title: Separation of the gluconeogenic and mitochondrial functions of PGC-1{alpha} through S6 kinase.
abstract: PGC-1α is a transcriptional coactivator that powerfully regulates many pathways linked to energy homeostasis. Specifically, PGC-1α controls mitochondrial biogenesis in most tissues but also initiates important tissue-specific functions, including fiber type switching in skeletal muscle and gluconeogenesis and fatty acid oxidation in the liver. We show here that S6 kinase, activated in the liver upon feeding, can phosphorylate PGC-1α directly on two sites within its arginine/serine-rich (RS) domain. This phosphorylation significantly attenuates the ability of PGC-1α to turn on genes of gluconeogenesis in cultured hepatocytes and in vivo, while leaving the functions of PGC-1α as an activator of mitochondrial and fatty acid oxidation genes completely intact. These phosphorylations interfere with the ability of PGC-1α to bind to HNF4α, a transcription factor required for gluconeogenesis, while leaving undisturbed the interactions of PGC-1α with ERRα and PPARα, factors important for mitochondrial biogenesis and fatty acid oxidation. These data illustrate that S6 kinase can modify PGC-1α and thus allow molecular dissection of its functions, providing metabolic flexibility needed for dietary adaptation.
authors.affiliation: Department of Cell Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yaniv
authors.initials: Y
authors.lastname: Lustig
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Ruas
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Estall
authors.forename: James C
authors.initials: JC
authors.lastname: Lo
authors.forename: Srikripa
authors.initials: S
authors.lastname: Devarakonda
authors.forename: Dina
authors.initials: D
authors.lastname: Laznik
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.forename: Hiraku
authors.initials: H
authors.lastname: Ono
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D000818:Animals; D002460:Cell Line; D005943:Gluconeogenesis / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D019893:Ribosomal Protein S6 Kinases