Apolipoprotein A-IV and its derived peptide, T55–121, improve glycemic control and increase energy expenditure

Abstract

It is crucial to understand the glucose control within our bodies. Bariatric/metabolic surgeries, including laparoscopic sleeve gastrectomy (LSG) and Roux-en-Y gastric bypass (RYGB), provide an avenue for exploring the potential key factors involved in maintaining glucose homeostasis since these surgeries have shown promising results in improving glycemic control among patients with severe type 2 diabetes (T2D). For the first time, a markedly altered population of serum proteins in patients after LSG was discovered and analyzed through proteomics. Apolipoprotein A-IV (apoA-IV) was revealed to be increased dramatically in diabetic obese patients following LSG, and a similar effect was observed in patients after RYGB surgery. Moreover, recombinant apoA-IV protein treatment was proven to enhance insulin secretion in isolated human islets. These results showed that apoA-IV may play a crucial role in glycemic control in humans, potentially through enhancing insulin secretion in human islets. ApoA-IV was further shown to enhance energy expenditure and improve glucose tolerance in diabetic rodents, through stimulating glucose-dependent insulin secretion in pancreatic β cells, partially via Gαs-coupled GPCR/cAMP (G protein-coupled receptor/cyclic adenosine monophosphate) signaling. Furthermore, T55–121, truncated peptide 55–121 of apoA-IV, was discovered to mediate the function of apoA-IV. These collective findings contribute to our understanding of the relationship between apoA-IV and glycemic control, highlighting its potential as a biomarker or therapeutic target in managing and improving glucose regulation.

Keywords

bariatric/metabolic surgeries / proteomics / apolipoprotein A-IV / glucose tolerance / glucose-stimulated insulin secretion / human islets

References

[1] Reed J, Bain S, Kanamarlapudi V. A review of current trends with type 2 diabetes epidemiology, aetiology, pathogenesis,treatments and future perspectives. Diabetes Metab Syndr Obes 2021;14:3567–602.

[2] Rubino F, Nathan DM, Eckel RH et al. Metabolic surgery in the treatment algorithm for type 2 diabetes: a joint statement by International Diabetes Organizations. Obes Surg 2017;27:2–21.

[3] Murshid KR, Alsisi GH, Almansouri FA et al. Laparoscopic sleevegastrectomy for weight loss and treatment of type 2 diabetesmellitus. J Taibah Univ Med Sci 2021;16:387–94.

[4] Malin SK, Kashyap SR. Effects of various gastrointestinal procedures on β-cell function in obesity and type 2 diabetes. Surg Obes Relat Dis 2016;12:1213–9.

[5] Wang Y, Song W, Wang J et al. Single-cell transcriptome analysis reveals differential nutrient absorption functions in human intestine. J Exp Med 2020;217:e20191130.

[6] Kohan AB, Wang F, Lo CM et al. ApoA-IV: current and emerging roles in intestinal lipid metabolism, glucose homeostasis, and satiety. Am J Physiol Gastrointest Liver Physiol 2015;308:G472–81.

[7] Kalogeris TJ, Monroe F, Demichele SJ et al. Intestinal synthesis and lymphatic secretion of apolipoprotein A-IV vary with chain length of intestinally infused fatty acids in rats. J Nutr 1996;126:2720–9.

[8] Kalogeris TJ, Fukagawa K, Tso P. Synthesis and lymphatic transport of intestinal apolipoprotein A-IV in response to gradeddoses of triglyceride. J Lipid Res 1994;35:1141–51.

[9] Bisgaier CL, Sachdev OP, Megna L et al. Distribution of apolipoprotein A-IV in human plasma. J Lipid Res 1985;26:11–25.

[10] Cao Z, Zhang Q, Zhou Z et al. Construction and application of artificial lipoproteins using adiposomes. J Lipid Res 2023;64:100436.

[11] Culnan DM, Cooney RN, Stanley B et al. Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass. Obesity (Silver Spring) 2009;17:46–52.

[12] Raffaelli M, Guidone C, Callari C et al. Effect of gastric bypass versus diet on cardiovascular risk factors. Ann Surg 2014;259:694–9.

[13] Menzel HJ, Sigurdsson G, Boerwinkle E et al. Frequency and effect of human apolipoprotein A-IV polymorphism on lipid and lipoprotein levels in an Icelandic population. Hum Genet 1990;84:344–6.

[14] Larson IA, Ordovas JM, Sun Z et al. Effects of apolipoprotein A-IV genotype on glucose and plasma lipoprotein levels. Clin Genet 2002;61:430–6.

[15] Wang F, Kohan AB, Kindel TL et al. Apolipoprotein A-IV improves glucose homeostasis by enhancing insulin secretion. Proc NatlAcad Sci U S A 2012;109:9641–6.

[16] Li X, Xu M, Wang F et al. Apolipoprotein A-IV reduces hepatic gluconeogenesis through nuclear receptor NR1D1. J Biol Chem 2014;289:2396–404.

[17] Li X, Xu M, Wang F et al. Interaction of ApoA-IV with NR4A1 and NR1D1 represses G6Pase and PEPCK transcription: nuclear receptor-mediated downregulation of hepatic gluconeogenesis in mice and a human hepatocyte cell line. PLoS One 2015;10:e0142098.

[18] Li X, Wang F, Xu M et al. ApoA-IV improves insulin sensitivity and glucose uptake in mouse adipocytes via PI3K-Akt Signaling. Sci Rep 2017;7:41289.

[19] Li QR, Wang ZM, Wewer Albrechtsen NJ et al. Systems signatures reveal unique remission-path of type 2 diabetes following Roux-en-Y gastric bypass surgery. EBioMedicine 2018;28:234–40.

[20] Cohen RD, Castellani LW, Qiao JH et al. Reduced aortic lesions and elevated high density lipoprotein levels in transgenic mice overexpressing mouse apolipoprotein A-IV. J Clin Invest 1997;99:1906–16.

[21] Fournier N, Atger V, Paul JL et al. Human ApoA-IV overexpression in transgenic mice induces cAMP-stimulated cholesterol efflux from J774 macrophages to whole serum. Arterioscler Thromb Vasc Biol 2000;20:1283–92.

[22] Ahren B. Islet G protein-coupled receptors as potential targets for treatment of type 2 diabetes. Nat Rev Drug Discov 2009;8:369–85.

[23] Liu M, Maiorano N, Shen L et al. Expression of biologically active rat apolipoprotein AIV in Escherichia coli. Physiol Behav 2003;78:149–55.

[24] Fujimoto K, Cardelli JA, Tso P. Increased apolipoprotein A-IV in rat mesenteric lymph after lipid meal acts as a physiological signal for satiation. Am J Physiol 1992;262:G1002–6.

[25] Pence S, Zhu Q, Binne E et al. Reduced diet-induced thermogenesis in apolipoprotein A-IV deficient mice. Int J Mol Sci 2019;20:3176.

[26] Yang LW, Bahar I. Coupling between catalytic site and collective dynamics: a requirement for mechanochemical activity of enzymes. Structure 2005;13:893–904.

[27] Dutta A, Bahar I. Metal-binding sites are designed to achieve optimal mechanical and signaling properties. Structure 2010;18:1140–8.

[28] Gerhard GS, Styer AM, Wood GC et al. A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass. Diabetes Care 2013;36:1859–64.

[29] Ding L, Zhang E, Yang Q et al. Vertical sleeve gastrectomy confers metabolic improvements by reducing intestinal bile acids and lipid absorption in mice. Proc Natl Acad Sci U S A 2021;118:e2019388118.

[30] Stefater MA, Wilson-Perez HE, Chambers AP et al. All bariatric surgeries are not created equal: insights from mechanistic comparisons. Endocr Rev 2012;33:595–622.

[31] Wewer Albrechtsen NJ, Geyer PE, Doll S et al. Plasma proteome profiling reveals dynamics of inflammatory and lipid homeostasis markers after Roux-En-Y gastric bypass surgery. Cell Syst 2018;7:601–12.e3.

[32] Wang Z, Wang L, Zhang Z et al. Apolipoprotein A-IV involves in glucose and lipid metabolism of rat. Nutr Metab (Lond) 2019;16:41.

[33] Steinmetz A, Barbaras R, Ghalim N et al. Human apolipoprotein A-IV binds to apolipoprotein A-I/A-II receptor sites and promotes cholesterol efflux from adipose cells. J Biol Chem 1990;265:7859–63.

[34] Qu J, Fourman S, Fitzgerald M et al. Low-density lipoprotein receptor-related protein 1 (LRP1) is a novel receptor for apolipoprotein A4 (APOA4) in adipose tissue. Sci Rep 2021;11:13289.

[35] Osei-Hwedieh DO, Amar M, Sviridov D et al. Apolipoprotein mimetic peptides: mechanisms of action as anti-atherogenic agents. Pharmacol Ther 2011;130:83–91.

[36] White CR, Garber DW, Anantharamaiah GM. Anti-inflammatory and cholesterol-reducing properties of apolipoprotein mimetics: a review. J Lipid Res 2014;55:2007–21.

[37] White CR, Smythies LE, Crossman DK et al. Regulation of pattern recognition receptors by the apolipoprotein A-I mimetic peptide 4F. Arterioscler Thromb Vasc Biol 2012;32:2631–9.

[38] Navab M, Reddy ST, Van Lenten BJ et al. High-density lipoprotein and 4F peptide reduce systemic inflammation by modulating intestinal oxidized lipid metabolism: novel hypotheses and review of literature. Arterioscler Thromb Vasc Biol 2012;32:2553–60.

[39] Croy JE, Brandon T, Komives EA. Two apolipoprotein E mimetic peptides, ApoE(130–149) and ApoE(141–155)², bind to LRP1. Biochemistry 2004;43:7328–35.

[40] Valanti EK, Chroni A, Sanoudou D. The future of apolipoprotein E mimetic peptides in the prevention of cardiovascular disease. Curr Opin Lipidol 2019;30:326–41.

[41] Ahmed S, Pande AH, Sharma SS. Therapeutic potential of ApoE-mimetic peptides in CNS disorders: current perspective. ExpNeurol 2022;353:114051.

[42] Wang L, Liu T, Liang R et al. Mesenchymal stem cells ameliorate β cell dysfunction of human type 2 diabetic islets by reversing β cell dedifferentiation. EBioMedicine 2020;51:102615.

[43] Deeds MC, Anderson JM, Armstrong AS et al. Single dose streptozotocin-induced diabetes: considerations for study design in islet transplantation models. Lab Anim 2011;45:131–40.

[44] Lei L, Liu Q, Liu S et al. Antidiabetic potential of a novel dual-target activator of glucokinase and peroxisome proliferator activated receptor-γ. Metabolism 2015;64:1250–61.

[45] Tewson PH, Martinka S, Shaner NC et al. New DAG and cAMP sensors optimized for live-cell assays in automated laboratories. J Biomol Screen 2016;21:298–305.

[46] Lei L, Huan Y, Liu Q et al. Morus alba L. (Sangzhi) alkaloids promote insulin secretion, restore diabetic β-cell function by preventing dedifferentiation and apoptosis. Front Pharmacol 2022;13:841981.

[47] Gong W, Liu Y, Zhao Y et al. Equally weighted multiscale elastic network model and its comparison with traditional and parameter-free models. J Chem Inf Model 2021;61:921–37.

[48] Burley SK, Bhikadiya C, Bi C et al. RCSB Protein Data Bank (RCSB.org): delivery of experimentally-determined PDB structures alongside one million computed structure models of proteins from artificial intelligence/machine learning. Nucleic Acids Res 2023;51:D488–508.

[49] Yang J, Yan R, Roy A et al. The I-TASSER Suite: protein structure and function prediction. Nat Methods 2015;12:7–8.

[50] Deng X, Morris J, Dressmen J et al. The structure of dimeric apolipoprotein A-IV and its mechanism of self-association. Structure 2012;20:767–79.

RIGHTS & PERMISSIONS

2024 The Author(s) 2024. Published by Oxford University Press on behalf of Higher Education Press.