title: The Signal Transducer and Activator of Transcription 1 (STAT1) Inhibits Mitochondrial Biogenesis in Liver and Fatty Acid Oxidation in Adipocytes.
abstract: The transcription factor STAT1 plays a central role in orchestrating responses to various pathogens by activating the transcription of nuclear-encoded genes that mediate the antiviral, the antigrowth, and immune surveillance effects of interferons and other cytokines. In addition to regulating gene expression, we report that STAT1-/- mice display increased energy expenditure and paradoxically decreased release of triglycerides from white adipose tissue (WAT). Liver mitochondria from STAT1-/- mice show both defects in coupling of the electron transport chain (ETC) and increased numbers of mitochondria. Consistent with elevated numbers of mitochondria, STAT1-/- mice expressed increased amounts of PGC1α, a master regulator of mitochondrial biogenesis. STAT1 binds to the PGC1α promoter in fed mice but not in fasted animals, suggesting that STAT1 inhibited transcription of PGC1α. Since STAT1-/- mice utilized more lipids we examined white adipose tissue (WAT) stores. Contrary to expectations, fasted STAT1-/- mice did not lose lipid from WAT. β-adrenergic stimulation of glycerol release from isolated STAT1-/- WAT was decreased, while activation of hormone sensitive lipase was not changed. These findings suggest that STAT1-/- adipose tissue does not release glycerol and that free fatty acids (FFA) re-esterify back to triglycerides, thus maintaining fat mass in fasted STAT1-/- mice.
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Sisler
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Vidisha
authors.initials: V
authors.lastname: Raje
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, United States of America.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Grande
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Marta
authors.initials: M
authors.lastname: Derecka
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Meier
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Marc
authors.initials: M
authors.lastname: Cantwell
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.|Medical Service, McGuire Department of Veterans Affairs Medical Center, Richmond, VA, 23249, United States of America.
authors.forename: Karol
authors.initials: K
authors.lastname: Szczepanek
authors.affiliation: Department of Clinical Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: William J
authors.initials: WJ
authors.lastname: Korzun
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.|Medical Service, McGuire Department of Veterans Affairs Medical Center, Richmond, VA, 23249, United States of America.|Department of Internal Medicine, Division of Cardiology, and Pauley Heart Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Lesnefsky
authors.affiliation: Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, 22908, United States of America.
authors.forename: Thurl E
authors.initials: TE
authors.lastname: Harris
authors.affiliation: Department of Nutrition, Case Western University School of Medicine, Cleveland, OH, 44106, United States of America.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Croniger
authors.affiliation: Department of Biochemistry and Molecular Biology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, United States of America.
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Larner
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D045222:Electron Transport Chain Complex Proteins / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000235:genetics / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020218:Response Elements; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: D045222:Electron Transport Chain Complex Proteins; D005227:Fatty Acids; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D014157:Transcription Factors; D014280:Triglycerides