Pathophysiology of non alcoholic fatty liver disease

International Journal of Molecular Sciences

Volumn 17, Issue 12, 2016, Pages

  Petta, Salvatore ^a   Gastaldelli, Amalia ^b   Rebelos, Eleni ^c   Bugianesi, Elisabetta ^d   Messa, Piergiorgio ^e   Miele, Luca ^f   Svegliati Baroni, Gianluca ^g   Valenti, Luca ^h   Bonino, Ferruccio ^c,i  

^a UNIVERSITY OF PALERMO   (Italy)

^b INSTITUTE OF CLINICAL PHYSIOLOGY   (Italy)

^c UNIVERSITY OF PISA   (Italy)

^d UNIVERSITY OF TURIN   (Italy)

^e IRCCS   (Italy)

^f FONDAZIONE POLICLINICO UNIVERSITARIO A GEMELLI IRCCS   (Italy)

^g UNIVERSITÀ POLITECNICA DELLE MARCHE   (Italy)

^h UNIVERSITY OF MILAN   (Italy)

ⁱ Institute for Health   (Italy)

Author keywords

Adiponectin; Cholesterol; Fatty liver; Free fatty acids; Ghrelin; Glucagon; Glucagon like peptide 1; Insulin; Insulin resistance; Irisin; Leptin; Selenoprotein P

Indexed keywords

ADIPONECTIN; CHOLESTEROL; FATTY ACID; FETUIN A; GHRELIN; GLUCAGON; GLUCAGON LIKE PEPTIDE 1; HORMONE; INSULIN; IRISIN; LEPTIN; SELENOPROTEIN P; GASTROINTESTINAL HORMONE; LIPID; PANCREAS HORMONE;

ATHEROSCLEROSIS; CELL DAMAGE; CHRONIC KIDNEY DISEASE; DIET; EXERCISE; HUMAN; INFLAMMATION; KIDNEY; LIPOTOXICITY; META ANALYSIS (TOPIC); METABOLIC SYNDROME X; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); REVIEW; ADIPOSE TISSUE; BLOOD; METABOLISM; MUSCLE;

ADIPOSE TISSUE; GASTROINTESTINAL HORMONES; HUMANS; LIPIDS; MUSCLES; NON-ALCOHOLIC FATTY LIVER DISEASE; PANCREATIC HORMONES;

EID: 85006134935     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms17122082     Document Type: Review

References (202)

1. Groop, L.C.; Bonadonna, R.C.; DelPrato, S.; Ratheiser, K.; Zyck, K.; Ferrannini, E.; DeFronzo, R.A. Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J. Clin. Investig. 1989, 84, 205–213.
2. Bugianesi, E.; Gastaldelli, A.; Vanni, E.; Gambino, R.; Cassader, M.; Baldi, S.; Ponti, V.; Pagano, G.; Ferrannini, E.; Rizzetto, M. Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 2005, 48, 634–642.
3. Lafontan, M.; Langin, D. Lipolysis and lipid mobilization in human adipose tissue. Prog. Lipid Res. 2009, 48, 275–297.
4. Ferrannini, E.; Camastra, S.; Coppack, S.W.; Fliser, D.; Golay, A.; Mitrakou, A. Insulin action and non-esterified fatty acids. The European Group for the Study of Insulin Resistance (EGIR). Proc. Nutr. Soc. 1997, 56, 753–761.
5. Legrand-Poels, S.; Esser, N.; L’Homme, L.; Scheen, A.; Paquot, N.; Piette, J. Free fatty acids as modulators of the NLRP3 inflammasome in obesity/type 2 diabetes. Biochem. Pharmacol. 2014, 92, 131–141.
6. Rocha, D.M.; Caldas, A.P.; Oliveira, L.L.; Bressan, J.; Hermsdorff, H.H. Saturated fatty acids trigger TLR4-mediated inflammatory response. Atherosclerosis 2016, 244, 211–215.
7. Moreira, A.P.; Texeira, T.F.; Ferreira, A.B.; Peluzio Mdo, C.; Alfenas Rde, C. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br. J. Nutr. 2012, 108, 801–809.
8. Mittendorfer, B.; Yoshino, M.; Patterson, B.W.; Klein, S. VLDL triglyceride kinetics in lean, overweight, and obese men and women. J. Clin. Endocrinol. Metab. 2016, 101, 4151–4160.
9. De Souza, R.J.; Mente, A.; Maroleanu, A.; Cozma, A.I.; Ha, V.; Kishibe, T.; Uleryk, E.; Budylowski, P.; Schunemann, H.; Beyene, J. et al. Intake of saturated and trans unsaturated fatty acids and risk of all cause mortality, cardiovascular disease, and type 2 diabetes: Systematic review and meta-analysis of observational studies. BMJ 2015, 351, h3978.
10. Patterson, E.; Wall, R.; Fitzgerald, G.F.; Ross, R.P.; Stanton, C. Health implications of high dietary omega-6 polyunsaturated Fatty acids. J. Nutr. Metab. 2012, 2012, 539426.
11. Maehre, H.K.; Jensen, I.J.; Elvevoll, E.O.; Eilertsen, K.E. Omega-3 fatty acids and cardiovascular diseases: Effects, mechanisms and dietary relevance. Int. J. Mol. Sci. 2015, 16, 22636–22661.
12. Romijn, J.A.; Coyle, E.F.; Sidossis, L.S.; Gastaldelli, A.; Horowitz, J.F.; Endert, E.; Wolfe, R.R. Regulation of endogenous fat and carbohydrate metabolism in relation to exercise intensity and duration. Am. J. Physiol. 1993, 265, E380–E391.
13. Boden, G. Fatty acid-induced inflammation and insulin resistance in skeletal muscle and liver. Curr. Diabetes Rep. 2006, 6, 177–181.
14. Gadang, V.; Kohli, R.; Myronovych, A.; Hui, D.Y.; Perez-Tilve, D.; Jaeschke, A. MLK3 promotes metabolic dysfunction induced by saturated fatty acid-enriched diet. Am. J. Physiol. Endocrinol. Metab. 2013, 305, E549–E556.
15. Leamy, A.K.; Egnatchik, R.A.; Shiota, M.; Ivanova, P.T.; Myers, D.S.; Brown, H.A.; Young, J.D. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate treated hepatic cells. J. Lipid Res. 2014, 55, 1478–1488.
16. Snodgrass, R.G.; Huang, S.; Choi, I.W.; Rutledge, J.C.; Hwang, D.H. Inflammasome-mediated secretion of IL-1β in human monocytes through TLR2 activation; modulation by dietary fatty acids. J. Immunol. 2013, 191, 4337–4347.
17. Das, S.K.; Mondal, A.K.; Elbein, S.C. Distinct gene expression profiles characterize cellular responses to palmitate and oleate. J. Lipid Res. 2010, 51, 2121–2131.
18. Yang, G.; Badeanlou, L.; Bielawski, J.; Roberts, A.J.; Hannun, Y.A.; Samad, F. Central role of ceramide biosynthesis in body weight regulation, energy metabolism, and the metabolic syndrome. Am. J. Physiol. Endocrinol. Metab. 2009, 297, E211–E224.
19. Ussher, J.R.; Koves, T.R.; Cadete, V.J.; Zhang, L.; Jaswal, J.S.; Swyrd, S.J.; Lopaschuk, D.G.; Proctor, S.D.; Keung, W.; Muoio, D.M. et al. Inhibition of de novo ceramide synthesis reverses diet-induced insulin resistance and enhances whole-body oxygen consumption. Diabetes 2010, 59, 2453–2464.
20. Wei, Y.; Wang, D.; Topczewski, F.; Pagliassotti, M.J. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am. J. Physiol. Endocrinol. Metab. 2006, 291, E275–E281.
21. Luukkonen, P.K.; Zhou, Y.; Sadevirta, S.; Leivonen, M.; Arola, J.; Oresic, M.; Hyotylainen, T.; Yki-Jarvinen, H. Hepatic ceramides dissociate steatosis and insulin resistance in patients with non-alcoholic fatty liver disease. J. Hepatol. 2016, 64, 1167–1175.
22. Gregor, M.F.; Yang, L.; Fabbrini, E.; Mohammed, B.S.; Eagon, J.C.; Hotamisligil, G.S.; Klein, S. Endoplasmic reticulum stress is reduced in tissues of obese subjects after weight loss. Diabetes 2009, 58, 693–700.
23. Mantzaris, M.D.; Tsianos, E.V.; Galaris, D. Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid-induced lipotoxicity in liver cells. FEBS J. 2011, 278, 519–530.
24. Listenberger, L.L.; Han, X.; Lewis, S.E.; Cases, S.; Farese, R.V., Jr.; Ory, D.S.; Schaffer, J.E. Triglyceride accumulation protects against fatty acid-induced lipotoxicity. Proc. Natl. Acad. Sci. USA 2003, 100, 3077–3082.
25. Saponaro, C.; Gaggini, M.; Carli, F.; Gastaldelli, A. The subtle balance between lipolysis and lipogenesis: A critical point in metabolic homeostasis. Nutrients 2015, 7, 9453–9474.
26. Yamaguchi, K.; Yang, L.; McCall, S.; Huang, J.; Yu, X.X.; Pandey, S.K.; Bhanot, S.; Monia, B.P.; Li, Y.X.; Diehl, A.M. Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 2007, 45, 1366–1374.
27. Sieber, J.; Jehle, A.W. Free fatty acids and their metabolism affect function and survival of podocytes. Front. Endocrinol. 2014, 5, 186.
28. Lennon, R.; Pons, D.; Sabin, M.A.; Wei, C.; Shield, J.P.; Coward, R.J.; Tavare, J.M.; Mathieson, P.W.; Saleem, M.A.; Welsh, G.I. Saturated fatty acids induce insulin resistance in human podocytes: Implications for diabetic nephropathy. Nephrol. Dial. Transplant. 2009, 24, 3288–3296.
29. Sieber, J.; Lindenmeyer, M.T.; Kampe, K.; Campbell, K.N.; Cohen, C.D.; Hopfer, H.; Mundel, P.; Jehle, A.W. Regulation of podocyte survival and endoplasmic reticulum stress by fatty acids. Am. J. Physiol. Ren. Physiol. 2010, 299, F821–F829.
30. Ioannou, G.N. The role of cholesterol in the pathogenesis of NASH. Trends Endocrinol. Metab. 2016, 27, 84–95.
31. Janoudi, A.; Shamoun, F.E.; Kalavakunta, J.K.; Abela, G.S. Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque. Eur. Heart J. 2016, 37, 1959–1967.
32. Tall, A.R.; Yvan-Charvet, L. Cholesterol, inflammation and innate immunity. Nat. Rev. Immunol. 2015, 15, 104–116.
33. Keys, A. Coronary heart disease, serum cholesterol, and the diet. Acta Med. Scand. 1980, 207, 153–160.
34. Franklin, B.A.; Durstine, J.L.; Roberts, C.K.; Barnard, R.J. Impact of diet and exercise on lipid management in the modern era. Best Pract. Res. Clin. Endocrinol. Metab. 2014, 28, 405–421.
35. Virtanen, J.K.; Mursu, J.; Virtanen, H.E.; Fogelholm, M.; Salonen, J.T.; Koskinen, T.T.; Voutilainen, S.; Tuomainen, T.P. Associations of egg and cholesterol intakes with carotid intima-media thickness and risk of incident coronary artery disease according to apolipoprotein E phenotype in men: The Kuopio Ischaemic Heart Disease Risk Factor Study. Am. J. Clin. Nutr. 2016, 103, 895–901.
36. Caesar, R.; Nygren, H.; Oresic, M.; Backhed, F. Interaction between dietary lipids and gut microbiota regulates hepatic cholesterol metabolism. J. Lipid Res. 2016, 57, 474–481.
37. Mann, S.; Beedie, C.; Jimenez, A. Differential effects of aerobic exercise, resistance training and combined exercise modalities on cholesterol and the lipid profile: Review, synthesis and recommendations. Sports Med. 2014, 44, 211–221.
38. O’Donovan, G.; Owen, A.; Bird, S.R.; Kearney, E.M.; Nevill, A.M.; Jones, D.W.; Woolf-May, K. Changes in cardiorespiratory fitness and coronary heart disease risk factors following 24 wk of moderate- or high-intensity exercise of equal energy cost. J. Appl. Physiol. 2005, 98, 1619–1625.
39. Lira, F.S.; Yamashita, A.S.; Uchida, M.C.; Zanchi, N.E.; Gualano, B.; Martins, E., Jr.; Caperuto, E.C.; Seelaender, M. Low and moderate, rather than high intensity strength exercise induces benefit regarding plasma lipid profile. Diabetol. Metab. Syndr. 2010, 2, 31.
40. Katzmarzyk, P.T.; Leon, A.S.; Rankinen, T.; Gagnon, J.; Skinner, J.S.; Wilmore, J.H.; Rao, D.C.; Bouchard, C. Changes in blood lipids consequent to aerobic exercise training related to changes in body fatness and aerobic fitness. Metabolism 2001, 50, 841–848.
41. Li, Y.; Schwabe, R.F.; Devries-Seimon, T.; Yao, P.M.; Gerbod-Giannone, M.C.; Tall, A.R.; Davis, R.J.; Flavell, R.; Brenner, D.A.; Tabas, I. Free cholesterol-loaded macrophages are an abundant source of tumor necrosis factor-α and interleukin-6: Model of NF-κB and map kinase-dependent inflammation in advanced atherosclerosis. J. Biol. Chem. 2005, 280, 21763–21772.
42. Puri, P.; Baillie, R.A.; Wiest, M.M.; Mirshahi, F.; Choudhury, J.; Cheung, O.; Sargeant, C.; Contos, M.J.; Sanyal, A.J. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 2007, 46, 1081–1090.
43. Min, H.K.; Kapoor, A.; Fuchs, M.; Mirshahi, F.; Zhou, H.; Maher, J.; Kellum, J.; Warnick, R.; Contos, M.J.; Sanyal, A.J. Increased hepatic synthesis and dysregulation of cholesterol metabolism is associated with the severity of nonalcoholic fatty liver disease. Cell Metab. 2012, 15, 665–674.
44. Dongiovanni, P.; Petta, S.; Maglio, C.; Fracanzani, A.L.; Pipitone, R.; Mozzi, E.; Motta, B.M.; Kaminska, D.; Rametta, R.; Grimaudo, S. et al. Transmembrane 6 superfamily member 2 gene variant disentangles nonalcoholic steatohepatitis from cardiovascular disease. Hepatology 2015, 61, 506–514.
45. Wahl, P.; Ducasa, G.M.; Fornoni, A. Systemic and renal lipids in kidney disease development and progression. Am. J. Physiol. Ren. Physiol. 2016, 310, F433–F445.
46. Lee, H.S.; Kruth, H.S. Accumulation of cholesterol in the lesions of focal segmental glomerulosclerosis. Nephrology 2003, 8, 224–223.
47. Fornoni, A.; Merscher, S.; Kopp, J.B. Lipid biology of the podocyte—New perspectives offer new opportunities. Nat. Rev. Nephrol. 2014, 10, 379–388.
48. Wang, X.X.; Jiang, T.; Shen, Y.; Caldas, Y.; Miyazaki-Anzai, S.; Santamaria, H.; Urbanek, C.; Solis, N.; Scherzer, P.; Lewis, L. et al. Diabetic nephropathy is accelerated by farnesoid X receptor deficiency and inhibited by farnesoid X receptor activation in a type 1 diabetes model. Diabetes 2010, 59, 2916–2927.
49. Kopp, J.B.; Smith, M.W.; Nelson, G.W.; Johnson, R.C.; Freedman, B.I.; Bowden, D.W.; Oleksyk, T.; McKenzie, L.M.; Kajiyama, H.; Ahuja, T.S. et al. MYH9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nat. Genet. 2008, 40, 1175–1184.
50. Kiss, E.; Kranzlin, B.; Wagenblabeta, K.; Bonrouhi, M.; Thiery, J.; Grone, E.; Nordstrom, V.; Teupser, D.; Gretz, N.; Malle, E. et al. Lipid droplet accumulation is associated with an increase in hyperglycemia-induced renal damage: Prevention by liver X receptors. Am. J. Pathol. 2013, 182, 727–741.
51. Agarwal, R. Effects of statins on renal function. Am. J. Cardiol. 2006, 97, 748–755.
52. Nigro, E.; Scudiero, O.; Monaco, M.L.; Palmieri, A.; Mazzarella, G.; Costagliola, C.; Bianco, A.; Daniele, A. New insight into adiponectin role in obesity and obesity-related diseases. BioMed Res. Int. 2014, 2014, 658913.
53. Scherer, P.E. The multifaceted roles of adipose tissue-therapeutic targets for diabetes and beyond: The 2015 banting lecture. Diabetes 2016, 65, 1452–1461.
54. Freitas Lima, L.C.; Braga, V.A.; do Socorro de Franca Silva, M.; Cruz, J.C.; Sousa Santos, S.H.; de Oliveira Monteiro, M.M.; Balarini, C.M. Adipokines, diabetes and atherosclerosis: An inflammatory association. Front. Physiol. 2015, 6, 304.
55. Von Frankenberg, A.D.; Silva, F.M.; de Almeida, J.C.; Piccoli, V.; do Nascimento, F.V.; Sost, M.M.; Leitao, C.B.; Remonti, L.L.; Umpierre, D.; Reis, A.F. et al. Effect of dietary lipids on circulating adiponectin: A systematic review with meta-analysis of randomised controlled trials. Br. J. Nutr. 2014, 112, 1235–1250.
56. Kamari, Y.; Grossman, E.; Oron-Herman, M.; Peleg, E.; Shabtay, Z.; Shamiss, A.; Sharabi, Y. Metabolic stress with a high carbohydrate diet increases adiponectin levels. Horm. Metab. Res. 2007, 39, 384–388.
57. Rezvani, R.; Cianflone, K.; McGahan, J.P.; Berglund, L.; Bremer, A.A.; Keim, N.L.; Griffen, S.C.; Havel, P.J.; Stanhope, K.L. Effects of sugar-sweetened beverages on plasma acylation stimulating protein, leptin and adiponectin: Relationships with metabolic outcomes. Obesity 2013, 21, 2471–2480.
58. Swarbrick, M.M.; Havel, P.J. Physiological, pharmacological, and nutritional regulation of circulating adiponectin concentrations in humans. Metab. Syndr. Relat. Disord. 2008, 6, 87–102.
59. Golbidi, S.; Laher, I. Exercise induced adipokine changes and the metabolic syndrome. J. Diabetes Res. 2014, 2014, 726861.
60. Ahmadi, N.; Eshaghian, S.; Huizenga, R.; Sosnin, K.; Ebrahimi, R.; Siegel, R. Effects of intense exercise and moderate caloric restriction on cardiovascular risk factors and inflammation. Am. J. Med. 2011, 124, 978–982.
61. Fantuzzi, G. Adiponectin and inflammation: Consensus and controversy. J. Allergy Clin. Immunol. 2008, 121, 326–330.
62. Bugianesi, E.; Pagotto, U.; Manini, R.; Vanni, E.; Gastaldelli, A.; de Iasio, R.; Gentilcore, E.; Natale, S.; Cassader, M.; Rizzetto, M. et al. Plasma adiponectin in nonalcoholic fatty liver is related to hepatic insulin resistance and hepatic fat content, not to liver disease severity. J. Clin. Endocrinol. Metab. 2005, 90, 3498–3504.
63. Gastaldelli, A.; Harrison, S.; Belfort-Aguiar, R.; Hardies, J.; Balas, B.; Schenker, S.; Cusi, K. Pioglitazone in the treatment of NASH: The role of adiponectin. Aliment. Pharmacol. Ther. 2010, 32, 769–775.
64. Kadowaki, T.; Yamauchi, T. Adiponectin and adiponectin receptors. Endocr. Rev. 2005, 26, 439–451.
65. Yano, Y.; Hoshide, S.; Ishikawa, J.; Hashimoto, T.; Eguchi, K.; Shimada, K.; Kario, K. Differential impacts of adiponectin on low-grade albuminuria between obese and nonobese persons without diabetes. J. Clin. Hypertens. 2007, 9, 775–782.
66. Ohashi, K.; Iwatani, H.; Kihara, S.; Nakagawa, Y.; Komura, N.; Fujita, K.; Maeda, N.; Nishida, M.; Katsube, F.; Shimomura, I. et al. Exacerbation of albuminuria and renal fibrosis in subtotal renal ablation model of adiponectin-knockout mice. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 1910–1917.
67. Sharma, K.; Ramachandrarao, S.; Qiu, G.; Usui, H.K.; Zhu, Y.; Dunn, S.R.; Ouedraogo, R.; Hough, K.; McCue, P.; Chan, L. et al. Adiponectin regulates albuminuria and podocyte function in mice. J. Clin. Investig. 2008, 118, 1645–1656.
68. Iwashima, Y.; Horio, T.; Kumada, M.; Suzuki, Y.; Kihara, S.; Rakugi, H.; Kawano, Y.; Funahashi, T.; Ogihara, T. Adiponectin and renal function, and implication as a risk of cardiovascular disease. Am. J. Cardiol. 2006, 98, 1603–1608.
69. Ignacy, W.; Chudek, J.; Adamczak, M.; Funahashi, T.; Matsuzawa, Y.; Kokot, F.; Wiecek, A. Reciprocal association of plasma adiponectin and serum C-reactive protein concentration in haemodialysis patients with end-stage kidney disease—A follow-up study. Nephron Clin. Pract. 2005, 101, c18–c24.
70. Marchlewska, A.; Stenvinkel, P.; Lindholm, B.; Danielsson, A.; Pecoits-Filho, R.; Lonnqvist, F.; Schalling, M.; Heimburger, O.; Nordfors, L. Reduced gene expression of adiponectin in fat tissue from patients with end-stage renal disease. Kidney Int. 2004, 66, 46–50.
71. Izadi, V.; Saraf-Bank, S.; Azadbakht, L. Dietary intakes and leptin concentrations. ARYA Atheroscler. 2014, 10, 266–272.
72. Gastaldelli, A.; Sironi, A.M.; Ciociaro, D.; Positano, V.; Buzzigoli, E.; Giannessi, D.; Lombardi, M.; Mari, A.; Ferrannini, E. Visceral fat and beta cell function in non-diabetic humans. Diabetologia 2005, 48, 2090–2096.
73. Maffei, M.; Halaas, J.; Ravussin, E.; Pratley, R.E.; Lee, G.H.; Zhang, Y.; Fei, H.; Kim, S.; Lallone, R.; Ranganathan, S. et al. Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat. Med. 1995, 1, 1155–1161.
74. Adya, R.; Tan, B.K.; Randeva, H.S. Differential effects of leptin and adiponectin in endothelial angiogenesis. J. Diabetes Res. 2015, 2015, 648239.
75. Martin, L.J.; Siliart, B.; Lutz, T.A.; Biourge, V.; Nguyen, P.; Dumon, H.J. Postprandial response of plasma insulin, amylin and acylated ghrelin to various test meals in lean and obese cats. Br. J. Nutr. 2010, 103, 1610–1619.
76. Hall, M.E.; Harmancey, R.; Stec, D.E. Lean heart: Role of leptin in cardiac hypertrophy and metabolism. World J. Cardiol. 2015, 7, 511–524.
77. Masquio, D.C.; de Piano, A.; Sanches, P.L.; Corgosinho, F.C.; Campos, R.M.; Carnier, J.; da Silva, P.L.; Caranti, D.A.; Tock, L.; Oyama, L.M. et al. The effect of weight loss magnitude on pro-/anti-inflammatory adipokines and carotid intima-media thickness in obese adolescents engaged in interdisciplinary weight loss therapy. Clin. Endocrinol. 2013, 79, 55–64.
78. La Cava, A.; Matarese, G. The weight of leptin in immunity. Nat. Rev. Immunol. 2004, 4, 371–379.
79. Cumin, F.; Baum, H.P.; de Gasparo, M.; Levens, N. Removal of endogenous leptin from the circulation by the kidney. Int. J. Obes. Relat. Metab. Disord. 1997, 21, 495–504.
80. Stenvinkel, P.; Lindholm, B.; Lonnqvist, F.; Katzarski, K.; Heimburger, O. Increases in serum leptin levels during peritoneal dialysis are associated with inflammation and a decrease in lean body mass. J. Am. Soc. Nephrol. 2000, 11, 1303–1309.
81. Polyzos, S.A.; Aronis, K.N.; Kountouras, J.; Raptis, D.D.; Vasiloglou, M.F.; Mantzoros, C.S. Circulating leptin in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Diabetologia 2016, 59, 30–43.
82. Mak, R.H.; Cheung, W.; Cone, R.D.; Marks, D.L. Leptin and inflammation-associated cachexia in chronic kidney disease. Kidney Int. 2006, 69, 794–797.
83. Carrero, J.J.; Nakashima, A.; Qureshi, A.R.; Lindholm, B.; Heimburger, O.; Barany, P.; Stenvinkel, P. Protein-energy wasting modifies the association of ghrelin with inflammation, leptin, and mortality in hemodialysis patients. Kidney Int. 2011, 79, 749–756.
84. Gastaldelli, A.; Cusi, K.; Pettiti, M.; Hardies, J.; Miyazaki, Y.; Berria, R.; Buzzigoli, E.; Sironi, A.M.; Cersosimo, E.; Ferrannini, E. et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology 2007, 133, 496–506.
85. Gastaldelli, A.; Baldi, S.; Pettiti, M.; Toschi, E.; Camastra, S.; Natali, A.; Landau, B.R.; Ferrannini, E. Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: A quantitative study. Diabetes 2000, 49, 1367–1373.
86. Khodabandehloo, H.; Gorgani-Firuzjaee, S.; Panahi, G.; Meshkani, R. Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction. Transl. Res. 2016, 167, 228–256.
87. Keane, K.N.; Cruzat, V.F.; Carlessi, R.; de Bittencourt, P.I., Jr.; Newsholme, P. Molecular events linking oxidative stress and inflammation to insulin resistance and β-cell dysfunction. Oxid. Med. Cell. Longev. 2015, 2015, 181643.
88. Chen, L.; Chen, R. Mechanisms linking inflammation to insulin resistance. Int. J. Endocrinol. 2015, 2015, 508409.
89. Lindgren, O.; Pacini, G.; Tura, A.; Holst, J.J.; Deacon, C.F.; Ahren, B. Incretin effect after oral amino acid ingestion in humans. J. Clin. Endocrinol. Metab. 2015, 100, 1172–1176.
90. Dobbins, R.L.; Szczepaniak, L.S.; Myhill, J.; Tamura, Y.; Uchino, H.; Giacca, A.; McGarry, J.D. The composition of dietary fat directly influences glucose-stimulated insulin secretion in rats. Diabetes 2002, 51, 1825–1833.
91. Kashyap, S.; Belfort, R.; Gastaldelli, A.; Pratipanawatr, T.; Berria, R.; Pratipanawatr, W.; Bajaj, M.; Mandarino, L.; DeFronzo, R.; Cusi, K. A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 2003, 52, 2461–2474.
92. Hyotylainen, T.; Jerby, L.; Petaja, E.M.; Mattila, I.; Jantti, S.; Auvinen, P.; Gastaldelli, A.; Yki-Jarvinen, H.; Ruppin, E.; Oresic, M. Genome-scale study reveals reduced metabolic adaptability in patients with non-alcoholic fatty liver disease. Nat. Commun. 2016, 7, 8994.
93. Donnelly, K.L.; Smith, C.I.; Schwarzenberg, S.J.; Jessurun, J.; Boldt, M.D.; Parks, E.J. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J. Clin. Investig. 2005, 115, 1343–1351.
94. Paradis, V.; Perlemuter, G.; Bonvoust, F.; Dargere, D.; Parfait, B.; Vidaud, M.; Conti, M.; Huet, S.; Ba, N.; Buffet, C. et al. High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: A potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Hepatology 2001, 34, 738–744.
95. Svegliati-Baroni, G.; Ridolfi, F.; Di Sario, A.; Casini, A.; Marucci, L.; Gaggiotti, G.; Orlandoni, P.; Macarri, G.; Perego, L.; Benedetti, A. et al. Insulin and insulin-like growth factor-1 stimulate proliferation and type I collagen accumulation by human hepatic stellate cells: Differential effects on signal transduction pathways. Hepatology 1999, 29, 1743–1751.
96. 2 peak in untrained humans. Am. J. Physiol. 1997, 273, E348–E354.
97. Cabrera, O.; Berman, D.M.; Kenyon, N.S.; Ricordi, C.; Berggren, P.O.; Caicedo, A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. USA 2006, 103, 2334–2339.
98. Wewer Albrechtsen, N.J.; Kuhre, R.E.; Pedersen, J.; Knop, F.K.; Holst, J.J. The biology of glucagon and the consequences of hyperglucagonemia. Biomark. Med. 2016, 10, 1141–1151.
99. Unger, R.H. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia 1985, 28, 574–578.
100. Gromada, J.; Franklin, I.; Wollheim, C.B. α-Cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr. Rev. 2007, 28, 84–116.
101. Mitrakou, A.; Ryan, C.; Veneman, T.; Mokan, M.; Jenssen, T.; Kiss, I.; Durrant, J.; Cryer, P.; Gerich, J. Hierarchy of glycemic thresholds for counterregulatory hormone secretion, symptoms, and cerebral dysfunction. Am. J. Physiol. 1991, 260, E67–E74.
102. Bagger, J.I.; Knop, F.K.; Lund, A.; Holst, J.J.; Vilsboll, T. Glucagon responses to increasing oral loads of glucose and corresponding isoglycaemic intravenous glucose infusions in patients with type 2 diabetes and healthy individuals. Diabetologia 2014, 57, 1720–1725.
103. Rocha, D.M.; Faloona, G.R.; Unger, R.H. Glucagon-stimulating activity of 20 amino acids in dogs. J. Clin. Investig. 1972, 51, 2346–2351.
104. Palmer, J.P.; Benson, J.W.; Walter, R.M.; Ensinck, J.W. Arginine-stimulated acute phase of insulin and glucagon secretion in diabetic subjects. J. Clin. Investig. 1976, 58, 565–570.
105. Radulescu, A.; Gannon, M.C.; Nuttall, F.Q. The effect on glucagon, glucagon-like peptide-1, total and acyl-ghrelin of dietary fats ingested with and without potato. J. Clin. Endocrinol. Metab. 2010, 95, 3385–3391.
106. Hippen, A.R. Glucagon as a potential therapy for ketosis and fatty liver. Vet. Clin. N. Am. Food Anim. Pract. 2000, 16, 267–282.
107. Jiang, G.; Zhang, B.B. Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 2003, 284, E671–E678.
108. Conarello, S.L.; Jiang, G.; Mu, J.; Li, Z.; Woods, J.; Zycband, E.; Ronan, J.; Liu, F.; Roy, R.S.; Zhu, L. et al. Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia. Diabetologia 2007, 50, 142–150.
109. Junker, A.E.; Gluud, L.; Holst, J.J.; Knop, F.K.; Vilsboll, T. Diabetic and nondiabetic patients with nonalcoholic fatty liver disease have an impaired incretin effect and fasting hyperglucagonaemia. J. Intern. Med. 2016, 279, 485–493.
110. Liang, Y.; Osborne, M.C.; Monia, B.P.; Bhanot, S.; Gaarde, W.A.; Reed, C.; She, P.; Jetton, T.L.; Demarest, K.T. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 2004, 53, 410–417.
111. Ortega, F.J.; Moreno-Navarrete, J.M.; Sabater, M.; Ricart, W.; Fruhbeck, G.; Fernandez-Real, J.M. Circulating glucagon is associated with inflammatory mediators in metabolically compromised subjects. Eur. J. Endocrinol. 2011, 165, 639–645.
112. Dandona, P.; Ghanim, H.; Abuaysheh, S.; Green, K.; Batra, M.; Dhindsa, S.; Makdissi, A.; Patel, R.; Chaudhuri, A. Decreased insulin secretion and incretin concentrations and increased glucagon concentrations after a high-fat meal when compared with a high-fruit and -fiber meal. Am. J. Physiol. Endocrinol. Metab. 2015, 308, E185–E191.
113. Pedersen, B.K.; Steensberg, A.; Schjerling, P. Exercise and interleukin-6. Curr. Opin. Hematol. 2001, 8, 137–141.
114. Bastard, J.P.; Maachi, M.; Van Nhieu, J.T.; Jardel, C.; Bruckert, E.; Grimaldi, A.; Robert, J.J.; Capeau, J.; Hainque, B. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J. Clin. Endocrinol. Metab. 2002, 87, 2084–2089.
115. Hirano, T. Interleukin 6 in autoimmune and inflammatory diseases: A personal memoir. Proc. Jpn. Acad. Ser. B Phys. Biol. Sci. 2010, 86, 717–730.
116. Tweedell, A.; Mulligan, K.X.; Martel, J.E.; Chueh, F.Y.; Santomango, T.; McGuinness, O.P. Metabolic response to endotoxin in vivo in the conscious mouse: Role of interleukin-6. Metabolism 2011, 60, 92–98.
117. Campbell, J.E.; Drucker, D.J. Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 2013, 17, 819–837.
118. Holst, J.J. Enteroendocrine secretion of gut hormones in diabetes, obesity and after bariatric surgery. Curr. Opin. Pharmacol. 2013, 13, 983–988.
119. Fava, S. Glucagon-like peptide 1 and the cardiovascular system. Curr. Diabetes Rev. 2014, 10, 302–310.
120. Unger, R.H.; Ohneda, A.; Valverde, I.; Eisentraut, A.M.; Exton, J. Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose. J. Clin. Investig. 1968, 47, 48–65.
121. McAlpine, C.S.; Bowes, A.J.; Werstuck, G.H. Diabetes, hyperglycemia and accelerated atherosclerosis: Evidence supporting a role for endoplasmic reticulum (ER) stress signaling. Cardiovasc. Hematol. Disord. Drug Targets 2010, 10, 151–157.
122. Lee, S.S.; Yoo, J.H.; So, Y.S. Effect of the low-versus high-intensity exercise training on endoplasmic reticulum stress and GLP-1 in adolescents with type 2 diabetes mellitus. J. Phys. Ther. Sci. 2015, 27, 3063–3068.
123. Kodera, R.; Shikata, K.; Kataoka, H.U.; Takatsuka, T.; Miyamoto, S.; Sasaki, M.; Kajitani, N.; Nishishita, S.; Sarai, K.; Hirota, D. et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes. Diabetologia 2011, 54, 965–978.
124. Arakawa, M.; Mita, T.; Azuma, K.; Ebato, C.; Goto, H.; Nomiyama, T.; Fujitani, Y.; Hirose, T.; Kawamori, R.; Watada, H. Inhibition of monocyte adhesion to endothelial cells and attenuation of atherosclerotic lesion by a glucagon-like peptide-1 receptor agonist, exendin-4. Diabetes 2010, 59, 1030–1037.
125. Varanasi, A.; Patel, P.; Makdissi, A.; Dhindsa, S.; Chaudhuri, A.; Dandona, P. Clinical use of liraglutide in type 2 diabetes and its effects on cardiovascular risk factors. Endocr. Pract. 2012, 18, 140–145.
126. Lehrskov-Schmidt, L.; Lehrskov-Schmidt, L.; Nielsen, S.T.; Holst, J.J.; Moller, K.; Solomon, T.P. The effects of TNF-α on GLP-1-stimulated plasma glucose kinetics. J. Clin. Endocrinol. Metab. 2015, 100, E616–E622.
127. Gupta, N.A.; Mells, J.; Dunham, R.M.; Grakoui, A.; Handy, J.; Saxena, N.K.; Anania, F.A. Glucagon-like peptide-1 receptor is present on human hepatocytes and has a direct role in decreasing hepatic steatosis in vitro by modulating elements of the insulin signaling pathway. Hepatology 2010, 51, 1584–1592.
128. Svegliati-Baroni, G.; Saccomanno, S.; Rychlicki, C.; Agostinelli, L.; de Minicis, S.; Candelaresi, C.; Faraci, G.; Pacetti, D.; Vivarelli, M.; Nicolini, D. et al. Glucagon-like peptide-1 receptor activation stimulates hepatic lipid oxidation and restores hepatic signalling alteration induced by a high-fat diet in nonalcoholic steatohepatitis. Liver Int. 2011, 31, 1285–1297.
129. Klonoff, D.C.; Buse, J.B.; Nielsen, L.L.; Guan, X.; Bowlus, C.L.; Holcombe, J.H.; Wintle, M.E.; Maggs, D.G. Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr. Med. Res. Opin. 2008, 24, 275–286.
130. Cuthbertson, D.J.; Irwin, A.; Gardner, C.J.; Daousi, C.; Purewal, T.; Furlong, N.; Goenka, N.; Thomas, E.L.; Adams, V.L.; Pushpakom, S.P. et al. Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists. PLoS ONE 2012, 7, e50117.
131. Kenny, P.R.; Brady, D.E.; Torres, D.M.; Ragozzino, L.; Chalasani, N.; Harrison, S.A. Exenatide in the treatment of diabetic patients with non-alcoholic steatohepatitis: A case series. Am. J. Gastroenterol. 2010, 105, 2707–2709.
132. Armstrong, M.J.; Gaunt, P.; Aithal, G.P.; Barton, D.; Hull, D.; Parker, R.; Hazlehurst, J.M.; Guo, K.; LEAN trial team; Abouda, G. et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 2015, 387, 679–690.
133. Gastaldelli, A.; Marchesini, G. Time for Glucagon like peptide-1 receptor agonists treatment for patients with NAFLD? J. Hepatol. 2016, 64, 262–264.
134. Jendle, J.; Nauck, M.A.; Matthews, D.R.; Frid, A.; Hermansen, K.; During, M.; Zdravkovic, M.; Strauss, B.J.; Garber, A.J.; LEAD-2 and LEAD-3 Study Groups. Weight loss with liraglutide, a once-daily human glucagon-like peptide-1 analogue for type 2 diabetes treatment as monotherapy or added to metformin, is primarily as a result of a reduction in fat tissue. Diabetes Obes. Metab. 2009, 11, 1163–1172.
135. Muller, T.D.; Nogueiras, R.; Andermann, M.L.; Andrews, Z.B.; Anker, S.D.; Argente, J.; Batterham, R.L.; Benoit, S.C.; Bowers, C.Y.; Broglio, F. et al. Ghrelin. Mol. Metab. 2015, 4, 437–460.
136. Buscher, A.K.; Buscher, R.; Hauffa, B.P.; Hoyer, P.F. Alterations in appetite-regulating hormones influence protein-energy wasting in pediatric patients with chronic kidney disease. Pediatr. Nephrol. 2010, 25, 2295–2301.
137. Zhang, S.R.; Fan, X.M. Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J. Gastroenterol. 2015, 21, 3214–3222.
138. Al Massadi, O.; Tschop, M.H.; Tong, J. Ghrelin acylation and metabolic control. Peptides 2011, 32, 2301–2308.
139. Cummings, D.E.; Frayo, R.S.; Marmonier, C.; Aubert, R.; Chapelot, D. Plasma ghrelin levels and hunger scores in humans initiating meals voluntarily without time- and food-related cues. Am. J. Physiol. Endocrinol. Metab. 2004, 287, E297–E304.
140. Rodriguez, A. Novel molecular aspects of ghrelin and leptin in the control of adipobiology and the cardiovascular system. Obes. Facts 2014, 7, 82–95.
141. Foster-Schubert, K.E.; Overduin, J.; Prudom, C.E.; Liu, J.; Callahan, H.S.; Gaylinn, B.D.; Thorner, M.O.; Cummings, D.E. Acyl and total ghrelin are suppressed strongly by ingested proteins, weakly by lipids, and biphasically by carbohydrates. J. Clin. Endocrinol. Metab. 2008, 93, 1971–1979.
142. Van Name, M.; Giannini, C.; Santoro, N.; Jastreboff, A.M.; Kubat, J.; Li, F.; Kursawe, R.; Savoye, M.; Duran, E.; Dziura, J. et al. Blunted suppression of acyl-ghrelin in response to fructose ingestion in obese adolescents: The role of insulin resistance. Obesity 2015, 23, 653–661.
143. Muller, T.D.; Tschop, M.H.; Jarick, I.; Ehrlich, S.; Scherag, S.; Herpertz-Dahlmann, B.; Zipfel, S.; Herzog, W.; de Zwaan, M.; Burghardt, R. et al. Genetic variation of the ghrelin activator gene ghrelin O-acyltransferase (GOAT) is associated with anorexia nervosa. J. Psychiatr. Res. 2011, 45, 706–711.
144. Burns, S.F.; Broom, D.R.; Miyashita, M.; Mundy, C.; Stensel, D.J. A single session of treadmill running has no effect on plasma total ghrelin concentrations. J. Sports Sci. 2007, 25, 635–642.
145. Schmidt, A.; Maier, C.; Schaller, G.; Nowotny, P.; Bayerle-Eder, M.; Buranyi, B.; Luger, A.; Wolzt, M. Acute exercise has no effect on ghrelin plasma concentrations. Horm. Metab. Res. 2004, 36, 174–177.
146. Mackelvie, K.J.; Meneilly, G.S.; Elahi, D.; Wong, A.C.; Barr, S.I.; Chanoine, J.P. Regulation of appetite in lean and obese adolescents after exercise: Role of acylated and desacyl ghrelin. J. Clin. Endocrinol. Metab. 2007, 92, 648–654.
147. Athinarayanan, S.; Wei, R.; Zhang, M.; Bai, S.; Traber, M.G.; Yates, K.; Cummings, O.W.; Molleston, J.; Liu, W.; Chalasani, N. Genetic polymorphism of cytochrome P450 4F2, vitamin E level and histological response in adults and children with nonalcoholic fatty liver disease who participated in PIVENS and TONIC clinical trials. PLoS ONE 2014, 9, e95366.
148. Prodam, F.; Filigheddu, N. Ghrelin gene products in acute and chronic inflammation. Arch. Immunol. Ther. Exp. 2014, 62, 369–384.
149. Delhanty, P.J.; Huisman, M.; Baldeon-Rojas, L.Y.; van den Berge, I.; Grefhorst, A.; Abribat, T.; Leenen, P.J.; Themmen, A.P.; van der Lely, A.J. Des-acyl ghrelin analogs prevent high-fat-diet-induced dysregulation of glucose homeostasis. FASEB J. 2013, 27, 1690–1700.
150. Tokudome, T.; Kishimoto, I.; Miyazato, M.; Kangawa, K. Ghrelin and the cardiovascular system. Front. Horm. Res. 2014, 43, 125–133.
151. Marchesini, G.; Pagotto, U.; Bugianesi, E.; de Iasio, R.; Manini, R.; Vanni, E.; Pasquali, R.; Melchionda, N.; Rizzetto, M. Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. J. Clin. Endocrinol. Metab. 2003, 88, 5674–5679.
152. Mykhalchyshyn, G.; Kobyliak, N.; Bodnar, P. Diagnostic accuracy of acyl-ghrelin and it association with non-alcoholic fatty liver disease in type 2 diabetic patients. J. Diabetes Metab. Disord. 2015, 14, 44.
153. Gunta, S.S.; Mak, R.H. Ghrelin and leptin pathophysiology in chronic kidney disease. Pediatr. Nephrol. 2013, 28, 611–616.
154. Suneja, M.; Murry, D.J.; Stokes, J.B.; Lim, V.S. Hormonal regulation of energy-protein homeostasis in hemodialysis patients: An anorexigenic profile that may predispose to adverse cardiovascular outcomes. Am. J. Physiol. Endocrinol. Metab. 2011, 300, E55–E64.
155. Raschke, S.; Eckel, J. Adipo-myokines: Two sides of the same coin—Mediators of inflammation and mediators of exercise. Mediat. Inflamm. 2013, 2013, 320724.
156. Arias-Loste, M.T.; Ranchal, I.; Romero-Gomez, M.; Crespo, J. Irisin, a link among fatty liver disease, physical inactivity and insulin resistance. Int. J. Mol. Sci. 2014, 15, 23163–23178.
157. Anastasilakis, A.D.; Polyzos, S.A.; Saridakis, Z.G.; Kynigopoulos, G.; Skouvaklidou, E.C.; Molyvas, D.; Vasiloglou, M.F.; Apostolou, A.; Karagiozoglou-Lampoudi, T.; Siopi, A. et al. Circulating irisin in healthy, young individuals: Day-night rhythm, effects of food intake and exercise, and associations with gender, physical activity, diet, and body composition. J. Clin. Endocrinol. Metab. 2014, 99, 3247–3255.
158. Ko, B.J.; Park, K.H.; Shin, S.; Zaichenko, L.; Davis, C.R.; Crowell, J.A.; Joung, H.; Mantzoros, C.S. Diet quality and diet patterns in relation to circulating cardiometabolic biomarkers. Clin. Nutr. 2016, 35, 484–490.
159. Schlogl, M.; Piaggi, P.; Votruba, S.B.; Walter, M.; Krakoff, J.; Thearle, M.S. Increased 24-hour ad libitum food intake is associated with lower plasma irisin concentrations the following morning in adult humans. Appetite 2015, 90, 154–159.
160. Qiu, S.; Cai, X.; Sun, Z.; Schumann, U.; Zugel, M.; Steinacker, J.M. Chronic exercise training and circulating irisin in adults: A meta-analysis. Sports Med. 2015, 45, 1577–1588.
161. Zhang, H.J.; Zhang, X.F.; Ma, Z.M.; Pan, L.L.; Chen, Z.; Han, H.W.; Han, C.K.; Zhuang, X.J.; Lu, Y.; Li, X.J. et al. Irisin is inversely associated with intrahepatic triglyceride contents in obese adults. J. Hepatol. 2013, 59, 557–562.
162. Polyzos, S.A.; Kountouras, J.; Anastasilakis, A.D.; Geladari, E.V.; Mantzoros, C.S. Irisin in patients with nonalcoholic fatty liver disease. Metabolism 2014, 63, 207–217.
163. Zurlo, F.; Larson, K.; Bogardus, C.; Ravussin, E. Skeletal muscle metabolism is a major determinant of resting energy expenditure. J. Clin. Investig. 1990, 86, 1423–1427.
164. Panesar, A.; Agarwal, R. Resting energy expenditure in chronic kidney disease: Relationship with glomerular filtration rate. Clin. Nephrol. 2003, 59, 360–366.
165. Lee, M.J.; Lee, S.A.; Nam, B.Y.; Park, S.; Lee, S.H.; Ryu, H.J.; Kwon, Y.E.; Kim, Y.L.; Park, K.S.; Oh, H.J. et al. Irisin, a novel myokine is an independent predictor for sarcopenia and carotid atherosclerosis in dialysis patients. Atherosclerosis 2015, 242, 476–482.
166. Wen, M.S.; Wang, C.Y.; Lin, S.L.; Hung, K.C. Decrease in irisin in patients with chronic kidney disease. PLoS ONE 2013, 8, e64025.
167. Ebert, T.; Focke, D.; Petroff, D.; Wurst, U.; Richter, J.; Bachmann, A.; Lossner, U.; Kralisch, S.; Kratzsch, J.; Beige, J. et al. Serum levels of the myokine irisin in relation to metabolic and renal function. Eur. J. Endocrinol. 2014, 170, 501–506.
168. Burk, R.F.; Hill, K.E. Selenoprotein P: An extracellular protein with unique physical characteristics and a role in selenium homeostasis. Annu. Rev. Nutr. 2005, 25, 215–235.
169. [Ser]Sec (Trsp) gene in mouse liver demonstrates an essential role of selenoproteins in liver function. J. Biol. Chem. 2004, 279, 8011–8017.
170. Hill, K.E.; Zhou, J.; McMahan, W.J.; Motley, A.K.; Atkins, J.F.; Gesteland, R.F.; Burk, R.F. Deletion of selenoprotein P alters distribution of selenium in the mouse. J. Biol. Chem. 2003, 278, 13640–13646.
171. Schomburg, L.; Schweizer, U.; Holtmann, B.; Flohe, L.; Sendtner, M.; Kohrle, J. Gene disruption discloses role of selenoprotein P in selenium delivery to target tissues. Biochem. J. 2003, 370, 397–402.
172. Misu, H.; Takamura, T.; Takayama, H.; Hayashi, H.; Matsuzawa-Nagata, N.; Kurita, S.; Ishikura, K.; Ando, H.; Takeshita, Y.; Ota, T. et al. A liver-derived secretory protein, selenoprotein P, causes insulin resistance. Cell Metab. 2010, 12, 483–495.
173. Misu, H.; Ishikura, K.; Kurita, S.; Takeshita, Y.; Ota, T.; Saito, Y.; Takahashi, K.; Kaneko, S.; Takamura, T. Inverse correlation between serum levels of selenoprotein P and adiponectin in patients with type 2 diabetes. PLoS ONE 2012, 7, e34952.
174. Yang, J.G.; Hill, K.E.; Burk, R.F. Dietary selenium intake controls rat plasma selenoprotein P concentration. J. Nutr. 1989, 119, 1010–1012.
175. Falnoga, I.; Kobal, A.B.; Stibilj, V.; Horvat, M. Selenoprotein P in subjects exposed to mercury and other stress situations such as physical load or metal chelation treatment. Biol. Trace Elem. Res. 2002, 89, 25–33.
176. Huang, Z.; Rose, A.H.; Hoffmann, P.R. The role of selenium in inflammation and immunity: From molecular mechanisms to therapeutic opportunities. Antioxid. Redox Signal. 2012, 16, 705–743.
177. Mattmiller, S.A.; Carlson, B.A.; Sordillo, L.M. Regulation of inflammation by selenium and selenoproteins: Impact on eicosanoid biosynthesis. J. Nutr. Sci. 2013, 2, e28.
178. Nichol, C.; Herdman, J.; Sattar, N.; O’Dwyer, P.J.; St, J.O.R.D.; Littlejohn, D.; Fell, G. Changes in the concentrations of plasma selenium and selenoproteins after minor elective surgery: Further evidence for a negative acute phase response? Clin. Chem. 1998, 44, 1764–1766.
179. Hesse-Bahr, K.; Dreher, I.; Kohrle, J. The influence of the cytokines Il-1beta and INFgamma on the expression of selenoproteins in the human hepatocarcinoma cell line HepG2. Biofactors 2000, 11, 83–85.
180. Dreher, I.; Jakobs, T.C.; Kohrle, J. Cloning and characterization of the human selenoprotein P promoter. Response of selenoprotein P expression to cytokines in liver cells. J. Biol. Chem. 1997, 272, 29364–29371.
181. Rayman, M.P. Selenium and human health. Lancet 2012, 379, 1256–1268.
182. Yang, S.J.; Hwang, S.Y.; Choi, H.Y.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H.; Choi, D.S.; Choi, K.M. Serum selenoprotein P levels in patients with type 2 diabetes and prediabetes: Implications for insulin resistance, inflammation, and atherosclerosis. J. Clin. Endocrinol. Metab. 2011, 96, E1325–E1329.
183. Rose, A.H.; Hoffmann, P.R. Selenoproteins and cardiovascular stress. Thromb. Haemost. 2015, 113, 494–504.
184. Choi, H.Y.; Hwang, S.Y.; Lee, C.H.; Hong, H.C.; Yang, S.J.; Yoo, H.J.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Baik, S.H. et al. Increased selenoprotein p levels in subjects with visceral obesity and nonalcoholic Fatty liver disease. Diabetes Metab. J. 2013, 37, 63–71.
185. Takayama, H.; Misu, H.; Iwama, H.; Chikamoto, K.; Saito, Y.; Murao, K.; Teraguchi, A.; Lan, F.; Kikuchi, A.; Saito, R. et al. Metformin suppresses expression of the selenoprotein P gene via an AMP-activated kinase (AMPK)/FoxO3a pathway in H4IIEC3 hepatocytes. J. Biol. Chem. 2014, 289, 335–345.
186. Burk, R.F.; Hill, K.E. Regulation of selenium metabolism and transport. Annu. Rev. Nutr. 2015, 35, 109–134.
187. Reinhardt, W.; Dolff, S.; Benson, S.; Broecker-Preuss, M.; Behrendt, S.; Hog, A.; Fuhrer, D.; Schomburg, L.; Kohrle, J. Chronic kidney disease distinctly affects relationship between selenoprotein P status and serum thyroid hormone parameters. Thyroid 2015, 25, 1091–1096.
188. Meyer, T.W.; Hostetter, T.H. Uremia. N. Engl. J. Med. 2007, 357, 1316–1325.
189. Denecke, B.; Graber, S.; Schafer, C.; Heiss, A.; Woltje, M.; Jahnen-Dechent, W. Tissue distribution and activity testing suggest a similar but not identical function of fetuin-B and fetuin-A. Biochem. J. 2003, 376, 135–145.
190. Mathews, S.T.; Chellam, N.; Srinivas, P.R.; Cintron, V.J.; Leon, M.A.; Goustin, A.S.; Grunberger, G. α2-HSG, a specific inhibitor of insulin receptor autophosphorylation, interacts with the insulin receptor. Mol. Cell. Endocrinol. 2000, 164, 87–98.
191. Stefan, N.; Hennige, A.M.; Staiger, H.; Machann, J.; Schick, F.; Krober, S.M.; Machicao, F.; Fritsche, A.; Haring, H.U. α2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 2006, 29, 853–857.
192. Mathews, S.T.; Singh, G.P.; Ranalletta, M.; Cintron, V.J.; Qiang, X.; Goustin, A.S.; Jen, K.L.; Charron, M.J.; Jahnen-Dechent, W.; Grunberger, G. Improved insulin sensitivity and resistance to weight gain in mice null for the Ahsg gene. Diabetes 2002, 51, 2450–2458.
193. Siddiq, A.; Lepretre, F.; Hercberg, S.; Froguel, P.; Gibson, F. A synonymous coding polymorphism in the α2-Heremans-schmid glycoprotein gene is associated with type 2 diabetes in French Caucasians. Diabetes 2005, 54, 2477–2481.
194. Dahlman, I.; Eriksson, P.; Kaaman, M.; Jiao, H.; Lindgren, C.M.; Kere, J.; Arner, P. α2-Heremans-Schmid glycoprotein gene polymorphisms are associated with adipocyte insulin action. Diabetologia 2004, 47, 1974–1979.
195. Nimptsch, K.; Janke, J.; Pischon, T.; Linseisen, J. Association between dietary factors and plasma fetuin-A concentrations in the general population. Br. J. Nutr. 2015, 114, 1278–1285.
196. Seyithanoglu, M.; Oner-Iyidogan, Y.; Dogru-Abbasoglu, S.; Tanrikulu-Kucuk, S.; Kocak, H.; Beyhan-Ozdas, S.; Kocak-Toker, N. The effect of dietary curcumin and capsaicin on hepatic fetuin-A expression and fat accumulation in rats fed on a high-fat diet. Arch. Physiol. Biochem. 2016, 122, 94–102.
197. Malin, S.K.; Mulya, A.; Fealy, C.E.; Haus, J.M.; Pagadala, M.R.; Scelsi, A.R.; Huang, H.; Flask, C.A.; McCullough, A.J.; Kirwan, J.P. Fetuin-A is linked to improved glucose tolerance after short-term exercise training in nonalcoholic fatty liver disease. J. Appl. Physiol. 2013, 115, 988–994.
198. Yang, S.J.; Hong, H.C.; Choi, H.Y.; Yoo, H.J.; Cho, G.J.; Hwang, T.G.; Baik, S.H.; Choi, D.S.; Kim, S.M.; Choi, K.M. Effects of a three-month combined exercise programme on fibroblast growth factor 21 and fetuin-A levels and arterial stiffness in obese women. Clin. Endocrinol. 2011, 75, 464–469.
199. Rametta, R.; Ruscica, M.; Dongiovanni, P.; Macchi, C.; Fracanzani, A.L.; Steffani, L.; Fargion, S.; Magni, P.; Valenti, L. Hepatic steatosis and PNPLA3 I148M variant are associated with serum Fetuin-A independently of insulin resistance. Eur. J. Clin. Investig. 2014, 44, 627–633.
200. Yilmaz, Y.; Yonal, O.; Kurt, R.; Ari, F.; Oral, A.Y.; Celikel, C.A.; Korkmaz, S.; Ulukaya, E.; Ozdogan, O.; Imeryuz, N. et al. Serum fetuin A/α2HS-glycoprotein levels in patients with non-alcoholic fatty liver disease: Relation with liver fibrosis. Ann. Clin. Biochem. 2010, 47, 549–553.
201. Ou, H.Y.; Yang, Y.C.; Wu, H.T.; Wu, J.S.; Lu, F.H.; Chang, C.J. Increased fetuin-A concentrations in impaired glucose tolerance with or without nonalcoholic fatty liver disease, but not impaired fasting glucose. J. Clin. Endocrinol. Metab. 2012, 97, 4717–4723.
202. Cottone, S.; Palermo, A.; Arsena, R.; Riccobene, R.; Guarneri, M.; Mule, G.; Tornese, F.; Altieri, C.; Vaccaro, F.; Previti, A. et al. Relationship of fetuin-A with glomerular filtration rate and endothelial dysfunction in moderate-severe chronic kidney disease. J. Nephrol. 2010, 23, 62–69.