title: Sirtuin 1 regulates SREBP-1c expression in a LXR-dependent manner in skeletal muscle.
abstract: Sirtuin 1 (SIRT1), a NAD(+)-dependent protein deacetylase, has emerged as a main determinant of whole body homeostasis in mammals by regulating a large spectrum of transcriptional regulators in metabolically relevant tissue such as liver, adipose tissue and skeletal muscle. Sterol regulatory element binding protein (SREBP)-1c is a transcription factor that controls the expression of genes related to fatty acid and triglyceride synthesis in tissues with high lipid synthesis rates such as adipose tissue and liver. Previous studies indicate that SIRT1 can regulate the expression and function of SREBP-1c in liver. In the present study, we determined whether SIRT1 regulates SREBP-1c expression in skeletal muscle. SREBP-1c mRNA and protein levels were decreased in the gastrocnemius muscle of mice harboring deletion of the catalytic domain of SIRT1 (SIRT1(Δex4/Δex4) mice). By contrast, adenoviral expression of SIRT1 in human myotubes increased SREBP-1c mRNA and protein levels. Importantly, SREBP-1c promoter transactivation, which was significantly increased in response to SIRT1 overexpression by gene electrotransfer in skeletal muscle, was completely abolished when liver X receptor (LXR) response elements were deleted. Finally, our in vivo data from SIRT1(Δex4/Δex4) mice and in vitro data from human myotubes overexpressing SIRT1 show that SIRT1 regulates LXR acetylation in skeletal muscle cells. This suggests a possible mechanism by which the regulation of SREBP-1c gene expression by SIRT1 may require the deacetylation of LXR transcription factors.
authors.affiliation: Laboratoire de Physiologie de l'Exercice, Université de Lyon, Saint Etienne, France.
authors.forename: Aurélia
authors.initials: A
authors.lastname: Defour
authors.forename: Kevin
authors.initials: K
authors.lastname: Dessalle
authors.forename: Andréa
authors.initials: A
authors.lastname: Castro Perez
authors.forename: Thomas
authors.initials: T
authors.lastname: Poyot
authors.forename: Josiane
authors.initials: J
authors.lastname: Castells
authors.forename: Yann Simon
authors.initials: YS
authors.lastname: Gallot
authors.forename: Christine
authors.initials: C
authors.lastname: Durand
authors.forename: Vanessa
authors.initials: V
authors.lastname: Euthine
authors.forename: Yansong
authors.initials: Y
authors.lastname: Gu
authors.forename: Daniel
authors.initials: D
authors.lastname: Béchet
authors.forename: André
authors.initials: A
authors.lastname: Peinnequin
authors.forename: Etienne
authors.initials: E
authors.lastname: Lefai
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
mesh_terms: D000107:Acetylation; D000818:Animals; D005786:Gene Expression Regulation; D006801:Humans; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000235:genetics
chemical_list: D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D051780:Sterol Regulatory Element Binding Protein 1; D056564:Sirtuin 1