Hepatic Suppression of Foxo1 and Foxo3 Causes Hypoglycemia and Hyperlipidemia in Mice

Endocrinology - Tập 153 Số 2 - Trang 631-646 - 2012
Kebin Zhang1, Ling Li1, Yajuan Qi1, Xiaoping Zhu1, Boyi Gan2, Ronald A. DePinho2, Travis Averitt1, Shaodong Guo1
1Division of Molecular Cardiology (K.Z., L.L., Y.Q., X.Z., T.A., S.G.), Cardiovascular Research Institute, College of Medicine, Texas A&M Health Science Center, Central Texas Veterans Health Care System, Temple, Texas 76504
2Departments of Medical Oncology, Medicine, and Genetics (B.G., R.A.D.), Belfer Institute for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115

Tóm tắt

Dysregulation of blood glucose and triglycerides are the major characteristics of type 2 diabetes mellitus. We sought to identify the mechanisms regulating blood glucose and lipid homeostasis. Cell-based studies established that the Foxo forkhead transcription factors Forkhead box O (Foxo)-1, Foxo3, and Foxo4 are inactivated by insulin via a phosphatidylinositol 3-kinase/Akt-dependent pathway, but the role of Foxo transcription factors in the liver in regulating nutrient metabolism is incompletely understood. In this study, we used the Cre/LoxP genetic approach to delete the Foxo1, Foxo3, and Foxo4 genes individually or a combination of two or all in the liver of lean or db/db mice and assessed the role of Foxo inactivation in regulating glucose and lipid homeostasis in vivo. In the lean mice or db/db mice, hepatic deletion of Foxo1, rather than Foxo3 or Foxo4, caused a modest reduction in blood glucose concentrations and barely affected lipid homeostasis. Combined deletion of Foxo1 and Foxo3 decreased blood glucose levels, elevated serum triglyceride and cholesterol concentrations, and increased hepatic lipid secretion and caused hepatosteatosis. Analysis of the liver transcripts established a prominent role of Foxo1 in regulating gene expression of gluconeogenic enzymes and Foxo3 in the expression of lipogenic enzymes. Our findings indicate that Foxo1 and Foxo3 inactivation serves as a potential mechanism by which insulin reduces hepatic glucose production and increases hepatic lipid synthesis and secretion in healthy and diabetic states.

Từ khóa


Tài liệu tham khảo

Saltiel, 2001, Insulin signalling and the regulation of glucose and lipid metabolism., Nature, 414, 799, 10.1038/414799a

Michael, 2000, Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction., Mol Cell, 6, 87, 10.1016/S1097-2765(05)00015-8

Guo, 2009, The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis., Mol Cell Biol, 29, 5070, 10.1128/MCB.00138-09

George, 2004, A family with severe insulin resistance and diabetes due to a mutation in AKT2., Science, 304, 1325, 10.1126/science.1096706

Cho, 2001, Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKBβ)., Science, 292, 1728, 10.1126/science.292.5522.1728

Gross, 2008, The role of FoxO in the regulation of metabolism., Oncogene, 27, 2320, 10.1038/onc.2008.25

Guo, 1999, Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin-like growth factor-binding protein-1 promoter activity through a conserved insulin response sequence., J Biol Chem, 274, 17184, 10.1074/jbc.274.24.17184

Schmoll, 2000, Regulation of glucose-6-phosphatase gene expression by protein kinase Bα and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity., J Biol Chem, 275, 36324, 10.1074/jbc.M003616200

Yeagley, 2001, Gene- and activation-specific mechanisms for insulin inhibition of basal and glucocorticoid-induced insulin-like growth factor binding protein-1 and phosphoenolpyruvate carboxykinase transcription. Roles of forkhead and insulin response sequences., J Biol Chem, 276, 33705, 10.1074/jbc.M101215200

Rena, 1999, Phosphorylation of the transcription factor forkhead family member FKHR by protein kinase B., J Biol Chem, 274, 17179, 10.1074/jbc.274.24.17179

Brunet, 1999, Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor., Cell, 96, 857, 10.1016/S0092-8674(00)80595-4

Kops, 1999, Direct control of the Forkhead transcription factor AFX by protein kinase B., Nature, 398, 630, 10.1038/19328

Huang, 2005, Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation., Proc Natl Acad Sci USA, 102, 1649, 10.1073/pnas.0406789102

Matsuzaki, 2003, Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation., Proc Natl Acad Sci USA, 100, 11285, 10.1073/pnas.1934283100

Biggs, 1999, Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1., Proc Natl Acad Sci USA, 96, 7421, 10.1073/pnas.96.13.7421

Matsumoto, 2007, Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver., Cell Metab, 6, 208, 10.1016/j.cmet.2007.08.006

Dong, 2008, Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation., Cell Metab, 8, 65, 10.1016/j.cmet.2008.06.006

Altomonte, 2003, Inhibition of Foxo1 function is associated with improved fasting glycemia in diabetic mice., Am J Physiol Endocrinol Metab, 285, E718, 10.1152/ajpendo.00156.2003

Nakae, 2002, Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1., Nat Genet, 32, 245, 10.1038/ng890

Barthel, 2005, FoxO proteins in insulin action and metabolism., Trends Endocrinol Metab, 16, 183, 10.1016/j.tem.2005.03.010

Hosaka, 2004, Disruption of forkhead transcription factor (FOXO) family members in mice reveals their functional diversification., Proc Natl Acad Sci USA, 101, 2975, 10.1073/pnas.0400093101

Haeusler, 2010, FoxOs function synergistically to promote glucose production., J Biol Chem, 285, 35245, 10.1074/jbc.C110.175851

Paik, 2007, FoxOs are lineage-restricted redundant tumor suppressors and regulate endothelial cell homeostasis., Cell, 128, 309, 10.1016/j.cell.2006.12.029

Postic, 2000, DNA excision in liver by an albumin-Cre transgene occurs progressively with age., Genesis, 26, 149, 10.1002/(SICI)1526-968X(200002)26:2<149::AID-GENE16>3.0.CO;2-V

Folch, 1957, A simple method for the isolation and purification of total lipides from animal tissues., J Biol Chem, 226, 497, 10.1016/S0021-9258(18)64849-5

Watkins, 2001, Unique phospholipid metabolism in mouse heart in response to dietary docosahexaenoic or α-linolenic acids., Lipids, 36, 247, 10.1007/s11745-001-0714-8

Lo, 1970, Determination of glycogen in small tissue samples., J Appl Physiol, 28, 234, 10.1152/jappl.1970.28.2.234

Guo, 2006, The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling., Mol Endocrinol, 20, 3389, 10.1210/me.2006-0092

Abid, 2004, Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells., Arterioscler Thromb Vasc Biol, 24, 294, 10.1161/01.ATV.0000110502.10593.06

Zang, 2004, AMP-activated protein kinase is required for the lipid-lowering effect of metformin in insulin-resistant human HepG2 cells., J Biol Chem, 279, 47898, 10.1074/jbc.M408149200

Hou, 2008, SIRT1 regulates hepatocyte lipid metabolism through activating AMP-activated protein kinase., J Biol Chem, 283, 20015, 10.1074/jbc.M802187200

Li, 1996, Method to measure apolipoprotein B-48 and B-100 secretion rates in an individual mouse: evidence for a very rapid turnover of VLDL and preferential removal of B-48- relative to B-100-containing lipoproteins., J Lipid Res, 37, 210, 10.1016/S0022-2275(20)37649-5

Essaghir, 2009, The transcription of FOXO genes is stimulated by FOXO3 and repressed by growth factors., J Biol Chem, 284, 10334, 10.1074/jbc.M808848200

O'Brien, 1990, Identification of a sequence in the PEPCK gene that mediates a negative effect of insulin on transcription., Science, 249, 533, 10.1126/science.2166335

Cichy, 1998, Protein kinase B/Akt mediates effects of insulin on hepatic insulin-like growth factor-binding protein-1 gene expression through a conserved insulin response sequence., J Biol Chem, 273, 6482, 10.1074/jbc.273.11.6482

O'Brien, 1996, Regulation of gene expression by insulin., Physiol Rev, 76, 1109, 10.1152/physrev.1996.76.4.1109

Hall, 2000, Regulation of phosphoenolpyruvate carboxykinase and insulin-like growth factor-binding protein-1 gene expression by insulin. The role of winged helix/forkhead proteins., J Biol Chem, 275, 30169, 10.1074/jbc.M004898200

Onuma, 2006, Correlation between FOXO1a (FKHR) and FOXO3a (FKHRL1) binding and the inhibition of basal glucose-6-phosphatase catalytic subunit gene transcription by insulin., Mol Endocrinol, 20, 2831, 10.1210/me.2006-0085

Ghosh, 2001, A nucleoprotein complex containing CCAAT/enhancer-binding protein β interacts with an insulin response sequence in the insulin-like growth factor-binding protein-1 gene and contributes to insulin-regulated gene expression., J Biol Chem, 276, 8507, 10.1074/jbc.M008541200

Wolfrum, 2004, Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes., Nature, 432, 1027, 10.1038/nature03047

Zhang, 2005, Foxa2 integrates the transcriptional response of the hepatocyte to fasting., Cell Metab, 2, 141, 10.1016/j.cmet.2005.07.002

Guo, 2001, Insulin suppresses transactivation by CAAT/enhancer-binding proteins β (C/EBPβ). Signaling to p300/CREB-binding protein by protein kinase B disrupts interaction with the major activation domain of C/EBPβ., J Biol Chem, 276, 8516, 10.1074/jbc.M008542200

Qiao, 2006, SIRT1 regulates adiponectin gene expression through Foxo1-C/enhancer-binding protein alpha transcriptional complex., J Biol Chem, 281, 39915, 10.1074/jbc.M607215200

Puigserver, 2003, Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1α interaction., Nature, 423, 550, 10.1038/nature01667

Hirota, 2008, A combination of HNF-4 and Foxo1 is required for reciprocal transcriptional regulation of glucokinase and glucose-6-phosphatase genes in response to fasting and feeding., J Biol Chem, 283, 32432, 10.1074/jbc.M806179200

Hall, 2007, Insulin represses phosphoenolpyruvate carboxykinase gene transcription by causing the rapid disruption of an active transcription complex: a potential epigenetic effect., Mol Endocrinol, 21, 550, 10.1210/me.2006-0307

Haeusler, 2010, Hepatic FOXO1 ablation exacerbates lipid abnormalities during hyperglycemia., J Biol Chem, 285, 26861, 10.1074/jbc.M110.134023

Tao, 2011, Hepatic FoxOs regulate lipid metabolism via modulation of expression of the nicotinamide phosphoribosyltransferase gene., J Biol Chem, 286, 14681, 10.1074/jbc.M110.201061

Xiong, 2011, FoxO1 mediates an autofeedback loop regulating SIRT1 expression., J Biol Chem, 286, 5289, 10.1074/jbc.M110.163667

Samuel, 2006, Targeting foxo1 in mice using antisense oligonucleotide improves hepatic and peripheral insulin action., Diabetes, 55, 2042, 10.2337/db05-0705

Liu, 2009, Hepatic autophagy is suppressed in the presence of insulin resistance and hyperinsulinemia: inhibition of FoxO1-dependent expression of key autophagy genes by insulin., J Biol Chem, 284, 31484, 10.1074/jbc.M109.033936

Singh, 2009, Autophagy regulates lipid metabolism., Nature, 458, 1131, 10.1038/nature07976

Kubota, 2008, Dynamic functional relay between insulin receptor substrate 1 and 2 in hepatic insulin signaling during fasting and feeding., Cell Metab, 8, 49, 10.1016/j.cmet.2008.05.007

Brown, 2008, Selective versus total insulin resistance: a pathogenic paradox., Cell Metab, 7, 95, 10.1016/j.cmet.2007.12.009

Griffin, 1999, Free fatty acid-induced insulin resistance is associated with activation of protein kinase Cθ and alterations in the insulin signaling cascade., Diabetes, 48, 1270, 10.2337/diabetes.48.6.1270

Samuel, 2010, Lipid-induced insulin resistance: unravelling the mechanism., Lancet, 375, 2267, 10.1016/S0140-6736(10)60408-4

Lewis, 1996, Acute effects of insulin in the control of VLDL production in humans. Implications for the insulin-resistant state., Diabetes Care, 19, 390, 10.2337/diacare.19.4.390