The L‐α‐Lysophosphatidylinositol/G Protein–Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis

Abstract

BaCKgRoUND aND aIMS: G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-αlysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. appRoaCH aND ReSUltS: We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CoNClUSIoNS: The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC. (Hepatology 2020;0:1-19). N onalcoholic fatty liver (NAFL) disease (NAFLD) is a major global health threat because of its growing incidence and prevalence. It is becoming the leading cause of liver disease and despite the many efforts to find therapeutic targets for this disease, there is no established therapy yet.

O-1602 Promotes Hepatic Steatosis through GPR55 and PI3 Kinase/Akt/SREBP-1c Signaling in Mice

“…In several animal models of non-alcoholic hepatic steatosis and steatohepatitis, GPR55 was found to increase lipid content by inducing de novo fatty acid synthesis and decreasing fatty acid β oxidation, which is consistent with our results [ 11 ]. Serum levels of lysophosphatidylinositol species of 16:0, 18:1, and 18:1 isomer were found to be higher in patients with non-alcoholic steatohepatitis than in those with only steatosis [ 11 ]. The increased levels of lysophosphatidylinositols might contribute to the development of non-alcoholic hepatic steatohepatitis through the activation of GPR55 in hepatic stellate cells [ 11 ].…”

“…Recently, Fondevila et al reported increased expression levels of liver GPR55 in human patients with non-alcoholic fatty liver diseases [ 11 ]. In several animal models of non-alcoholic hepatic steatosis and steatohepatitis, GPR55 was found to increase lipid content by inducing de novo fatty acid synthesis and decreasing fatty acid β oxidation, which is consistent with our results [ 11 ].…”

“…Recently, Fondevila et al reported increased expression levels of liver GPR55 in human patients with non-alcoholic fatty liver diseases [ 11 ]. In several animal models of non-alcoholic hepatic steatosis and steatohepatitis, GPR55 was found to increase lipid content by inducing de novo fatty acid synthesis and decreasing fatty acid β oxidation, which is consistent with our results [ 11 ]. Serum levels of lysophosphatidylinositol species of 16:0, 18:1, and 18:1 isomer were found to be higher in patients with non-alcoholic steatohepatitis than in those with only steatosis [ 11 ].…”

“…Serum levels of lysophosphatidylinositol species of 16:0, 18:1, and 18:1 isomer were found to be higher in patients with non-alcoholic steatohepatitis than in those with only steatosis [ 11 ]. The increased levels of lysophosphatidylinositols might contribute to the development of non-alcoholic hepatic steatohepatitis through the activation of GPR55 in hepatic stellate cells [ 11 ]. Our measurement of lysophosphatidylinositols also suggests that high-fat diets increase the levels of endogenous GPR55 agonists in the liver, which may activate GPR55 in hepatocytes and stellate cells, resulting in the development of hepatic steatosis and steatohepatitis.…”

Cannabinoid receptor type 1 antagonist inhibits progression of obesity‐associated nonalcoholic steatohepatitis in a mouse model by remodulating immune system disturbances

“…Of note, it has been recently reported that liver GPR55 is increased in the liver of patients and mouse models with NAFLD, and further participating in the progression of NASH. 36 It seems to be a contradiction between AM251 and the role of GPR55 in the therapy of NASH. However, our results could not provide related information now.…”