Assessment of common and differentially expressed proteins between diabetes mellitus and fatty liver disease: a network analysis
Gastroenterology and Hepatology from Bed to Bench,
Vol. 14 No. Supplement 1 (2021),
30 December 2021
https://doi.org/10.22037/ghfbb.vi.2426
Abstract
Aim: This study aimed to introduce the main biomarkers related to NFLD and diabetes II to determine common pathogenic and metabolite factors linking NFLD to diabetes II.
Background: Nonalcoholic fatty liver disease (NFLD) is chronic hepatic failure with a broad range of hepatic disorders. NFLD and diabetes type 2 coexist regularly to drive adverse outcomes such as hepatocellular carcinoma and vascular complications
Methods: The proteins related to NFDL and diabetes mellitus were extracted from String database. Proteins related to each disease were included in protein-protein interaction networks in Cytoscape software. Obtained networks were analyzed using Cytoscape network analyzer. The central nodes were determined as top hubs based on degree value. The top hubs related to NFLD and diabetes mellites were compared.
Results: In total, 200 proteins related to NFDL and diabetes mellitus were found separately in String database and connected through undirected edges in individual networks. Central nodes based on degree value were determined for each disease. Ten percent of top nodes were selected based on degree value as the 20 top hubs for each disease. Target common hub proteins between NFDL and diabetes mellitus comprised INS, AKT1, ALB, PPARG, IL6, GPDPH, LEP, TNF, ADIPOQ, IGF1, TP53, MAPK3, and SIRT1.
Conclusion: According to the results, 13 common and 14 discriminatory central dysregulated proteins were determined for NAFLD and diabetes mellitus.
Keywords:
- Nonalcoholic fatty liver disease, Diabetes mellitus, Network analysis, Bioinformatics, Biomarkers
How to Cite
Saki, K. ., Mansouri, V. ., Abdi , S. ., Fathi, M. ., Razzaghi, Z. ., & Haghazali, M. . (2021). Assessment of common and differentially expressed proteins between diabetes mellitus and fatty liver disease: a network analysis. Gastroenterology and Hepatology from Bed to Bench, 14(Supplement 1). https://doi.org/10.22037/ghfbb.vi.2426
References
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17. Tavirani MR, Tavirani MR, Azodi MZ. ANXA2, PRKCE, and OXT are critical differentially genes in Nonalcoholic fatty liver disease. Gastroenterology and hepatology from bed to bench. 2019;12(2):131.
18. Tousoulis D, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, et al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. Journal of the American College of Cardiology. 2013;62(8):667-76.
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22. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30(6):1356-62.
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25. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806.
26. Sivaskandarajah GA, Jeansson M, Maezawa Y, Eremina V, Baelde HJ, Quaggin SE. Vegfa protects the glomerular microvasculature in diabetes. Diabetes. 2012;61(11):2958-66.
27. Mashili F, Chibalin AV, Krook A, Zierath JR. Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes. Diabetes. 2013;62(2):457-65.
28. Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney international. 2004;65(1):116-28.
29. Giunti S, Barutta F, Cavallo Perin P, Gruden G. Targeting the MCP-1/CCR2 system in diabetic kidney disease. Current vascular pharmacology. 2010;8(6):849-60.
30. Liadis N, Murakami K, Eweida M, Elford AR, Sheu L, Gaisano HY, et al. Caspase-3-dependent β-cell apoptosis in the initiation of autoimmune diabetes mellitus. Molecular and cellular biology. 2005;25(9):3620-9.
31. Dallongeville J, Lussier-Cacan S, Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. Journal of lipid research. 1992;33(4):447-54.
32. Schmechel D, Saunders A, Strittmatter W, Crain BJ, Hulette C, Joo S, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proceedings of the National Academy of Sciences. 1993;90(20):9649-53.
33. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes. 2002;51(4):1256-62.
34. Foretz M, Guichard C, Ferré P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proceedings of the National Academy of Sciences. 1999;96(22):12737-42.
35. Faulds MH, Zhao C, Dahlman-Wright K. Molecular biology and functional genomics of liver X receptors (LXR) in relationship to metabolic diseases. Current opinion in pharmacology. 2010;10(6):692-7.
36. Moslehi A, Hamidi-Zad Z. Role of SREBPs in liver diseases: a mini-review. Journal of clinical and translational hepatology. 2018;6(3):332.
37. Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, et al. Lipoprotein lipase up‐regulation in hepatic stellate cells exacerbates liver fibrosis in nonalcoholic steatohepatitis in mice. Hepatology communications. 2019;3(8):1098-112.
38. Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017;136:65-74.
39. Cladaras C, Hadzopoulou‐Cladaras M, Nolte RT, Atkinson D, Zannis VI. The complete sequence and structural analysis of human apolipoprotein B‐100: relationship between apoB‐100 and apoB‐48 forms. The EMBO journal. 1986;5(13):3495-507.
40. Schonfeld G. Familial hypobetalipoproteinemia: a review. Journal of lipid research. 2003;44(5):878-83.
41. Rückert I-M, Heier M, Rathmann W, Baumeister SE, Döring A, Meisinger C. Association between markers of fatty liver disease and impaired glucose regulation in men and women from the general population: the KORA-F4-study. PloS one. 2011;6(8):e22932.
42. Lawan A, Bennett AM. Mitogen-activated protein kinase regulation in hepatic metabolism. Trends in Endocrinology & Metabolism. 2017;28(12):868-78.
43. Dorn C, Riener M-O, Kirovski G, Saugspier M, Steib K, Weiss TS, et al. Expression of fatty acid synthase in nonalcoholic fatty liver disease. International journal of clinical and experimental pathology. 2010;3(5):505.
44. Xia M-F, Bian H, Gao X. NAFLD and diabetes: Two sides of the same coin? Rationale for gene-based personalized NAFLD treatment. Frontiers in pharmacology. 2019;10:877.
45. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519-23.
46. Stefan N, Häring H-U. The metabolically benign and malignant fatty liver. Diabetes. 2011;60(8).
47. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. The Lancet. 2010;375(9733):2267-77.
48. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713-23.
49. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. The Journal of clinical investigation. 1998;102(7):1369-76.
50. Hamid YH, Urhammer SA, Jensen DP, Glümer C, Borch-Johnsen K, Jørgensen T, et al. Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites. Diabetes. 2004;53(12):3342-5.
51. Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Digestive diseases. 2010;28(1):179-85.
52. Matsubara A, Wasson J, Donelan S, Welling C, Glaser B, Permutt M. Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes. Diabetologia. 2001;44(7):910-3.
53. Eshaghi FS, Ghazizadeh H, Kazami-Nooreini S, Timar A, Esmaeily H, Mehramiz M, et al. Association of a genetic variant in AKT1 gene with features of the metabolic syndrome. Genes & diseases. 2019;6(3):290-5.
54. Lee YK, Park JE, Lee M, Hardwick JP. Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2. Liver research. 2018;2(4):209-15.
2. Hossain N, Afendy A, Stepanova M, Nader F, Srishord M, Rafiq N, et al. Independent predictors of fibrosis in patients with nonalcoholic fatty liver disease. Clinical Gastroenterology and Hepatology. 2009;7(11):1224-9. e2.
3. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(S1):S99-S112.
4. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Digestive diseases. 2010;28(1):155-61.
5. Meex RC, Watt MJ. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nature Reviews Endocrinology. 2017;13(9):509-20.
6. Lonardo A, Nascimbeni F, Ballestri S, Fairweather D, Win S, Than TA, et al. Sex differences in nonalcoholic fatty liver disease: state of the art and identification of research gaps. Hepatology. 2019;70(4):1457-69.
7. Mavrogiannaki A, Migdalis I. Nonalcoholic fatty liver disease, diabetes mellitus and cardiovascular disease: newer data. International journal of endocrinology. 2013;2013.
8. Hadizadeh F, Faghihimani E, Adibi P. Nonalcoholic fatty liver disease: Diagnostic biomarkers. World journal of gastrointestinal pathophysiology. 2017;8(2):11.
9. Diez-Vallejo J, Comas-Fuentes A. Asymptomatic hypertransaminasemia in patients in primary care. Revista espanola de enfermedades digestivas: organo oficial de la Sociedad Espanola de Patologia Digestiva. 2011;103(10):530-5.
10. Siebler J, Galle PR, Weber MM. The gut–liver-axis: endotoxemia, inflammation, insulin resistance and NASH. Journal of hepatology. 2008;48(6):1032-4.
11. Yoneda M, Uchiyama T, Kato S, Endo H, Fujita K, Yoneda K, et al. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC gastroenterology. 2008;8(1):1-9.
12. Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Official journal of the American College of Gastroenterology| ACG. 2010;105(11):2389-95.
13. Bhatt HB, Smith RJ. Fatty liver disease in diabetes mellitus. Hepatobiliary surgery and nutrition. 2015;4(2):101.
14. Smith BW, Adams LA. Nonalcoholic fatty liver disease and diabetes mellitus: pathogenesis and treatment. Nature Reviews Endocrinology. 2011;7(8):456-65.
15. Sharma A, Demissei BG, Tromp J, Hillege HL, Cleland JG, O'Connor CM, et al. A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure. European Journal of Heart Failure. 2017;19(10):1310-20.
16. Liu X-L, Ming Y-N, Zhang J-Y, Chen X-Y, Zeng M-D, Mao Y-M. Gene-metabolite network analysis in different nonalcoholic fatty liver disease phenotypes. Experimental & molecular medicine. 2017;49(1):e283-e.
17. Tavirani MR, Tavirani MR, Azodi MZ. ANXA2, PRKCE, and OXT are critical differentially genes in Nonalcoholic fatty liver disease. Gastroenterology and hepatology from bed to bench. 2019;12(2):131.
18. Tousoulis D, Papageorgiou N, Androulakis E, Siasos G, Latsios G, Tentolouris K, et al. Diabetes mellitus-associated vascular impairment: novel circulating biomarkers and therapeutic approaches. Journal of the American College of Cardiology. 2013;62(8):667-76.
19. Dai W, Ye L, Liu A, Wen SW, Deng J, Wu X, et al. Prevalence of nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus: a meta-analysis. Medicine. 2017;96(39).
20. Zsombok A, Smith BN. Plasticity of central autonomic neural circuits in diabetes. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease. 2009;1792(5):423-31.
21. Pocai A. Obici S, Schwartz GJ, and Rossetti L. A brain-liver circuit regulates glucose homeostasis Cell Metab. 2005;1:53-61.
22. Angulo P, Keach JC, Batts KP, Lindor KD. Independent predictors of liver fibrosis in patients with nonalcoholic steatohepatitis. Hepatology. 1999;30(6):1356-62.
23. Finan B, Capozzi ME, Campbell JE. Repositioning glucagon action in the physiology and pharmacology of diabetes. Diabetes. 2020;69(4):532-41.
24. Whitehead JP, Clark SF, Ursø B, James DE. Signalling through the insulin receptor. Current opinion in cell biology. 2000;12(2):222-8.
25. Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799-806.
26. Sivaskandarajah GA, Jeansson M, Maezawa Y, Eremina V, Baelde HJ, Quaggin SE. Vegfa protects the glomerular microvasculature in diabetes. Diabetes. 2012;61(11):2958-66.
27. Mashili F, Chibalin AV, Krook A, Zierath JR. Constitutive STAT3 phosphorylation contributes to skeletal muscle insulin resistance in type 2 diabetes. Diabetes. 2013;62(2):457-65.
28. Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney international. 2004;65(1):116-28.
29. Giunti S, Barutta F, Cavallo Perin P, Gruden G. Targeting the MCP-1/CCR2 system in diabetic kidney disease. Current vascular pharmacology. 2010;8(6):849-60.
30. Liadis N, Murakami K, Eweida M, Elford AR, Sheu L, Gaisano HY, et al. Caspase-3-dependent β-cell apoptosis in the initiation of autoimmune diabetes mellitus. Molecular and cellular biology. 2005;25(9):3620-9.
31. Dallongeville J, Lussier-Cacan S, Davignon J. Modulation of plasma triglyceride levels by apoE phenotype: a meta-analysis. Journal of lipid research. 1992;33(4):447-54.
32. Schmechel D, Saunders A, Strittmatter W, Crain BJ, Hulette C, Joo S, et al. Increased amyloid beta-peptide deposition in cerebral cortex as a consequence of apolipoprotein E genotype in late-onset Alzheimer disease. Proceedings of the National Academy of Sciences. 1993;90(20):9649-53.
33. Peila R, Rodriguez BL, Launer LJ. Type 2 diabetes, APOE gene, and the risk for dementia and related pathologies: The Honolulu-Asia Aging Study. Diabetes. 2002;51(4):1256-62.
34. Foretz M, Guichard C, Ferré P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proceedings of the National Academy of Sciences. 1999;96(22):12737-42.
35. Faulds MH, Zhao C, Dahlman-Wright K. Molecular biology and functional genomics of liver X receptors (LXR) in relationship to metabolic diseases. Current opinion in pharmacology. 2010;10(6):692-7.
36. Moslehi A, Hamidi-Zad Z. Role of SREBPs in liver diseases: a mini-review. Journal of clinical and translational hepatology. 2018;6(3):332.
37. Teratani T, Tomita K, Furuhashi H, Sugihara N, Higashiyama M, Nishikawa M, et al. Lipoprotein lipase up‐regulation in hepatic stellate cells exacerbates liver fibrosis in nonalcoholic steatohepatitis in mice. Hepatology communications. 2019;3(8):1098-112.
38. Liss KH, Finck BN. PPARs and nonalcoholic fatty liver disease. Biochimie. 2017;136:65-74.
39. Cladaras C, Hadzopoulou‐Cladaras M, Nolte RT, Atkinson D, Zannis VI. The complete sequence and structural analysis of human apolipoprotein B‐100: relationship between apoB‐100 and apoB‐48 forms. The EMBO journal. 1986;5(13):3495-507.
40. Schonfeld G. Familial hypobetalipoproteinemia: a review. Journal of lipid research. 2003;44(5):878-83.
41. Rückert I-M, Heier M, Rathmann W, Baumeister SE, Döring A, Meisinger C. Association between markers of fatty liver disease and impaired glucose regulation in men and women from the general population: the KORA-F4-study. PloS one. 2011;6(8):e22932.
42. Lawan A, Bennett AM. Mitogen-activated protein kinase regulation in hepatic metabolism. Trends in Endocrinology & Metabolism. 2017;28(12):868-78.
43. Dorn C, Riener M-O, Kirovski G, Saugspier M, Steib K, Weiss TS, et al. Expression of fatty acid synthase in nonalcoholic fatty liver disease. International journal of clinical and experimental pathology. 2010;3(5):505.
44. Xia M-F, Bian H, Gao X. NAFLD and diabetes: Two sides of the same coin? Rationale for gene-based personalized NAFLD treatment. Frontiers in pharmacology. 2019;10:877.
45. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science. 2011;332(6037):1519-23.
46. Stefan N, Häring H-U. The metabolically benign and malignant fatty liver. Diabetes. 2011;60(8).
47. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. The Lancet. 2010;375(9733):2267-77.
48. Birkenfeld AL, Shulman GI. Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 diabetes. Hepatology. 2014;59(2):713-23.
49. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, et al. The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. The Journal of clinical investigation. 1998;102(7):1369-76.
50. Hamid YH, Urhammer SA, Jensen DP, Glümer C, Borch-Johnsen K, Jørgensen T, et al. Variation in the interleukin-6 receptor gene associates with type 2 diabetes in Danish whites. Diabetes. 2004;53(12):3342-5.
51. Tilg H. The role of cytokines in non-alcoholic fatty liver disease. Digestive diseases. 2010;28(1):179-85.
52. Matsubara A, Wasson J, Donelan S, Welling C, Glaser B, Permutt M. Isolation and characterization of the human AKT1 gene, identification of 13 single nucleotide polymorphisms (SNPs), and their lack of association with Type II diabetes. Diabetologia. 2001;44(7):910-3.
53. Eshaghi FS, Ghazizadeh H, Kazami-Nooreini S, Timar A, Esmaeily H, Mehramiz M, et al. Association of a genetic variant in AKT1 gene with features of the metabolic syndrome. Genes & diseases. 2019;6(3):290-5.
54. Lee YK, Park JE, Lee M, Hardwick JP. Hepatic lipid homeostasis by peroxisome proliferator-activated receptor gamma 2. Liver research. 2018;2(4):209-15.
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