title: Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver.
abstract: Sterol regulatory element-binding protein-1 (SREBP-1) is a key transcription factor that regulates genes in the de novo lipogenesis and glycolysis pathways. The levels of SREBP-1 are significantly elevated in obese patients and in animal models of obesity and type 2 diabetes, and a vast number of studies have implicated this transcription factor as a contributor to hepatic lipid accumulation and insulin resistance. However, its role in regulating carbohydrate metabolism is poorly understood. Here we have addressed whether SREBP-1 is needed for regulating glucose homeostasis. Using RNAi and a new generation of adenoviral vector, we have silenced hepatic SREBP-1 in normal and obese mice. In normal animals, SREBP-1 deficiency increased Pck1 and reduced glycogen deposition during fed conditions, providing evidence that SREBP-1 is necessary to regulate carbohydrate metabolism during the fed state. Knocking SREBP-1 down in db/db mice resulted in a significant reduction in triglyceride accumulation, as anticipated. However, mice remained hyperglycemic, which was associated with up-regulation of gluconeogenesis gene expression as well as decreased glycolysis and glycogen synthesis gene expression. Furthermore, glycogen synthase activity and glycogen accumulation were significantly reduced. In conclusion, silencing both isoforms of SREBP-1 leads to significant changes in carbohydrate metabolism and does not improve insulin resistance despite reducing steatosis in an animal model of obesity and type 2 diabetes.
authors.affiliation: From the Departments of Medical and Molecular Genetics and.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Ruiz
authors.forename: Victoria
authors.initials: V
authors.lastname: Jideonwo
authors.forename: Miwon
authors.initials: M
authors.lastname: Ahn
authors.forename: Sneha
authors.initials: S
authors.lastname: Surendran
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Tagliabracci
authors.forename: Yongyong
authors.initials: Y
authors.lastname: Hou
authors.forename: Aisha
authors.initials: A
authors.lastname: Gamble
authors.forename: Janos
authors.initials: J
authors.lastname: Kerner
authors.forename: José M
authors.initials: JM
authors.lastname: Irimia-Dominguez
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Puchowicz
authors.forename: Anna
authors.initials: A
authors.lastname: DePaoli-Roach
authors.forename: Charles
authors.initials: C
authors.lastname: Hoppel
authors.forename: Peter
authors.initials: P
authors.lastname: Roach
authors.forename: Núria
authors.initials: N
authors.lastname: Morral
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation / Q000502:physiology*; D055785:Gene Knockdown Techniques; D005943:Gluconeogenesis / Q000502:physiology*; D006003:Glycogen / Q000096:biosynthesis* / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D006003:Glycogen
keywords: Gene Expression; Gluconeogenesis; Glucose Metabolism; Insulin Resistance; Liver Metabolism