An insulin-independent mechanism for transcriptional regulation of Foxo1 in type 2 diabetic mice

Abstract

Hepatic gluconeogenesis is the major contributor to the hyperglycemia observed in both patients and animals with type 2 diabetes. The transcription factor FOXO1 plays a dominant role in stimulating hepatic gluconeogenesis. FOXO1 is mainly regulated by insulin under physiological conditions, but liver-specific disruption of Foxo1 transcription restores normal gluconeogenesis in mice in which insulin signaling has been blocked, suggesting that additional regulatory mechanisms exist. Understanding the transcriptional regulation of Foxo1 may be conducive to the development of insulin-independent strategies for the control of hepatic gluconeogenesis. Here, we found that elevated plasma levels of adenine nucleotide in type 2 diabetes are the major regulators of Foxo1 transcription. We treated lean mice with 5′-AMP and examined their transcriptional profiles using RNA-seq. KEGG analysis revealed that the 5′-AMP treatment led to shifted profiles that were similar to db/db mice. Many of the upregulated genes were in pathways associated with the pathology of type 2 diabetes including Foxo1 signaling. As observed in diabetic db/db mice, lean mice treated with 5′-AMP displayed enhanced Foxo1 transcription, involving an increase in cellular adenosine levels and a decrease in the S-adenosylmethionine to S-adenosylhomocysteine ratio. This reduced methylation potential resulted in declining histone H3K9 methylation in the promoters of Foxo1, G6Pc, and Pepck. In mouse livers and cultured cells, 5′-AMP induced expression of more FOXO1 protein, which was found to be localized in the nucleus, where it could promote gluconeogenesis. Our results revealed that adenine nucleotide-driven Foxo1 transcription is crucial for excessive glucose production in type 2 diabetic mice. Hepatic gluconeogenesis is the major contributor to the hyperglycemia observed in both patients and animals with type 2 diabetes. The transcription factor FOXO1 plays a dominant role in stimulating hepatic gluconeogenesis. FOXO1 is mainly regulated by insulin under physiological conditions, but liver-specific disruption of Foxo1 transcription restores normal gluconeogenesis in mice in which insulin signaling has been blocked, suggesting that additional regulatory mechanisms exist. Understanding the transcriptional regulation of Foxo1 may be conducive to the development of insulin-independent strategies for the control of hepatic gluconeogenesis. Here, we found that elevated plasma levels of adenine nucleotide in type 2 diabetes are the major regulators of Foxo1 transcription. We treated lean mice with 5′-AMP and examined their transcriptional profiles using RNA-seq. KEGG analysis revealed that the 5′-AMP treatment led to shifted profiles that were similar to db/db mice. Many of the upregulated genes were in pathways associated with the pathology of type 2 diabetes including Foxo1 signaling. As observed in diabetic db/db mice, lean mice treated with 5′-AMP displayed enhanced Foxo1 transcription, involving an increase in cellular adenosine levels and a decrease in the S-adenosylmethionine to S-adenosylhomocysteine ratio. This reduced methylation potential resulted in declining histone H3K9 methylation in the promoters of Foxo1, G6Pc, and Pepck. In mouse livers and cultured cells, 5′-AMP induced expression of more FOXO1 protein, which was found to be localized in the nucleus, where it could promote gluconeogenesis. Our results revealed that adenine nucleotide-driven Foxo1 transcription is crucial for excessive glucose production in type 2 diabetic mice. The liver plays a central role in whole-body homeostasis and metabolic health. Many metabolic functions, including lipid processing and distribution, amino acid synthesis, and gluconeogenesis, are performed or controlled by the liver (1Rhoads T.W. Burhans M.S. Chen V.B. Hutchins P.D. Rush M.J.P. Clark J.P. Stark J.L. McIlwain S.J. Eghbalnia H.R. Pavelec D.M. Ong I.M. Denu J.M. Markley J.L. Coon J.J. Colman R.J. et al.Caloric restriction engages hepatic RNA processing mechanisms in Rhesus monkeys.Cell Metab. 2018; 27: 677-688.e675Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar). Hepatic gluconeogenesis is primarily responsible for the increase of fasting hepatic glucose production in individuals with type 2 diabetes (2Petersen M.C. Vatner D.F. Shulman G.I. Regulation of hepatic glucose metabolism in health and disease.Nat. Rev. Endocrinol. 2017; 13: 572-587Crossref PubMed Scopus (359) Google Scholar). The transcription factor forkhead box protein O1 (FOXO1) plays a dominant role in regulating hepatic gluconeogenesis (3Haeusler R.A. Kaestner K.H. Accili D. FoxOs function synergistically to promote glucose production.J. Biol. Chem. 2010; 285: 35245-35248Abstract Full Text Full Text PDF PubMed Scopus (127) Google Scholar, 4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1105) Google Scholar). The FOXO1 interacts directly with DNA-binding sites in the promoter region of several genes related to gluconeogenesis (5Schmoll D. Walker K.S. Alessi D.R. Grempler R. Burchell A. Guo S. Walther R. Unterman T.G. Regulation of glucose-6-phosphatase gene expression by protein kinase Balpha and the forkhead transcription factor FKHR. Evidence for insulin response unit-dependent and -independent effects of insulin on promoter activity.J. Biol. Chem. 2000; 275: 36324-36333Abstract Full Text Full Text PDF PubMed Scopus (285) Google Scholar, 6Hall R.K. Yamasaki T. Kucera T. Waltner-Law M. O'Brien R. Granner D.K. 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. 2000; 275: 30169-30175Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar), stimulating glucose production in both mouse livers and isolated hepatocytes (4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1105) Google Scholar). The phosphorylation state of FOXO1 determines its cellular localization and transcription activity of FOXO1, which is mainly regulated by the insulin signaling pathway under physiological conditions (7Kops G.J. de Ruiter N.D. De Vries-Smits A.M. Powell D.R. Bos J.L. Burgering B.M. Direct control of the Forkhead transcription factor AFX by protein kinase B.Nature. 1999; 398: 630-634Crossref PubMed Scopus (932) Google Scholar). Insulin activates Akt to phosphorylate FOXO1 protein and causes a higher binding affinity of FOXO1 with chaperone protein, thus facilitating the cytoplasmic retention and nuclear export of FOXO1 (4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1105) Google Scholar, 8Nakae J. Oki M. Cao Y. The FoxO transcription factors and metabolic regulation.FEBS Lett. 2008; 582: 54-67Crossref PubMed Scopus (145) Google Scholar). Phosphorylated FOXO1 in the cytoplasm remains inactive and is finally degraded by the ubiquitin-proteasome pathway (8Nakae J. Oki M. Cao Y. The FoxO transcription factors and metabolic regulation.FEBS Lett. 2008; 582: 54-67Crossref PubMed Scopus (145) Google Scholar, 9Armoni M. Harel C. Karni S. Chen H. Bar-Yoseph F. Ver M.R. Quon M.J. Karnieli E. FOXO1 represses peroxisome proliferator-activated receptor-gamma1 and -gamma2 gene promoters in primary adipocytes. A novel paradigm to increase insulin sensitivity.J. Biol. Chem. 2006; 281: 19881-19891Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar). Increased Foxo1 transcription has been observed in the livers of db/db diabetic mice and patients with insulin resistance (10Qu S. Altomonte J. Perdomo G. He J. Fan Y. Kamagate A. Meseck M. Dong H.H. Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism.Endocrinology. 2006; 147: 5641-5652Crossref PubMed Scopus (85) Google Scholar, 11Valenti L. Rametta R. Dongiovanni P. Maggioni M. Fracanzani A.L. Zappa M. Lattuada E. Roviaro G. Fargion S. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis.Diabetes. 2008; 57: 1355-1362Crossref PubMed Scopus (126) Google Scholar). Deletion of hepatic Foxo1 in diabetic mice improves insulin sensitivity and glucose tolerance (12Zhang K. Li L. Qi Y. Zhu X. Gan B. DePinho R.A. Averitt T. Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice.Endocrinology. 2012; 153: 631-646Crossref PubMed Scopus (98) Google Scholar, 13Matsumoto M. Pocai A. Rossetti L. Depinho R.A. Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver.Cell Metab. 2007; 6: 208-216Abstract Full Text Full Text PDF PubMed Scopus (435) Google Scholar). Transgenic mice expressing the constitutively active Foxo1 allele show an increase in gluconeogenesis and hepatic glucose production (14Nakae J. Biggs 3rd, W.H. Kitamura T. Cavenee W.K. Wright C.V. Arden K.C. Accili D. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.Nat. Genet. 2002; 32: 245-253Crossref PubMed Scopus (516) Google Scholar). Foxo1 haploinsufficiency rescues diabetes in IRS2-deficient diabetic mice and prevents the development of high-fat diet-induced insulin resistance in wild-type (WT) mice (14Nakae J. Biggs 3rd, W.H. Kitamura T. Cavenee W.K. Wright C.V. Arden K.C. Accili D. Regulation of insulin action and pancreatic beta-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1.Nat. Genet. 2002; 32: 245-253Crossref PubMed Scopus (516) Google Scholar, 15Kim J.J. Li P. Huntley J. Chang J.P. Arden K.C. Olefsky J.M. FoxO1 haploinsufficiency protects against high-fat diet-induced insulin resistance with enhanced peroxisome proliferator-activated receptor gamma activation in adipose tissue.Diabetes. 2009; 58: 1275-1282Crossref PubMed Scopus (77) Google Scholar). Especially, disruption of Foxo1 in a liver-specific manner restores glucose tolerance in insulin signal blocking mice (16Dong X.C. Copps K.D. Guo S. Li Y. Kollipara R. DePinho R.A. White M.F. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation.Cell Metab. 2008; 8: 65-76Abstract Full Text Full Text PDF PubMed Scopus (294) Google Scholar, 17Lu M. Wan M. Leavens K.F. Chu Q. Monks B.R. Fernandez S. Ahima R.S. Ueki K. Kahn C.R. Birnbaum M.J. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1.Nat. Med. 2012; 18: 388-395Crossref PubMed Scopus (240) Google Scholar), implying suppression of Foxo1 transcription may be an insulin-independent therapeutic approach for diabetes mellitus. While insulin exerts its effects on gluconeogenesis in the liver by inactivating FOXO1 proteins (4Puigserver P. Rhee J. Donovan J. Walkey C.J. Yoon J.C. Oriente F. Kitamura Y. Altomonte J. Dong H. Accili D. Spiegelman B.M. Insulin-regulated hepatic gluconeogenesis through FOXO1-PGC-1alpha interaction.Nature. 2003; 423: 550-555Crossref PubMed Scopus (1105) Google Scholar), insulin has no effects on Foxo1 transcription. The mechanism of hepatic Foxo1 transcriptional regulation in type 2 diabetes mellitus is unknown. The factors that stimulate hepatic Foxo1 transcription are generally considered to be less important than FOXO1 protein phosphorylation and are almost ignored in type 2 diabetes. Our previous observations demonstrate that the elevation of plasma adenine is an in type 2 diabetic db/db mice Y. Y. M. S. J. The plasma a potential of hyperglycemia in type 2 diabetic J. Endocrinol. Metab. 2012; PubMed Scopus Google Scholar, X. Y. Q. Y. Y. J. X. D. S. J. regulation of hepatic activity in mouse of type 2 PubMed Scopus Google Scholar). of a role for the adenine in the regulation of glucose homeostasis and the of diabetes mellitus L. C. B. P. G. in diabetes and therapeutic Rev. Endocrinol. PubMed Scopus Google Scholar). In the we that adenine stimulate hepatic Foxo1 transcription methylation in type 2 diabetic db/db mice, that adenine hepatic Foxo1 transcription is crucial for excessive glucose production in type 2 diabetic mice. the of the role of adenine in we RNA to in the livers of control and mice. The pathways were by using the KEGG of to KEGG pathways resulted in of pathways and of pathways in the livers of and db/db mice a of KEGG pathways were in both mouse a of in gene transcription the and the The genes that are in the with the genes in the A of the genes with regulatory was analysis that was a in we pathway analysis to the pathways by gene expression metabolic including insulin and insulin which in the and the the signaling pathway was found to be of the and was in the KEGG of the and the genes in the signaling pathway were the signaling pathway in the has KEGG pathway analysis the and the was no in the pathways related to type 2 diabetes we that 5′-AMP is to hepatic gluconeogenesis through signaling. the of genes of genes both in the and the were by As in the levels of Foxo1, G6Pc, and were elevated in both 5′-AMP the transcription of genes including Foxo1, G6Pc, and which were related to signaling and insulin we the function of 5′-AMP in regulating hepatic gluconeogenesis in 5′-AMP the glucose under the the tolerance that gluconeogenesis in the db/db mice we found that 5′-AMP glucose with of and The results were with db/db mice that 5′-AMP the of of FOXO1 function by FOXO1 Li J.L. mechanisms of in 2006; 27: PubMed Scopus (33) Google hepatic gluconeogenesis results that 5′-AMP Foxo1 transcription and hepatic gluconeogenesis. the mechanism of hepatic gluconeogenesis, we examined the effects of 5′-AMP on the expression levels of Foxo1 and 5′-AMP a increase in the levels of Foxo1, and in mouse livers analysis that the FOXO1 protein was in livers 5′-AMP the phosphorylation of FOXO1 analysis that the of FOXO1 was and the of FOXO1 was mainly localized in the observations that 5′-AMP Foxo1 transcription FOXO1 nuclear 5′-AMP hepatic Foxo1 transcription, a transcription was to the The results revealed that the the transcription of Foxo1 in the livers of mice and db/db mice, the of regulation of Foxo1 by 5′-AMP A and suggesting that 5′-AMP Foxo1 through a involving de gene transcription. 5′-AMP be adenosine by on the the function of 5′-AMP may a role adenosine levels or on Li J.L. mechanisms of in 2006; 27: PubMed Scopus (33) Google Scholar). of adenosine hepatic Foxo1 transcription and gluconeogenesis in mice the effects of adenosine were to the of adenosine mice were treated with the adenosine receptor treatment Foxo1 levels in 5′-AMP mice we found that a reduced Foxo1 in the livers of mice and db/db mice a of in regulating the of S-adenosylmethionine the cellular methylation potential P. of and of the the of 6: Google Scholar). The methylation Foxo1 levels in livers analysis that but the of in the livers of 5′-AMP mice and and db/db mice As reduced the of to in mouse livers results demonstrate that Foxo1 transcription is related to cellular methylation we examined 5′-AMP As in the methylation levels of the Foxo1 promoter in the livers of mice. results were observed in that of db/db mice are to control gene expression T. Fan G. methylation and its PubMed Scopus Google Scholar). Increased methylation of amino acid is generally associated with transcriptional and which and C. E. J. S. of The and of Rev. Biol. PubMed Scopus Google Scholar). we a in methylation in the livers of mice The of a in methylation associated with transcriptional that may the analysis was performed to histone methylation levels in Foxo1, G6Pc, and promoter with the control 5′-AMP resulted in a decrease of levels in the promoter of Foxo1, G6Pc, and The results of the analysis were by We a in H3K9 methylation in db/db livers by analysis and analysis that the observed in mice, were in the promoter of Foxo1, G6Pc, and in db/db mice and results that the decrease of the of Foxo1, G6Pc, and promoter results in transcriptional of genes in and db/db mice. the results we the mouse we to the effects of 5′-AMP on the regulation of Foxo1 in The results that 5′-AMP resulted in a increase of glucose production in analysis revealed that 5′-AMP a decrease in the we adenosine receptor and adenosine methylation potential and are related to Foxo1 transcription. As in the cellular methylation and the adenosine the of 5′-AMP on methylation potential the of cellular methylation we and the methylation to the in the The of the of the of the The analysis that 5′-AMP Foxo1 levels in cells, and the of the regulation of Foxo1 transcription by 5′-AMP Foxo1 transcription In cells, Foxo1 transcription 5′-AMP and the effects of 5′-AMP on Foxo1 transcription regulation that 5′-AMP regulates Foxo1 transcription by the methylation potential of analysis was performed to show the of While FOXO1 was mainly in the cytoplasm in control cells, 5′-AMP in the The FOXO1 nuclear but the of FOXO1 in the the cytoplasmic FOXO1 protein and reduced the nuclear FOXO1 the of FOXO1 in the Hepatic Foxo1 transcription is in the livers of patients with insulin resistance and type 2 diabetic mice (10Qu S. Altomonte J. Perdomo G. He J. Fan Y. Kamagate A. Meseck M. Dong H.H. Aberrant Forkhead box O1 function is associated with impaired hepatic metabolism.Endocrinology. 2006; 147: 5641-5652Crossref PubMed Scopus (85) Google Scholar, 11Valenti L. Rametta R. Dongiovanni P. Maggioni M. Fracanzani A.L. Zappa M. Lattuada E. Roviaro G. Fargion S. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis.Diabetes. 2008; 57: 1355-1362Crossref PubMed Scopus (126) Google Scholar), a crucial role in excessive glucose production T. The role of FOXO1 in and type 2 diabetes Rev. Endocrinol. PubMed Scopus (126) Google Scholar). The mechanism that hepatic Foxo1 transcription in type 2 diabetes is and almost In the we that 5′-AMP FOXO1 in the both in vivo and in thus gluconeogenesis. This was on the of Foxo1 the transcription for the that adenine Foxo1 transcription is for glucose production in type 2 diabetes. acid is an important insulin and type 2 diabetes M. J. P. D. E. A. K. of elevated acid levels to the of glucose in type 2 2003; PubMed Scopus Google Scholar). adenine Y. Y. M. S. J. The plasma a potential of hyperglycemia in type 2 diabetic J. Endocrinol. Metab. 2012; PubMed Scopus Google Scholar, X. Y. Q. Y. W.H. X. role of adenine on hyperglycemia in Endocrinol. PubMed Google and the resistance of to to plasma adenine X. Y. Q. Y. W.H. X. role of adenine on hyperglycemia in Endocrinol. PubMed Google Scholar). adenine to adenosine R. Y. and signaling of Rev. PubMed Scopus Google Scholar). by adenosine and are the Rev. PubMed Scopus Google Scholar). physiological conditions, adenosine been to a role in the function of FOXO1 B. C. receptor signaling FoxO associated in PubMed Scopus Google Scholar). In adenosine but adenosine receptor reduced Foxo1 transcription. has its which is directly related to the adenosine receptor pathway Y. Y. M. S. J. The plasma a potential of hyperglycemia in type 2 diabetic J. Endocrinol. Metab. 2012; PubMed Scopus Google Scholar, Y. P. T. L. M. Y. S. J. liver through an adenosine mechanism in PubMed Scopus Google Scholar). The adenosine by M. S. is in adenosine 2018; PubMed Scopus Google Scholar). the state of type 2 the of adenosine may the regulatory of adenosine Our results that Foxo1 transcription is related to the than 5′-AMP results in a elevation in adenosine levels in the and L. S. Y. T. M. J. in and methylation in mouse Google Scholar). Our that 5′-AMP hepatic gluconeogenesis and glucose which was by the methylation associated with the ratio. is a of methylation The of and are associated with diabetes C.J. S-adenosylmethionine and activity in diabetes mellitus and diabetic Full Text PDF PubMed Scopus Google Scholar, S. B. of diabetes and insulin on expression in J. Endocrinol. Metab. 2006; PubMed Scopus Google Scholar). In patients with in patients with the of and related in C.J. S-adenosylmethionine and activity in diabetes mellitus and diabetic Full Text PDF PubMed Scopus Google Scholar). with the of in plasma and of patients with type 2 diabetes is higher A. C. T. S. J.M. G. R.J. and S-adenosylmethionine in of effects in diabetic and 2003; Full Text Full Text PDF PubMed Scopus Google Scholar). has been found to the methylation through the regulation of the E. S. S. R. J. L. E. M. J. B. J. regulates methylation 2018; PubMed Scopus Google Scholar), and signaling is of The directly the in methylation L. S. Y. T. M. J. in and methylation in mouse Google Scholar). In the the methylation of the Foxo1 but it resulted in histone methylation associated with the Foxo1 promoter of H3K9 is in transcriptional Y. A in and Rev. Genet. 2012; 13: PubMed Scopus Google Scholar), and H3K9 methylation is an inactive Li J. J. histone transcription and protein Biol. PubMed Scopus Google Scholar). the methylation of histone H3K9 in the Foxo1 promoter region led to the activation of Foxo1 gene transcription. In the of that may the genes related to diabetes pathways are In we found that and were elevated in both the and the Our analysis a more role for adenine in diabetes Our previous that plasma 5′-AMP was elevated in type 2 diabetic db/db mice, and 5′-AMP type 2 hyperglycemia in lean mice Y. Y. M. S. J. The plasma a potential of hyperglycemia in type 2 diabetic J. Endocrinol. Metab. 2012; PubMed Scopus Google Scholar). 5′-AMP was elevated in patients with type 2 diabetes X. Y. Q. Y. Y. J. X. D. S. J. regulation of hepatic activity in mouse of type 2 PubMed Scopus Google Scholar). adenosine was a potential of insulin receptor was by 5′-AMP in a of insulin sensitivity L. Y. X. R. regulation of insulin and plasma in glucose homeostasis in Endocrinol. PubMed Scopus Google Scholar). We for adenine regulating the activity of in type 2 diabetic mice X. Y. Q. Y. Y. J. X. D. S. J. regulation of hepatic activity in mouse of type 2 PubMed Scopus Google Scholar). it that adenine and may on glucose In we revealed a novel mechanism that adenine Foxo1 transcription for excessive glucose production in type 2 diabetes The mechanism of stimulating Foxo1 transcription in type 2 diabetes is almost Our the of regulation of hepatic gluconeogenesis through Foxo1, the crucial role of adenine in the development of type 2 and a novel for diabetes db/db mice, and their lean were in were in a under a with to and were by the and of and 5′-AMP was in and to mice by in of or was in and to mice by in of was a cellular methylation was in the a of for 2 the J. X. X. Y. function of is in the effects of on PubMed Google Scholar). decrease was R. and central by an of PubMed Scopus Google Scholar). transcription, was db/db mice, and their lean The transcriptional was the of the role of adenosine adenosine receptor was the of FOXO1, mice were treated with or the the of the of or mice were by and the livers were and in for were for The plasma was and were was were performed B. C. S. M. M. D. J. M. T. R. M. L. C. et acid regulates and insulin sensitivity in PubMed Scopus Google Scholar, Y. E. B. G. of de glucose production to fasting in PubMed Scopus Google Scholar). mice were to with or 5′-AMP or adenosine was with and mice. glucose levels were the and with a Hepatic was with to the were in the were for acid was to the protein of the RNA the livers of and control mice was for and were performed by using a were to the mouse by using The expression levels for of the genes were to of using by promoter methylation of Foxo1 was performed by S.J. J. M. sensitivity of PubMed Google Scholar). The were in was the and E. were and The results were by and were liver or using acid X. Y. Q. Y. Y. J. X. D. S. J. regulation of hepatic activity in mouse of type 2 PubMed Scopus Google Scholar, R.S. M.R. M.J. of on and in the PubMed Google Scholar). and were by a to the L. S. Y. T. M. J. in and methylation in mouse Google Scholar). The acid to with and The were on a with an a of and retention with of the were to and was on was was RNA was livers and with to the was by to the was performed with the the on an in a The levels of Foxo1, and were with for The for were in livers and were and proteins were with an to the The was by The were with primary and by with and by enhanced was a were performed M. in is associated with reduced PubMed Google Scholar, J.M. Li L. A for histone and transcription factor 2003; PubMed Scopus Google Scholar). was with of or control was a for The for were in and were performed G. Li C. F. W.H. Y. is required for 2018; PubMed Scopus Google Scholar). liver were in and using a The cultured were with with for with for and were with primary and by were with of liver were observed with The of cultured were on a were in with and of in the mechanisms responsible for the the was and with of the to be for 5′-AMP 5′-AMP or the regulatory of methylation were treated with 5′-AMP for with or 2 were treated with for and were A was to glucose production H. S. pathway signaling to hepatic Biol. Chem. 2017; Full Text Full Text PDF PubMed Scopus Google Scholar). was in in for were in and were with to of glucose and with and for 2 were treated with 5′-AMP in glucose production and 2 and and to A of of the was for of glucose using a glucose were with cellular protein The results were was by and were performed using A of less than of are in and in the for and are the This The that no of with the of This was by the the of R. and J. J. Y. and R. C. Y. Y. and X. X. J. Y. X. and R. C. J. Y. Y. X. D. 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