Susceptibility to Diet-Induced Hepatic Steatosis and Glucocorticoid Resistance in FK506-Binding Protein 52-Deficient Mice
Open Access
- 28 April 2010
- journal article
- other
- Published by The Endocrine Society in Endocrinology
- Vol. 151 (7), 3225-3236
- https://doi.org/10.1210/en.2009-1158
Abstract
Although FK506-binding protein 52 (FKBP52) is an established positive regulator of glucocorticoid receptor (GR) activity, an in vivo role for FKBP52 in glucocorticoid control of metabolism has not been reported. To address this question, FKBP52+/− mice were placed on a high-fat (HF) diet known to induce obesity, hepatic steatosis, and insulin resistance. Tissue profiling of wild-type mice showed high levels of FKBP52 in the liver but little to no expression in muscle or adipose tissue, predicting a restricted pattern of FKBP52 effects on metabolism. In response to HF, FKBP52+/− mice demonstrated a susceptibility to hyperglycemia and hyperinsulinemia that correlated with reduced insulin clearance and reduced expression of hepatic CEACAM1 (carcinoembryonic antigen-related cell adhesion molecule 1), a mediator of clearance. Livers of HF-fed mutant mice had high lipid content and elevated expression of lipogenic genes (peroxisome proliferator-activated receptor γ, fatty acid synthase, and sterol regulatory element-binding protein 1c) and inflammatory markers (TNFα). Interestingly, mutant mice under HF showed elevated serum corticosterone, but their steatotic livers had reduced expression of gluconeogenic genes (phosphoenolpyruvate carboxy kinase, glucose 6 phosphatase, and pyruvate dehydrogenase kinase 4), whereas muscle and adipose expressed normal to elevated levels of glucocorticoid markers. These data suggest a state of glucocorticoid resistance arising from liver-specific loss of GR activity. Consistent with this hypothesis, reduced expression of gluconeogenic genes and CEACAM1 was observed in dexamethasone-treated FKBP52-deficient mouse embryonic fibroblast cells. We propose a model in which FKBP52 loss reduces GR control of gluconeogenesis, predisposing the liver to steatosis under HF-diet conditions attributable to a shunting of metabolism from glucose production to lipogenesis.Keywords
This publication has 70 references indexed in Scilit:
- Development of Nonalcoholic Steatohepatitis in Insulin-Resistant Liver-Specific S503A Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 Mutant MiceGastroenterology, 2008
- Minireview: The Intersection of Steroid Receptors with Molecular Chaperones: Observations and QuestionsMolecular Endocrinology, 2008
- Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1Diabetes, 2008
- The Glucocorticoid Receptor Controls Hepatic Dyslipidemia through Hes1Cell Metabolism, 2008
- Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivoAmerican Journal of Physiology-Endocrinology and Metabolism, 2008
- Essential Role for Co-chaperone Fkbp52 but Not Fkbp51 in Androgen Receptor-mediated Signaling and PhysiologyJournal of Biological Chemistry, 2007
- FK506-Binding Protein 52 Is Essential to Uterine Reproductive Physiology Controlled by the Progesterone Receptor A IsoformMolecular Endocrinology, 2006
- CEACAM1 regulates insulin clearance in liverNature Genetics, 2002
- Association of Glucocorticoid Insensitivity with Increased Expression of Glucocorticoid Receptor βThe Journal of Experimental Medicine, 1997
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970