title: FOXO1-dependent up-regulation of MAP kinase phosphatase 3 (MKP-3) mediates glucocorticoid-induced hepatic lipid accumulation in mice.
abstract: Long-term treatment with glucocorticoids (GCs) or dysregulation of endogenous GC levels induces a series of metabolic diseases, such as insulin resistance, obesity and type 2 diabetes. We previously showed that MAP kinase phosphatase-3 (MKP-3) plays an important role in glucose metabolism. The aim of this study is to investigate the role of MKP-3 in GC-induced metabolic disorders. Dexamethasone (Dex), a synthetic GC, increases MKP-3 protein expression both in cultured hepatoma cells and in the liver of lean mice. This effect is likely mediated by forkhead box protein O1 (FOXO1) because disruption of endogenous FOXO1 function by either interfering RNA mediated FOXO1 knockdown or overexpression of a dominant negative FOXO1 mutant blocks Dex-induced upregulation of MKP-3 protein. In addition, overexpression of FOXO1 is sufficient to induce MKP-3 protein expression. MKP-3 deficient mice are protected from several side effects of chronic Dex exposure, such as body weight gain, adipose tissue enlargement, hepatic lipid accumulation, and insulin resistance. The beneficial phenotypes in mice lacking MKP-3 are largely attributed to the absence of MKP-3 in the liver since only hepatic insulin signaling has been preserved among the three insulin target tissues (liver, muscle and adipose tissue).
authors.affiliation: Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Electronic address: bfeng@lifespan.org.
authors.forename: Bin
authors.initials: B
authors.lastname: Feng
authors.affiliation: Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Electronic address: qinh123d@gmail.com.
authors.forename: Qin
authors.initials: Q
authors.lastname: He
authors.affiliation: Hallett Center for Diabetes and Endocrinology, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA. Electronic address: hxu@lifespan.org.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics* / Q000378:metabolism*; D005234:Fatty Liver / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005938:Glucocorticoids / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation
chemical_list: C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D005938:Glucocorticoids; D003907:Dexamethasone; D054642:Dual Specificity Phosphatase 6
keywords: Dexamethasone; Hepatosteatosis; Insulin resistance; Lipogenesis; Obesity