title: Glucocorticoid Receptor β Induces Hepatic Steatosis by Augmenting Inflammation and Inhibition of the Peroxisome Proliferator-activated Receptor (PPAR) α.
abstract: Glucocorticoids (GCs) regulate energy supply in response to stress by increasing hepatic gluconeogenesis during fasting. Long-term GC treatment induces hepatic steatosis and weight gain. GC signaling is coordinated via the GC receptor (GR) GRα, as the GRβ isoform lacks a ligand-binding domain. The roles of the GR isoforms in the regulation of lipid accumulation is unknown. The purpose of this study was to determine whether GRβ inhibits the actions of GCs in the liver, or enhances hepatic lipid accumulation. We show that GRβ expression is increased in adipose and liver tissues in obese high-fat fed mice. Adenovirus-mediated delivery of hepatic GRβ overexpression (GRβ-Ad) resulted in suppression of gluconeogenic genes and hyperglycemia in mice on a regular diet. Furthermore, GRβ-Ad mice had increased hepatic lipid accumulation and serum triglyceride levels possibly due to the activation of NF-κB signaling and increased tumor necrosis factor α (TNFα) and inducible nitric-oxide synthase expression, indicative of enhanced M1 macrophages and the development of steatosis. Consequently, GRβ-Ad mice had increased glycogen synthase kinase 3β (GSK3β) activity and reduced hepatic PPARα and fibroblast growth factor 21 (FGF21) expression and lower serum FGF21 levels, which are two proteins known to increase during fasting to enhance the burning of fat by activating the β-oxidation pathway. In conclusion, GRβ antagonizes the GC-induced signaling during fasting via GRα and the PPARα-FGF21 axis that reduces fat burning. Furthermore, hepatic GRβ increases inflammation, which leads to hepatic lipid accumulation.
authors: From the Department of Kinesiology, Laboratory of Systems Physiology, University of North Carolina, Charlotte, North Carolina 28223.
authors: Joseph S
authors: JS
authors: Marino
authors: the Department of Orthopedics.
authors: Lance A
authors: LA
authors: Stechschulte
authors: the Department of Physiology and Biophysics, Mississippi Center for Obesity Research, Cardiovascular-Renal Research Center, University of Mississippi Medical Center, Jackson, Mississippi 39216, and.
authors: David E
authors: DE
authors: Stec
authors: Advanced Microscopy & Imaging Center, Department of Surgery, and.
authors: Andrea
authors: A
authors: Nestor-Kalinoski
authors: the University of Cincinnati, College of Medicine, Cincinnati, Ohio 45220.
authors: Sydni
authors: S
authors: Coleman
authors: Center for Hypertension and Personalized Medicine, Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, Ohio 43614, Terry.Hinds@utoledo.edu.
authors: Terry D
authors: http://orcid.org/0000-0002-7599-1529
authors: TD
authors: Hinds
mesh_terms: D000818:Animals; D005234:Fatty Liver / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism; D005938:Glucocorticoids / Q000494:pharmacology*; D000071679:Glycogen Synthase Kinase 3 beta / Q000235:genetics / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011965:Receptors, Glucocorticoid / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D005938:Glucocorticoids; D016328:NF-kappa B; D047493:PPAR alpha; D011965:Receptors, Glucocorticoid; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; C414620:fibroblast growth factor 21; C121943:glucocorticoid receptor beta; D005346:Fibroblast Growth Factors; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse
keywords: NAFLD; NASH; PPARα; fatty acid metabolism; fatty acid synthase (FAS); fatty liver; glucocorticoid receptor; hepatic steatosis; inflammation; lipid