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Literature DB >> 22927400

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase.

Joshua L Owen¹, Yuanyuan Zhang, Soo-Han Bae, Midhat S Farooqi, Guosheng Liang, Robert E Hammer, Joseph L Goldstein, Michael S Brown.

Abstract

Insulin activates sterol regulatory element-binding protein-1c (SREBP-1c) in liver, thereby increasing fatty acid and triglyceride synthesis. We created a line of transgenic rats that produce epitope-tagged human SREBP-1c in liver under control of the constitutive apolipoprotein E promoter/enhancer. This system allows us to dissect the pathway by which insulin stimulates SREBP-1c processing without interference by the insulin-mediated increase in SREBP-1c mRNA. Rats are used because freshly isolated rat hepatocytes respond much more robustly to insulin than do mouse hepatocytes. The data reveal that insulin-mediated stimulation of SREBP-1c processing requires the mechanistic target of rapamycin complex 1 (mTORC1), which also is required for insulin-mediated SREBP-1c mRNA induction. However, in contrast to mRNA induction, insulin stimulation of SREBP-1c processing is blocked by an inhibitor of p70 S6-kinase. The data indicate that the pathways for insulin enhancement of SREBP-1c mRNA and proteolytic processing diverge after mTORC1. Stimulation of processing requires the mTORC1 target p70 S6-kinase, whereas induction of mRNA bypasses this enzyme. Insulin stimulation of both processes is blocked by glucagon. The transgenic rat system will be useful in further defining the molecular mechanism for insulin stimulation of lipid synthesis in liver in normal and diabetic states.

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Year: 2012 PMID： 22927400 PMCID： PMC3479583 DOI： 10.1073/pnas.1213343109

Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205

22 in total

1. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.

Authors: I Shimomura; M Matsuda; R E Hammer; Y Bashmakov; M S Brown; J L Goldstein
Journal: Mol Cell Date: 2000-07 Impact factor: 17.970

Review 2. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.

Authors: Jay D Horton; Joseph L Goldstein; Michael S Brown
Journal: J Clin Invest Date: 2002-05 Impact factor: 14.808

Review 3. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.

Authors: M S Brown; J L Goldstein
Journal: Cell Date: 1997-05-02 Impact factor: 41.582

4. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes.

Authors: I Shimomura; Y Bashmakov; S Ikemoto; J D Horton; M S Brown; J L Goldstein
Journal: Proc Natl Acad Sci U S A Date: 1999-11-23 Impact factor: 11.205

5. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes.

Authors: M Foretz; C Guichard; P Ferré; F Foufelle
Journal: Proc Natl Acad Sci U S A Date: 1999-10-26 Impact factor: 11.205

6. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c.

Authors: Bronwyn D Hegarty; Alexandre Bobard; Isabelle Hainault; Pascal Ferré; Pascale Bossard; Fabienne Foufelle
Journal: Proc Natl Acad Sci U S A Date: 2005-01-06 Impact factor: 11.205

7. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis.

Authors: Luke J Engelking; Hiroshi Kuriyama; Robert E Hammer; Jay D Horton; Michael S Brown; Joseph L Goldstein; Guosheng Liang
Journal: J Clin Invest Date: 2004-04 Impact factor: 14.808

Review 8. Molecular mediators of hepatic steatosis and liver injury.

Authors: Jeffrey D Browning; Jay D Horton
Journal: J Clin Invest Date: 2004-07 Impact factor: 14.808

9. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver.

Authors: Guoxun Chen; Guosheng Liang; Jiafu Ou; Joseph L Goldstein; Michael S Brown
Journal: Proc Natl Acad Sci U S A Date: 2004-07-20 Impact factor: 11.205

10. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.

Authors: X Wang; R Sato; M S Brown; X Hua; J L Goldstein
Journal: Cell Date: 1994-04-08 Impact factor: 41.582

110 in total

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Authors: Uma Kant Misra; Salvatore Vincent Pizzo
Journal: J Biol Chem Date: 2015-02-26 Impact factor: 5.157

2. Pathogenesis of selective insulin resistance in isolated hepatocytes.

Authors: Joshua R Cook; Fanny Langlet; Yoshiaki Kido; Domenico Accili
Journal: J Biol Chem Date: 2015-04-14 Impact factor: 5.157

3. 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice.

Authors: Jin Zhang; Li-na Zhang; Dong-mei Chen; Yan-yun Fu; Feng Zhang; Ling-ling Yang; Chun-mei Xia; Hao-wen Jiang; Chun-lan Tang; Zhi-fu Xie; Fan Yang; Jia Li; Jie Tang; Jing-ya Li
Journal: Acta Pharmacol Sin Date: 2015-03-16 Impact factor: 6.150

Insulin stimulation of SREBP-1c processing in transgenic rat hepatocytes requires p70 S6-kinase.

1. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice.

Review 2. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver.

Review 3. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.

4. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes.

5. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes.

6. Distinct roles of insulin and liver X receptor in the induction and cleavage of sterol regulatory element-binding protein-1c.

7. Overexpression of Insig-1 in the livers of transgenic mice inhibits SREBP processing and reduces insulin-stimulated lipogenesis.

Review 8. Molecular mediators of hepatic steatosis and liver injury.

9. Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver.

10. SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis.

1. Activated α2-macroglobulin binding to human prostate cancer cells triggers insulin-like responses.

2. Pathogenesis of selective insulin resistance in isolated hepatocytes.

3. 2-(3-Benzoylthioureido)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid ameliorates metabolic disorders in high-fat diet-fed mice.

4. Distinct mTORC1 pathways for transcription and cleavage of SREBP-1c.

Review 5. The lysosome as a cellular centre for signalling, metabolism and quality control.

Review 6. Omega-3 polyunsaturated fatty acids as a treatment strategy for nonalcoholic fatty liver disease.

Review 7. Insulin signaling, resistance, and the metabolic syndrome: insights from mouse models into disease mechanisms.

8. Insulin-induced de novo lipid synthesis occurs mainly via mTOR-dependent regulation of proteostasis of SREBP-1c.

9. Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms.

10. MicroRNA 33 regulates glucose metabolism.