Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver

Rafaela Ruiz, Victoria Jideonwo, Miwon Ahn, Sneha Surendran, Vincent S. Tagliabracci, Yongyong Hou, Aisha Gamble, Janos Kerner, José M. Irimia-Dominguez, Michelle A. Puchowicz, Anna DePaoli-Roach, Charles Hoppel, Peter Roach, Núria Morral

Research output: Contribution to journalArticle

43 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)5510-5517
Number of pages8
JournalJournal of Biological Chemistry
Volume289
Issue number9
DOIs
StatePublished - Feb 28 2014

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Sterol Regulatory Element Binding Protein 1
Glycogen
Gene expression
Liver
Gene Expression
Carbohydrate Metabolism
Obese Mice
Animals
Glycolysis
Medical problems
Type 2 Diabetes Mellitus
Insulin Resistance
Transcription Factors
Animal Models
Obesity
Insulin
Protein Deficiency
Glycogen Synthase
Lipogenesis
Gluconeogenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. / Ruiz, Rafaela; Jideonwo, Victoria; Ahn, Miwon; Surendran, Sneha; Tagliabracci, Vincent S.; Hou, Yongyong; Gamble, Aisha; Kerner, Janos; Irimia-Dominguez, José M.; Puchowicz, Michelle A.; DePaoli-Roach, Anna; Hoppel, Charles; Roach, Peter; Morral, Núria.

In: Journal of Biological Chemistry, Vol. 289, No. 9, 28.02.2014, p. 5510-5517.

Research output: Contribution to journalArticle

Ruiz, R, Jideonwo, V, Ahn, M, Surendran, S, Tagliabracci, VS, Hou, Y, Gamble, A, Kerner, J, Irimia-Dominguez, JM, Puchowicz, MA, DePaoli-Roach, A, Hoppel, C, Roach, P & Morral, N 2014, 'Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver', Journal of Biological Chemistry, vol. 289, no. 9, pp. 5510-5517. https://doi.org/10.1074/jbc.M113.541110
Ruiz, Rafaela ; Jideonwo, Victoria ; Ahn, Miwon ; Surendran, Sneha ; Tagliabracci, Vincent S. ; Hou, Yongyong ; Gamble, Aisha ; Kerner, Janos ; Irimia-Dominguez, José M. ; Puchowicz, Michelle A. ; DePaoli-Roach, Anna ; Hoppel, Charles ; Roach, Peter ; Morral, Núria. / Sterol regulatory element-binding protein-1 (SREBP-1) is required to regulate glycogen synthesis and gluconeogenic gene expression in mouse liver. In: Journal of Biological Chemistry. 2014 ; Vol. 289, No. 9. pp. 5510-5517.
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