and Crebh in this process. We found that alcohol exposure or Cb1r-agonist 2-AG treatment increases hepatic bile acid synthesis and serum ALT, AST levels in vivo alongwith significant increase in Crebh gene expression and activation. Alcohol exposure activated Cb1r, Crebh, and perturbed bile acid homeostasis. Overexpression of Crebh increased the expression of key bile acid synthesis enzyme genes via direct binding of Crebh to their promoters, whereas Cb1r knockout and Crebh-knockdown mice were protected against alcohol-induced perturbation of bile acid homeostasis. Interestingly, insulin treatment protected against Cb1r-mediated Crebh-induced disruption of bile acid homeostasis. Furthermore, Crebh expression and activation was found to be markedly increased in insulin resistance conditions and Crebh knockdown in diabetic mice model (db/db) significantly reversed alcohol-induced disruption of bile acid homeostasis. Overall, our study demonstrates a novel regulatory mechanism of hepatic bile acid metabolism by alcohol via Cb1r-mediated activation of Crebh, and suggests that targeting Crebh can be of therapeutic potential in ameliorating alcohol-induced perturbation of bile acid homeostasis.
Highlights
Endogenous cannabinoids are lipid mediators that interact with cannabinoid receptors; the two main endocannabinoids being arachidonoyl ethanolamide (AEA, anandamide) and 2-arachidonoyl glycerol (2-AG)
It has been reported that chronic alcohol exposure increases hepatic endocannabinoid, 2-AG levels and induces hepatic Cb1r, which perpetuates into a hepatic steatosis condition [30,31]
The role of Crebh in hepatic transcriptional regulation has recently been established in studies demonstrating that Crebh is a crucial mediator of the acute inflammatory response elicited by various pro-inflammatory cytokines and transcriptional activation of acute-phase response genes, such as serum amyloid P component (Srp) and Creactive protein (Crp), in the liver; Crebh modulates gene expression of the iron-regulatory hormone, hepcidin, as well several key genes involved in hepatic triglyceride metabolism and lipogenesis [11,12,13,14]
Summary
Endogenous cannabinoids (endocannabinoids) are lipid mediators that interact with cannabinoid receptors; the two main endocannabinoids being arachidonoyl ethanolamide (AEA, anandamide) and 2-arachidonoyl glycerol (2-AG). The endocannabinoid system (ECS) includes the Cb1r, which has high expression levels in the brain but is present at much lower concentrations in peripheral tissues, whereas the Cb2r is expressed predominantly in immune and hematopoietic cells [1]. In obese or hyperglycemic type 2 diabetic patients, circulating levels of AEA and 2-AG are increased and elevated levels of 2-AG are found in visceral adipose tissue [2,5,6], while hepatic Cb1r activation leads to impaired insulin sensitivity as well as reduced insulin clearance in mice [7]. A recent study, using a liver-specific Cb1r knockout mouse model, demonstrated that peripheral Cb1r could be selectively targeted for the treatment of fatty liver, impaired glucose homeostasis, and dyslipidemia to reduce the neuropsychiatric side effects of nonselective Cb1r signaling blockade in treatment of obesity-associated conditions [9] thereby demonstrating the beneficial actions of blocking the CB1R signaling pathway to restore hepatic metabolic homeostasis
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