lysophosphatidylinositol and Non-alcoholic-Fatty-Liver-Disease

We previously demonstrated that antisense oligonucleotide-mediated knockdown of Mboat7, the gene encoding membrane bound O-acyltransferase 7, in the liver and adipose tissue of mice promoted high fat diet-induced hepatic steatosis, hyperinsulinemia, and systemic insulin resistance. Thereafter, other groups showed that hepatocyte-specific genetic deletion of Mboat7 promoted striking fatty liver and NAFLD progression in mice but does not alter insulin sensitivity, suggesting the potential for cell autonomous roles. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. We generated Mboat7 floxed mice and created hepatocyte- and adipocyte-specific Mboat7 knockout mice using Cre-recombinase mice under the control of the albumin and adiponectin promoter, respectively. Here, we show that MBOAT7 function in adipocytes contributes to diet-induced metabolic disturbances including hyperinsulinemia and systemic insulin resistance. The expression of Mboat7 in white adipose tissue closely correlates with diet-induced obesity across a panel of ∼100 inbred strains of mice fed a high fat/high sucrose diet. Moreover, we found that adipocyte-specific genetic deletion of Mboat7 is sufficient to promote hyperinsulinemia, systemic insulin resistance, and mild fatty liver. Unlike in the liver, where Mboat7 plays a relatively minor role in maintaining arachidonic acid-containing PI pools, Mboat7 is the major source of arachidonic acid-containing PI pools in adipose tissue. Our data demonstrate that MBOAT7 is a critical regulator of adipose tissue PI homeostasis, and adipocyte MBOAT7-driven PI biosynthesis is closely linked to hyperinsulinemia and insulin resistance in mice.

Topics: Acylation; Adipocytes; Animals; Arachidonic Acid; Diet, High-Fat; Glucose; Homeostasis; Hyperinsulinism; Insulin Resistance; Mice; Mice, Inbred C57BL; Mice, Knockout; Non-alcoholic Fatty Liver Disease

G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (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.. 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.. The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC.

Topics: Acetyl-CoA Carboxylase; Adult; Aged; Animals; Biopsy; Cannabinoid Receptor Agonists; Cell Line; Cohort Studies; Diet, High-Fat; Disease Models, Animal; Female; Gene Knockdown Techniques; Hepatic Stellate Cells; Hepatocytes; Humans; Lipogenesis; Liver; Lysophospholipids; Male; Mice; Middle Aged; Non-alcoholic Fatty Liver Disease; Obesity; Receptors, Cannabinoid; Up-Regulation

Non-alcoholic fatty liver disease is recognized as the leading cause of chronic liver disease. Overnutrition and obesity are associated with hepatic steatosis. G protein-coupled receptor 55 (GPR55) has not been extensively studied in hepatic steatosis, although its endogenous ligands have been implicated in liver disease progression. Therefore, the functions of GPR55 were investigated in Hep3B human hepatoma cells and mice fed high-fat diets. O-1602, the most potent agonist of GPR55, induced lipid accumulation in hepatocytes, which was reversed by treatment with CID16020046, an antagonist of GPR55. O-1602 also induced intracellular calcium rise in Hep3B cells in a GPR55-independent manner. O-1602-induced lipid accumulation was dependent on the PI3 kinase/Akt/SREBP-1c signaling cascade. Furthermore, we found increased levels of lysophosphatidylinositol species of 16:0, 18:0, 18:1, 18:2, 20:1, and 20:2 in the livers of mice fed a high-fat diet for 4 weeks. One-week treatment with CID16020046 suppressed high-fat diet-induced lipid accumulation and O-1602-induced increase of serum triglyceride levels in vivo. Therefore, the present data suggest the pro-steatotic function of GPR55 signaling in hepatocytes and provide a potential therapeutic target for non-alcoholic fatty liver disease.

Topics: Animals; Azabicyclo Compounds; Benzoates; Calcium; Cannabidiol; Diet, High-Fat; Hep G2 Cells; Humans; Intracellular Space; Lipids; Liver; Lysophospholipids; Mice; Models, Biological; Non-alcoholic Fatty Liver Disease; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Receptors, Cannabinoid; Signal Transduction; Sterol Regulatory Element Binding Protein 1; Triglycerides

Topics: Case-Control Studies; Humans; Lipid Metabolism; Lysophospholipids; Non-alcoholic Fatty Liver Disease; Phosphatidylcholines; Plasmalogens; Triglycerides