Home LiteratureArticle Details
PMID: 20197055 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Specific roles of the p110alpha isoform of phosphatidylinsositol 3-kinase in hepatic insulin signaling and metabolic regulation.

Cell metabolism ·Vol. 11 ·No. 3 ·2010-03-03 ·Pages 220-30

Sopasakis VR, Liu P, Suzuki R, Kondo T, Winnay J, Tran TT, Asano T, Smyth G, Sajan MP, Farese RV, Kahn CR, Zhao JJ

Abstract

The class I(A) phosphatidylinsositol 3-kinases (PI3Ks) form a critical node in the insulin metabolic pathway; however, the precise roles of the different isoforms of this enzyme remain elusive. Using tissue-specific gene inactivation, we demonstrate that p110alpha catalytic subunit of PI3K is a key mediator of insulin metabolic actions in the liver. Thus, deletion of p110alpha in liver results in markedly blunted insulin signaling with decreased generation of PIP(3) and loss of insulin activation of Akt, defects that could not be rescued by overexpression of p110beta. As a result, mice with hepatic knockout of p110alpha display reduced insulin sensitivity, impaired glucose tolerance, and increased gluconeogenesis, hypolipidemia, and hyperleptinemia. The diabetic syndrome induced by loss of p110alpha in liver did not respond to metformin treatment. Together, these data indicate that the p110alpha isoform of PI3K plays a fundamental role in insulin signaling and control of hepatic glucose and lipid metabolism.

MeSH Terms
Animals Blood Glucose/metabolism Class I Phosphatidylinositol 3-Kinases Diabetes Mellitus/drug therapy,metabolism Down-Regulation Energy Metabolism Glucose Intolerance/metabolism Insulin/metabolism Leptin/metabolism Lipids/physiology Liver/metabolism Metformin/therapeutic use Mice Mice, Knockout Phosphatidylinositol 3-Kinases/genetics,metabolism Phosphatidylinositol Phosphates/metabolism Proto-Oncogene Proteins c-akt/metabolism Signal Transduction
Chemicals
Blood Glucose Insulin Leptin Lipids Phosphatidylinositol Phosphates phosphatidylinositol 3,4,5-triphosphate Metformin Phosphatidylinositol 3-Kinases 1-phosphatidylinositol 3-kinase p110 subunit, mouse Class I Phosphatidylinositol 3-Kinases Proto-Oncogene Proteins c-akt
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Sopasakis Victoria Rotter
Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA.
Liu Pixu
Suzuki Ryo
Kondo Tatsuya
Winnay Jonathon
Tran Thien T
Asano Tomoichiro
Smyth Graham
Sajan Mini P
Farese Robert V
Kahn C Ronald
Zhao Jean J
References (44)
44 references, click to expand
  1. Proliferative defect and embryonic lethality in mice homozygous for a deletion in the p110alpha subunit of phosphoinositide 3-kinase.
    J Biol Chem. 1999 Apr 16;274(16):10963-8 PMID: 10196176
  2. Therapeutic potential of phosphoinositide 3-kinase inhibitors.
    Chem Biol. 2003 Mar;10(3):207-13 PMID: 12670534
  3. Insulin resistance differentially affects the PI 3-kinase- and MAP kinase-mediated signaling in human muscle.
    J Clin Invest. 2000 Feb;105(3):311-20 PMID: 10675357
  4. Essential roles of PI(3)K-p110beta in cell growth, metabolism and tumorigenesis.
    Nature. 2008 Aug 7;454(7205):776-9 PMID: 18594509
  5. PKClambda in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity.
    J Clin Invest. 2003 Sep;112(6):935-44 PMID: 12975478
  6. Divergent regulation of hepatic glucose and lipid metabolism by phosphoinositide 3-kinase via Akt and PKClambda/zeta.
    Cell Metab. 2006 May;3(5):343-53 PMID: 16679292
  7. Structure and function of phosphoinositide 3-kinases.
    Biochim Biophys Acta. 1998 Dec 8;1436(1-2):127-50 PMID: 9838078
  8. Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.
    Mol Cell Biol. 1998 Mar;18(3):1379-87 PMID: 9488453
  9. Phosphoinositide 3-kinase p110beta activity: key role in metabolism and mammary gland cancer but not development.
    Sci Signal. 2008 Sep 09;1(36):ra3 PMID: 18780892
  10. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer.
    Annu Rev Cell Dev Biol. 2001;17:615-75 PMID: 11687500
  11. Phosphoinositide 3-kinases: a conserved family of signal transducers.
    Trends Biochem Sci. 1997 Jul;22(7):267-72 PMID: 9255069
  12. p110beta is up-regulated during differentiation of 3T3-L1 cells and contributes to the highly insulin-responsive glucose transport activity.
    J Biol Chem. 2000 Jun 9;275(23):17671-6 PMID: 10748220
  13. Phosphoinositide 3-kinase regulatory subunit p85alpha suppresses insulin action via positive regulation of PTEN.
    Proc Natl Acad Sci U S A. 2006 Aug 8;103(32):12093-7 PMID: 16880400
  14. Comparison of the kinetic properties of the lipid- and protein-kinase activities of the p110alpha and p110beta catalytic subunits of class-Ia phosphoinositide 3-kinases.
    Biochem J. 2000 Sep 1;350 Pt 2:353-9 PMID: 10947948
  15. Atypical protein kinase C in insulin action and insulin resistance.
    Biochem Soc Trans. 2005 Apr;33(Pt 2):350-3 PMID: 15787604
  16. Role of AMP-activated protein kinase in mechanism of metformin action.
    J Clin Invest. 2001 Oct;108(8):1167-74 PMID: 11602624
  17. Insulin-induced activation of atypical protein kinase C, but not protein kinase B, is maintained in diabetic (ob/ob and Goto-Kakazaki) liver. Contrasting insulin signaling patterns in liver versus muscle define phenotypes of type 2 diabetic and high fat-induced insulin-resistant states.
    J Biol Chem. 2004 Jun 11;279(24):24929-34 PMID: 15069067
  18. Phosphatidylinositol 3-kinase activation is required for insulin stimulation of pp70 S6 kinase, DNA synthesis, and glucose transporter translocation.
    Mol Cell Biol. 1994 Jul;14(7):4902-11 PMID: 8007986
  19. Phosphoinositide kinases.
    Annu Rev Biochem. 1998;67:481-507 PMID: 9759495
  20. Mosaic analysis of insulin receptor function.
    J Clin Invest. 2004 Jan;113(2):209-19 PMID: 14722613
  21. Modeling error and apparent isotope discrimination confound estimation of endogenous glucose production during euglycemic glucose clamps.
    Diabetes. 1988 Aug;37(8):1025-34 PMID: 3292323
  22. Ablation of ARNT/HIF1beta in liver alters gluconeogenesis, lipogenic gene expression, and serum ketones.
    Cell Metab. 2009 May;9(5):428-39 PMID: 19416713
  23. High circulating leptin receptors with normal leptin sensitivity in liver-specific insulin receptor knock-out (LIRKO) mice.
    J Biol Chem. 2007 Aug 10;282(32):23672-8 PMID: 17556363
  24. Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet.
    Diabetes. 2002 Jan;51(1):139-43 PMID: 11756333
  25. The p110alpha isoform of PI3K is essential for proper growth factor signaling and oncogenic transformation.
    Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16296-300 PMID: 17060635
  26. Phosphoinositide 3-kinase catalytic subunit deletion and regulatory subunit deletion have opposite effects on insulin sensitivity in mice.
    Mol Cell Biol. 2005 Mar;25(5):1596-607 PMID: 15713620
  27. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.
    Cell. 2006 May 19;125(4):733-47 PMID: 16647110
  28. Determinants affecting physical activity levels in animal models.
    Exp Biol Med (Maywood). 2002 Sep;227(8):587-600 PMID: 12192100
  29. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus.
    N Engl J Med. 1995 Aug 31;333(9):550-4 PMID: 7623903
  30. The critical role of atypical protein kinase C in activating hepatic SREBP-1c and NFkappaB in obesity.
    J Lipid Res. 2009 Jun;50(6):1133-45 PMID: 19202134
  31. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus.
    N Engl J Med. 1998 Mar 26;338(13):867-72 PMID: 9516221
  32. Muscle-specific PPARgamma-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones.
    J Clin Invest. 2003 Aug;112(4):608-18 PMID: 12925701
  33. Early embryonic lethality in mice deficient in the p110beta catalytic subunit of PI 3-kinase.
    Mamm Genome. 2002 Mar;13(3):169-72 PMID: 11919689
  34. The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity.
    Mol Cell Biol. 1994 Apr;14(4):2675-85 PMID: 8139567
  35. Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.
    Proc Natl Acad Sci U S A. 2007 May 8;104(19):7809-14 PMID: 17470792
  36. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction.
    Mol Cell. 2000 Jul;6(1):87-97 PMID: 10949030
  37. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents.
    Curr Opin Pharmacol. 2003 Aug;3(4):426-34 PMID: 12901953
  38. Mechanism by which metformin reduces glucose production in type 2 diabetes.
    Diabetes. 2000 Dec;49(12):2063-9 PMID: 11118008
  39. Positive and negative regulation of phosphoinositide 3-kinase-dependent signaling pathways by three different gene products of the p85alpha regulatory subunit.
    Mol Cell Biol. 2000 Nov;20(21):8035-46 PMID: 11027274
  40. Tissue-specific differences in activation of atypical protein kinase C and protein kinase B in muscle, liver, and adipocytes of insulin receptor substrate-1 knockout mice.
    Mol Endocrinol. 2004 Oct;18(10):2513-21 PMID: 15256535
  41. Structure and function of phosphatidylinositol-3,4 kinase.
    Cell Signal. 2000 Mar;12(3):135-42 PMID: 10704820
  42. Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.
    Nature. 2006 May 18;441(7091):366-70 PMID: 16625210
  43. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
    Nat Rev Genet. 2006 Aug;7(8):606-19 PMID: 16847462
  44. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin.
    Science. 2005 Dec 9;310(5754):1642-6 PMID: 16308421
Article Info
Journal
Cell metabolism
Abbr.
Cell Metab
ISSN
1932-7420
DOI
10.1016/j.cmet.2010.02.002
Published
2010-03-03
Pages
220-30
Language
English
Region
United States
NLM ID
101233170
PMCID
PMC3144706
Subset
IM
Grants
NIDDK NIH HHS · R01 DK033201-26 · United States
NIDDK NIH HHS · DK34834 · United States
NIDDK NIH HHS · R01 DK055545-12 · United States
NCI NIH HHS · R01 CA134502 · United States
NIDDK NIH HHS · R01 DK055545 · United States
NIDDK NIH HHS · P30 DK036836 · United States
NIDDK NIH HHS · R01 DK33201 · United States
NIDDK NIH HHS · R01 DK065969 · United States
NCI NIH HHS · P50 CA089393 · United States
NIDDK NIH HHS · P30 DK036836-13 · United States
NCI NIH HHS · R01 CA089393 · United States
NIDDK NIH HHS · R01 DK55545 · United States
NIDDK NIH HHS · R01 DK033201 · United States
External Links
PubMed source DOI: 10.1016/j.cmet.2010.02.002 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: [email protected]

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2