title: The Effect of Sustained Inflammation on Hepatic Mevalonate Pathway Results in Hyperglycemia.
abstract: Control of plasma glucose level is essential to organismal survival. Sustained inflammation has been implicated in control of glucose homeostasis in cases of infection, obesity, and type 2 diabetes; however, the precise role of inflammation in these complex disease states remains poorly understood. Here, we find that sustained inflammation results in elevated plasma glucose due to increased hepatic glucose production. We find that sustained inflammation suppresses CYP7A1, leading to accumulation of intermediate metabolites at the branch point of the mevalonate pathway. This results in prenylation of RHOC, which is concomitantly induced by inflammatory cytokines. Subsequent activation of RHO-associated protein kinase results in elevated plasma glucose. These findings uncover an unexpected mechanism by which sustained inflammation alters glucose homeostasis.
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Okin
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA; Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: ruslan.medzhitov@yale.edu.
authors.forename: Ruslan
authors.initials: R
authors.lastname: Medzhitov
mesh_terms: D000818:Animals; D053898:Biosynthetic Pathways; D001786:Blood Glucose / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005215:Fasting / Q000097:blood; D006505:Hepatitis / Q000378:metabolism*; D006943:Hyperglycemia / Q000378:metabolism*; D008070:Lipopolysaccharides; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008820:Mice, Obese; D017368:Protein Prenylation; D014158:Transcription, Genetic; D014280:Triglycerides / Q000097:blood; D018631:ras Proteins / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D000075024:rhoC GTP-Binding Protein
chemical_list: D001786:Blood Glucose; D008070:Lipopolysaccharides; D014280:Triglycerides; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D054460:rho-Associated Kinases; C512911:Rhoc protein, mouse; D018631:ras Proteins; D000075024:rhoC GTP-Binding Protein; D008798:Mevalonic Acid