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Endocrine, Metabolic & Immune Disorders - Drug Targets


ISSN (Print): 1871-5303
ISSN (Online): 2212-3873

Research Article

Insulin Resistance in Apolipoprotein M Knockout Mice is Mediated by the Protein Kinase Akt Signaling Pathway

Author(s): Shuang Yao, Jun Zhang, Yuxia Zhan, Yuanping Shi, Yang Yu, Lu Zheng, Ning Xu* and Guanghua Luo*

Volume 20, Issue 5, 2020

Page: [771 - 780] Pages: 10

DOI: 10.2174/1871530319666191023125820

open access plus


Background: Previous clinical studies have suggested that apolipoprotein M (apoM) is involved in glucose metabolism and plays a causative role in insulin sensitivity.

Objective: The potential mechanism of apoM on modulating glucose homeostasis is explored and differentially expressed genes are analyzed by employing ApoM deficient (ApoM-/- ) and wild type (WT) mice.

Methods: The metabolism of glucose in the hepatic tissues of high-fat diet ApoM-/- and WT mice was measured by a glycomics approach. Bioinformatic analysis was applied for analyzing the levels of differentially expressed mRNAs in the liver tissues of these mice. The insulin sensitivity of ApoM-/- and WT mice was compared using the insulin tolerance test and the phosphorylation levels of protein kinase Akt (AKT) and insulin stimulation in different tissues were examined by Western blot.

Results: The majority of the hepatic glucose metabolites exhibited lower concentration levels in the ApoM-/- mice compared with those of the WT mice. Gene Ontology (GO) classification and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that ApoM deficiency affected the genes associated with the metabolism of glucose. The insulin tolerance test suggested that insulin sensitivity was impaired in ApoM-/- mice. The phosphorylation levels of AKT in muscle and adipose tissues of ApoM-/- mice were significantly diminished in response to insulin stimulation compared with those noted in WT mice.

Conclusion: ApoM deficiency led to the disorders of glucose metabolism and altered genes related to glucose metabolism in mice liver. In vivo data indicated that apoM might augment insulin sensitivity by AKT-dependent mechanism.

Keywords: Apolipoprotein M, glucose metabolism, microarray, insulin resistance, protein kinase akt phosphorylation, type 2 diabetes.

Graphical Abstract
Chen, L.; Magliano, D.J.; Zimmet, P.Z. The worldwide epidemiology of type 2 diabetes mellitus--present and future perspectives. Nat. Rev. Endocrinol., 2011, 8(4), 228-236.
[] [PMID: 22064493]
Jones, J.G. Hepatic glucose and lipid metabolism. Diabetologia, 2016, 59(6), 1098-1103.
[] [PMID: 27048250]
Xu, H.; Li, X.; Adams, H.; Kubena, K.; Guo, S. Etiology of Metabolic Syndrome and Dietary Intervention. Int. J. Mol. Sci., 2018, 20(1)E128
[] [PMID: 30602666]
Rye, K.A.; Barter, P.J.; Cochran, B.J. Apolipoprotein A-I interactions with insulin secretion and production. Curr. Opin. Lipidol., 2016, 27(1), 8-13.
[] [PMID: 26655291]
Van Linthout, S.; Foryst-Ludwig, A.; Spillmann, F.; Peng, J.; Feng, Y.; Meloni, M.; Van Craeyveld, E.; Kintscher, U.; Schultheiss, H.P.; De Geest, B.; Tschöpe, C. Impact of HDL on adipose tissue metabolism and adiponectin expression. Atherosclerosis, 2010, 210(2), 438-444.
[] [PMID: 20202635]
Stenkula, K.G.; Lindahl, M.; Petrlova, J.; Dalla-Riva, J.; Göransson, O.; Cushman, S.W.; Krupinska, E.; Jones, H.A.; Lagerstedt, J.O. Single injections of apoA-I acutely improve in vivo glucose tolerance in insulin-resistant mice. Diabetologia, 2014, 57(4), 797-800.
[] [PMID: 24442447]
McGrath, K.C.; Li, X.H.; Whitworth, P.T.; Kasz, R.; Tan, J.T.; McLennan, S.V.; Celermajer, D.S.; Barter, P.J.; Rye, K.A.; Heather, A.K. High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation. J. Lipid Res., 2014, 55(3), 421-430.
[] [PMID: 24347528]
Poteryaeva, O.N.; Usynin, I.F. [Antidiabetic role of high density lipoproteins]. Biomed. Khim., 2018, 64(6), 463-471.
[] [PMID: 30632974]
Wolfrum, C.; Poy, M.N.; Stoffel, M. Apolipoprotein M is required for prebeta-HDL formation and cholesterol efflux to HDL and protects against atherosclerosis. Nat. Med., 2005, 11(4), 418-422.
[] [PMID: 15793583]
Croyal, M.; Billon-Crossouard, S.; Goulitquer, S.; Aguesse, A.; León, L.; Fall, F.; Chétiveaux, M.; Moyon, T.; Blanchard, V.; Ouguerram, K.; Lambert, G.; Nobécourt, E.; Krempf, M. Stable Isotope Kinetic Study of ApoM (Apolipoprotein M). Arterioscler. Thromb. Vasc. Biol., 2018, 38(1), 255-261.
[] [PMID: 29146748]
Xu, N.; Dahlbäck, B. A novel human apolipoprotein (apoM). J. Biol. Chem., 1999, 274(44), 31286-31290.
[] [PMID: 10531326]
Borup, A.; Christensen, P.M.; Nielsen, L.B.; Christoffersen, C. Apolipoprotein M in lipid metabolism and cardiometabolic diseases. Curr. Opin. Lipidol., 2015, 26(1), 48-55.
[] [PMID: 25551802]
Christoffersen, C.; Federspiel, C.K.; Borup, A.; Christensen, P.M.; Madsen, A.N.; Heine, M.; Nielsen, C.H.; Kjaer, A.; Holst, B.; Heeren, J.; Nielsen, L.B. The Apolipoprotein M/S1P Axis Controls Triglyceride Metabolism and Brown Fat Activity. Cell Rep., 2018, 22(1), 175-188.
[] [PMID: 29298420]
Ooi, E.M.; Watts, G.F.; Chan, D.C.; Nielsen, L.B.; Plomgaard, P.; Dahlbäck, B.; Barrett, P.H. Association of apolipoprotein M with high-density lipoprotein kinetics in overweight-obese men. Atherosclerosis, 2010, 210(1), 326-330.
[] [PMID: 20031132]
Niu, N.; Zhu, X.; Liu, Y.; Du, T.; Wang, X.; Chen, D.; Sun, B.; Gu, H.F.; Liu, Y. Single nucleotide polymorphisms in the proximal promoter region of apolipoprotein M gene (apoM) confer the susceptibility to development of type 2 diabetes in Han Chinese. Diabetes Metab. Res. Rev., 2007, 23(1), 21-25.
[] [PMID: 16572495]
Cervin, C.; Axler, O.; Holmkvist, J.; Almgren, P.; Rantala, E.; Tuomi, T.; Groop, L.; Dahlbäck, B.; Karlsson, E. An investigation of serum concentration of apoM as a potential MODY3 marker using a novel ELISA. J. Intern. Med., 2010, 267(3), 316-321.
[] [PMID: 19754856]
Richter, S.; Shih, D.Q.; Pearson, E.R.; Wolfrum, C.; Fajans, S.S.; Hattersley, A.T.; Stoffel, M. Regulation of apolipoprotein M gene expression by MODY3 gene hepatocyte nuclear factor-1alpha: haploinsufficiency is associated with reduced serum apolipoprotein M levels. Diabetes, 2003, 52(12), 2989-2995.
[] [PMID: 14633861]
Sramkova, V.; Berend, S.; Siklova, M.; Caspar-Bauguil, S.; Carayol, J.; Bonnel, S.; Marques, M.; Decaunes, P.; Kolditz, C.I.; Dahlman, I.; Arner, P.; Stich, V.; Saris, W.H.M.; Astrup, A.; Valsesia, A.; Rossmeislova, L.; Langin, D.; Viguerie, N.; Apolipoprotein, M. Apolipoprotein M: a novel adipokine decreasing with obesity and upregulated by calorie restriction. Am. J. Clin. Nutr., 2019, 109(6), 1499-1510.
[] [PMID: 30869115]
Yang, L.; Li, T.; Zhao, S.; Zhang, S. Expression of apolipoprotein M and its association with adiponectin in an obese mouse model. Exp. Ther. Med., 2019, 18(3), 1685-1692.
[] [PMID: 31410126]
Lee, M.; Kim, J.I.; Choi, S.; Jang, Y.; Sorn, S.R. The effect of apoM polymorphism associated with HDL metabolism on obese korean adults. J. Nutrigenet. Nutrigenomics, 2016, 9(5-6), 306-317.
[] [PMID: 28245483]
Huang, X.; Liu, G.; Guo, J.; Su, Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int. J. Biol. Sci., 2018, 14(11), 1483-1496.
[] [PMID: 30263000]
Cignarelli, A.; Genchi, V.A.; Perrini, S.; Natalicchio, A.; Laviola, L.; Giorgino, F. Insulin and insulin receptors in adipose tissue development. Int. J. Mol. Sci., 2019, 20(3), 759.
[] [PMID: 30754657]
Haeusler, R.A.; McGraw, T.E.; Accili, D. Biochemical and cellular properties of insulin receptor signalling. Nat. Rev. Mol. Cell Biol., 2018, 19(1), 31-44.
[] [PMID: 28974775]
Boucher, J.; Kleinridders, A.; Kahn, C.R. Insulin receptor signaling in normal and insulin-resistant states. Cold Spring Harb. Perspect. Biol., 2014, 6(1)a009191
[] [PMID: 24384568]
Petersen, M.C.; Shulman, G.I. Mechanisms of Insulin Action and Insulin Resistance. Physiol. Rev., 2018, 98(4), 2133-2223.
[] [PMID: 30067154]
Zheng, Z.; Zeng, Y.; Zhu, X.; Tan, Y.; Li, Y.; Li, Q.; Yi, G. ApoM-S1P Modulates Ox-LDL-Induced Inflammation Through the PI3K/Akt Signaling Pathway in HUVECs. Inflammation, 2019, 42(2), 606-617.
[] [PMID: 30377890]
Christoffersen, C.; Obinata, H.; Kumaraswamy, S.B.; Galvani, S.; Ahnström, J.; Sevvana, M.; Egerer-Sieber, C.; Muller, Y.A.; Hla, T.; Nielsen, L.B.; Dahlbäck, B. Endothelium-protective sphingosine-1-phosphate provided by HDL-associated apolipoprotein M. Proc. Natl. Acad. Sci. USA, 2011, 108(23), 9613-9618.
[] [PMID: 21606363]
Zhu, Y.; Luo, G.; Jiang, B.; Yu, M.; Feng, Y.; Wang, M.; Xu, N.; Zhang, X. Apolipoprotein M promotes proliferation and invasion in non-small cell lung cancers via upregulating S1PR1 and activating the ERK1/2 and PI3K/AKT signaling pathways. Biochem. Biophys. Res. Commun., 2018, 501(2), 520-526.
[] [PMID: 29750961]
Wang, Z.; Luo, G.; Feng, Y.; Zheng, L.; Liu, H.; Liang, Y.; Liu, Z.; Shao, P.; Berggren-Söderlund, M.; Zhang, X.; Xu, N. Decreased splenic CD4(+) T-lymphocytes in apolipoprotein M gene deficient mice. BioMed Res. Int., 2015, 2015293512
[] [PMID: 26543853]
Yu, Y.; Zheng, L.; Liang, Y.; Pan, L.; Zhang, J.; Wei, J.; Yu, M.; Luo, G. Establishment of duplex fluorescence RT-PCR for identification of apolipoprotein M gene knockout mice. Chin J Clin Lab Sci, 2015, 33(6), 412-414.
Surwit, R.S.; Kuhn, C.M.; Cochrane, C.; McCubbin, J.A.; Feinglos, M.N. Diet-induced type II diabetes in C57BL/6J mice. Diabetes, 1988, 37(9), 1163-1167.
[] [PMID: 3044882]
Sündermann, A.; Eggers, L.F.; Schwudke, D. Liquid Extraction: Bligh and Dyer.Encyclopedia of Lipidomics; Wenk, M.R., Ed.; Springer Netherlands: Dordrecht, 2016, pp. 1-4.
Lam, S.M.; Wang, Z.; Li, J.; Huang, X.; Shui, G. Sequestration of polyunsaturated fatty acids in membrane phospholipids of Caenorhabditis elegans dauer larva attenuates eicosanoid biosynthesis for prolonged survival. Redox Biol., 2017, 12, 967-977.
[] [PMID: 28499251]
Vinnakota, K.C.; Pannala, V.R.; Wall, M.L.; Rahim, M.; Estes, S.K.; Trenary, I.; O’Brien, T.P.; Printz, R.L.; Reifman, J.; Shiota, M.; Young, J.D.; Wallqvist, A. Network Modeling of Liver Metabolism to Predict Plasma Metabolite Changes During Short-Term Fasting in the Laboratory Rat. Front. Physiol., 2019, 10, 161.
[] [PMID: 30881311]
Ho, J.E.; Larson, M.G.; Vasan, R.S.; Ghorbani, A.; Cheng, S.; Rhee, E.P.; Florez, J.C.; Clish, C.B.; Gerszten, R.E.; Wang, T.J. Metabolite profiles during oral glucose challenge. Diabetes, 2013, 62(8), 2689-2698.
[] [PMID: 23382451]
Fang, Q.; Yao, S.; Luo, G.; Zhang, X. Identification of differentially expressed genes in human breast cancer cells induced by 4-hydroxyltamoxifen and elucidation of their pathophysiological relevance and mechanisms. Oncotarget, 2017, 9(2), 2475-2501.
[PMID: 29416786]
Ferreira, J.A. The Benjamini-Hochberg method in the case of discrete test statistics. Int. J. Biostat., 2007, 3(1), 11.
[] [PMID: 22550651]
Shannon, W.; Culverhouse, R.; Duncan, J. Analyzing microarray data using cluster analysis. Pharmacogenomics, 2003, 4(1), 41-52.
[] [PMID: 12517285]
Kurano, M.; Hara, M.; Tsuneyama, K.; Sakoda, H.; Shimizu, T.; Tsukamoto, K.; Ikeda, H.; Yatomi, Y. Induction of insulin secretion by apolipoprotein M, a carrier for sphingosine 1-phosphate. Biochim. Biophys. Acta, 2014, 1841(9), 1217-1226.
[] [PMID: 24814049]
Roberts, L. D.; Souza, A. L.; Gerszten, R. E.; Clish, C. B. Targeted Metabolomics. Curr. Protoc. Mol. Biol, 2012. 98(1), 30.2.1-30.2.24.
Bain, J.R.; Stevens, R.D.; Wenner, B.R.; Ilkayeva, O.; Muoio, D.M.; Newgard, C.B. Metabolomics applied to diabetes research: moving from information to knowledge. Diabetes, 2009, 58(11), 2429-2443.
[] [PMID: 19875619]
Luo, G.; Feng, Y.; Zhang, J.; Mu, Q.; Shi, Y.; Qin, L.; Zheng, L.; Berggren-Söderlund, M.; Nilsson-Ehle, P.; Zhang, X.; Xu, N. Rosiglitazone enhances apolipoprotein M (Apom) expression in rat’s liver. Int. J. Med. Sci., 2014, 11(10), 1015-1021.
[] [PMID: 25136257]
Ren, K.; Tang, Z.L.; Jiang, Y.; Tan, Y.M.; Yi, G.H.; Apolipoprotein, M. Apolipoprotein M. Clin. Chim. Acta, 2015, 446, 21-29.
[] [PMID: 25858547]
Adeva-Andany, M.M.; Pérez-Felpete, N.; Fernández-Fernández, C.; Donapetry-García, C.; Pazos-García, C. Liver glucose metabolism in humans. Biosci. Rep., 2016, 36(6)e00416
[] [PMID: 27707936]
Froissart, R.; Piraud, M.; Boudjemline, A.M.; Vianey-Saban, C.; Petit, F.; Hubert-Buron, A.; Eberschweiler, P.T.; Gajdos, V.; Labrune, P. Glucose-6-phosphatase deficiency. Orphanet J. Rare Dis., 2011, 6, 27.
[] [PMID: 21599942]
Schormann, N.; Hayden, K. L.; Lee, P.; Banerjee, S.; Chattopadhyay, D. An overview of structure, function, and regulation of pyruvate kinases, 2019.
Kruger, N.J.; von Schaewen, A. The oxidative pentose phosphate pathway: structure and organisation. Curr. Opin. Plant Biol., 2003, 6(3), 236-246.
[] [PMID: 12753973]
Stincone, A.; Prigione, A.; Cramer, T.; Wamelink, M.M.; Campbell, K.; Cheung, E.; Olin-Sandoval, V.; Grüning, N.M.; Krüger, A.; Tauqeer Alam, M.; Keller, M.A.; Breitenbach, M.; Brindle, K.M.; Rabinowitz, J.D.; Ralser, M. The return of metabolism: biochemistry and physiology of the pentose phosphate pathway. Biol. Rev. Camb. Philos. Soc., 2015, 90(3), 927-963.
[] [PMID: 25243985]
Wang, K.; Holterman, A.X. Pathophysiologic role of hepatocyte nuclear factor 6. Cell. Signal., 2012, 24(1), 9-16.
[] [PMID: 21893194]
Zhang, Y.; Fang, B.; Damle, M.; Guan, D.; Li, Z.; Kim, Y.H.; Gannon, M.; Lazar, M.A. HNF6 and Rev-erbα integrate hepatic lipid metabolism by overlapping and distinct transcriptional mechanisms. Genes Dev., 2016, 30(14), 1636-1644.
[] [PMID: 27445394]
Kropp, P.A.; Dunn, J.C.; Carboneau, B.A.; Stoffers, D.A.; Gannon, M. Cooperative function of Pdx1 and Oc1 in multipotent pancreatic progenitors impacts postnatal islet maturation and adaptability. Am. J. Physiol. Endocrinol. Metab., 2018, 314(4), E308-E321.
[] [PMID: 29351489]
Gannon, M.; Ray, M.K.; Van Zee, K.; Rausa, F.; Costa, R.H.; Wright, C.V. Persistent expression of HNF6 in islet endocrine cells causes disrupted islet architecture and loss of beta cell function. Development, 2000, 127(13), 2883-2895.
[PMID: 10851133]
Okazaki, Y.; Ohshima, N.; Yoshizawa, I.; Kamei, Y.; Mariggiò, S.; Okamoto, K.; Maeda, M.; Nogusa, Y.; Fujioka, Y.; Izumi, T.; Ogawa, Y.; Shiro, Y.; Wada, M.; Kato, N.; Corda, D.; Yanaka, N. A novel glycerophosphodiester phosphodiesterase, GDE5, controls skeletal muscle development via a non-enzymatic mechanism. J. Biol. Chem., 2010, 285(36), 27652-27663.
[] [PMID: 20576599]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[] [PMID: 19131956]
Plomgaard, P.; Dullaart, R.P.; de Vries, R.; Groen, A.K.; Dahlbäck, B.; Nielsen, L.B. Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects. J. Intern. Med., 2009, 266(3), 258-267.
[] [PMID: 19457058]
Saltiel, A.R.; Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 2001, 414(6865), 799-806.
[] [PMID: 11742412]
Kubota, T.; Kubota, N.; Kadowaki, T. Imbalanced insulin actions in obesity and type 2 diabetes: Key mouse models of insulin signaling pathway. Cell Metab., 2017, 25(4), 797-810.
[] [PMID: 28380373]
Lo, K.A.; Labadorf, A.; Kennedy, N.J.; Han, M.S.; Yap, Y.S.; Matthews, B.; Xin, X.; Sun, L.; Davis, R.J.; Lodish, H.F.; Fraenkel, E. Analysis of in vitro insulin-resistance models and their physiological relevance to in vivo diet-induced adipose insulin resistance. Cell Rep., 2013, 5(1), 259-270.
[] [PMID: 24095730]
Wang, C.Y.; Liao, J.K. A mouse model of diet-induced obesity and insulin resistance. Methods Mol. Biol., 2012, 821, 421-433.
[] [PMID: 22125082]
Girard, J. The inhibitory effects of insulin on hepatic glucose production are both direct and indirect. Diabetes, 2006, 55, S65-S69.

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