Abstract
Activation of hepatic cannabinoid 1 receptor (Cb1r) signaling has been implicated in the development of phenotypes associated with fatty liver, hypertriglyceridemia, and insulin resistance. In the current study, we have elucidated the critical role of endoplasmic reticulum-bound transcription factor cyclic AMP-response element-binding protein H (Crebh) in mediating activated Cb1r signaling in inducing phosphatidic acid phosphatase Lipin1 gene expression and subsequently deregulating hepatic insulin receptor signaling. Cb1r agonist (2-arachidonoylglycerol (2-AG)) treatment induced Lipin1 gene expression in a Crebh-dependent manner via recruiting CREBH to the endogenous Lipin1 gene promoter. Adenoviral overexpression of Crebh or 2-AG treatment in mice induced Lipin1 gene expression to increase the hepatic diacylglycerol (DAG) level and phosphorylation of protein kinase Cε (PKCε). This in turn inhibited hepatic insulin receptor signaling. Knockdown of Crebh or Cb1r antagonism attenuated 2-AG-mediated induction of Lipin1 gene expression and decreased DAG production in mouse liver and subsequently restored insulin receptor signaling. Similarly, knockdown of Lipin1 attenuated the 2-AG-induced increase in the DAG level and PKCε phosphorylation. Finally, shRNA-mediated knockdown of Crebh partially but significantly blunted Lipin1 expression and the DAG level in db/db mice. These results demonstrate a novel mechanism by which Cb1r signaling induces Lipin1 gene expression and increases DAG production by activating Crebh, thereby deregulating insulin receptor signaling pathway and lipid homeostasis.
Highlights
The role of cannabinoid 1 receptor (Cb1r) signaling-mediated activation of cyclic AMPresponse element-binding protein H (Crebh) in regulating lipid metabolism and insulin signaling is currently unknown
We have elucidated the critical role of endoplasmic reticulum-bound transcription factor cyclic AMPresponse element-binding protein H (Crebh) in mediating activated Cb1r signaling in inducing phosphatidic acid phosphatase Lipin1 gene expression and subsequently deregulating hepatic insulin receptor signaling
To dissect the role of Cb1r and Crebh in lipid metabolism, we initially treated mice with 2-AG or infected mice with adenovirus (Ad) cyclic AMP-response element-binding protein H (CREBH)-N and analyzed the expression of key genes involved in lipid metabolism (Table 1). 2-AG treatment led to an increase in several genes involved in this pathway (Srebp1c, mtGPAT1, Cd36, Dgat1, Dgat2, and Lipin1) along with a significant decrease in genes involved in fatty acid oxidation (Cpt1 and Ucp2)
Summary
The role of Cb1r signaling-mediated activation of Crebh in regulating lipid metabolism and insulin signaling is currently unknown. ShRNA-mediated knockdown of Crebh partially but significantly blunted Lipin expression and the DAG level in db/db mice These results demonstrate a novel mechanism by which Cb1r signaling induces Lipin gene expression and increases DAG production by activating Crebh, thereby deregulating insulin receptor signaling pathway and lipid homeostasis. Using a liver-specific Cb1r knock-out mouse model, it was 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 [5] Overall, both clinical [3, 4, 6] and animal data regarding the Cb1r blockade [2, 5] overwhelmingly suggest the beneficial actions of Cb1r antagonism on lipid metabolism and insulin receptor signaling. Our study delineates an unprecedented link by which Cb1r signaling pathway-induced activation of Crebh regulates Lipin gene expression and hepatic insulin receptor signaling
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