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2017, Number 5

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Ann Hepatol 2017; 16 (5)

Models of non-Alcoholic Fatty Liver Disease and Potential Translational Value: the Effects of 3,5-L-diiodothyronine

Grasselli E, Canesi L, Portincasa P, Voci A, Vergani L, Demori I

Language: English
References: 85
Page: 707-719
PDF size: 858.27 Kb.


ABSTRACT

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disorder in industrialized countries and is associated with increased risk of cardiovascular, hepatic and metabolic diseases. Molecular mechanisms on the root of the disrupted lipid homeostasis in NAFLD and potential therapeutic strategies can benefit of in vivo and in vitro experimental models of fatty liver. Here, we describe the high fat diet (HFD)-fed rat in vivo model, and two in vitro models, the primary cultured rat fatty hepatocytes or the FaO rat hepatoma fatty cells, mimicking human NAFLD. Liver steatosis was invariably associated with increased number/size of lipid droplets (LDs) and modulation of expression of genes coding for key genes of lipid metabolism such as peroxisome proliferator-activated receptors (Ppars) and perilipins (Plins). In these models, we tested the anti-steatotic effects of 3,5-L-diiodothyronine (T2), a metabolite of thyroid hormones. T2 markedly reduced triglyceride content and LD size acting on mRNA expression of both Ppars and Plins. T2 also stimulated mitochondrial oxidative metabolism of fatty acids. We conclude that in vivo and especially in vitro models of NAFLD are valuable tools to screen a large number of compounds counteracting the deleterious effect of liver steatosis. Because of the high and negative impact of liver steatosis on human health, ongoing experimental studies from our group are unravelling the ultimate translational value of such cellular models of NAFLD.


REFERENCES

  1. Hoyumpa AM, Greene HL, Dunn GD, Schenker S. Fatty liver: biochemical and clinical considerations. Am J Dig Dis 1975; 20: 1142-70.

  2. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005; 41: 1313-21.

  3. Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 2010; 24: 695-708.

  4. Love-Osborne KA, Nadeau KJ, Sheeder J, Fenton LZ, Zeitler P. Presence of the metabolic syndrome in obese adolescents predicts impaired glucose tolerance and nonalcoholic fatty liver disease. J Adolesc Health 2008; 42: 543-8.

  5. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012; 55: 2005-23.

  6. Basaranoglu M, Basaranoglu G, Sabuncu T, Senturk H. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol 2013; 19: 1166-72.

  7. Abenavoli L, Milic N, Di Renzo L, Preveden T, Mediæ-Stojanoska M, De Lorenzo A. Metabolic aspects of adult patients with nonalcoholic fatty liver disease. World J Gastroenterol 2016; 22: 7006-16.

  8. Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009; 48: 1-26.

  9. Calamita G, Portincasa P. Present and future therapeutic strategies in non-alcoholic fatty liver disease. Expert Opin Ther Targets 2007; 11: 1231-49.

  10. Walther TC, Farese RV. The life of lipid droplets. Biochim Biophys Acta-Mol Cell Biol Lipids 2013; 1791: 459-66.

  11. Thiam AR, Farese RV, Walther TC. The biophysics and cell biology of lipid droplets. Nat Rev Mol Cell Biol 2013; 14: 775-86.

  12. Pol A, Gross SP, Parton RG. Biogenesis of the multifunctional lipid droplet: Lipids, proteins, and sites. J Cell Biol 2014; 204: 635-46.

  13. Kimmel AR, Brasaemle DL, McAndrews-Hill M, Sztalryd C, Londos C. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J Lipid Res 2010, 51: 468-71.

  14. Bickel PE, Tansey JT, Welte MA. PAT proteins, an ancient family of lipid droplet proteins that regulate cellular lipid stores. Biochim Biophys. Acta - Mol Cell Biol Lipids 2009; 1791: 419-40.

  15. Ducharme NA, Bickel PE. Minireview: Lipid Droplets in Lipogenesis and Lipolysis. Endocrinology 2008; 149: 942-9.

  16. Dalen KT. PPAR activators and fasting induce the expression of adipose differentiation-related protein in liver. J Lipid Res 2006; 47: 931-43.

  17. Grasselli E, Voci A, Pesce C, Canesi L, Fugassa E, Gallo G, Vergani L. PAT protein mRNA expression in primary rat hepatocytes: Effects of exposure to fatty acids. Int J Mol Med 2010; 25: 505-12.

  18. Straub BK, Stoeffel P, Heid H, Zimbelmann R, Schirmacher. Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 2008; 47: 1936-46.

  19. Varela GM, Antwi DA, Dhir R, Yin X, Singhal NS, Graham MJ, Crooke RM, et al. Inhibition of ADRP prevents diet-induced insulin resistance. AJP Gastrointest Liver Physiol 2008; 295: G621-G628.

  20. Imai Y, Varela GM, Jackson MB, Graham MJ, Crooke RM, Ahima, RS. Reduction of Hepatosteatosis and Lipid Levels by an Adipose Differentiation-Related Protein Antisense Oligonucleotide. Gastroenterology 2007; 132: 1947-54.

  21. Magnusson B. Adipocyte Differentiation-Related Protein Promotes Fatty Acid Storage in Cytosolic Triglycerides and Inhibits Secretion of Very Low-Density Lipoproteins. Arterioscler Thromb Vasc Biol 2006; 26: 1566-71.

  22. Chang BH-J, Li L, Saha P, Chan L. Absence of adipose differentiation related protein upregulates hepatic VLDL secretion, relieves hepatosteatosis, and improves whole body insulin resistance in leptin-deficient mice. J Lipid Res 2010; 51: 2132-42.

  23. Chang BH-J, Li L, Paul A, Taniguchi S, Nannegari V, Heird WC, Chan L. Protection against Fatty Liver but Normal Adipogenesis in Mice Lacking Adipose Differentiation-Related Protein. Mol Cell Biol 2006; 26: 1063-76

  24. Carr RM, Patel RT, Rao V, Dhir R, Graham MJ, Crooke RM, Ahima RS. Reduction of TIP47 improves hepatic steatosis and glucose homeostasis in mice. AJP Regul Integr Comp Physiol 2012; 302: R996-R1003.

  25. Hall AM, Brunt EM, Chen Z, Viswakarma N, Reddy JK, Wolins NE, Finck BN. Dynamic and differential regulation of proteins that coat lipid droplets in fatty liver dystrophic mice. J Lipid Res 2010; 51: 554-63.

  26. Wang C, Zhao Y, Gao X, Li L, Yuan Y, Liu F, Zhang L, et al. Perilipin 5 improves hepatic lipotoxicity by inhibiting lipolysis. Hepatology 2015; 61: 870-82.

  27. Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease. World J Hepatol 2015; 7: 1012-9.

  28. Moras D, Gronemeyer H. The nuclear receptor ligand-binding domain: structure and function. Curr Opin Cell Biol 1998; 10: 384-91.

  29. Wahli W, Michalik L. PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 2012; 23: 351-63.

  30. de Lange P, Lombardi A, Silvestri E, Goglia F, Lanni A, Moreno M. Peroxisome Proliferator-Activated Receptor Delta: A Conserved Director of Lipid Homeostasis through Regulation of the Oxidative Capacity of Muscle. PPAR Res 2008; 2008: 172676.

  31. Akbiyik F, Cinar K, Demirpence E, Ozsullu T, Tunca R, Haziroglu R, Yurdaydin C, et al. Ligand-induced expression of peroxisome proliferator-activated receptor alpha and activa tion of fatty acid oxidation enzymes in fatty liver. Eur J Clin Invest 2004; 34: 429-35.

  32. Hsu S-C, Huang C. Changes in liver PPARa mRNA expression in response to two levels of high-safflower-oil diets correlate with changes in adiposity and serum leptin in rats and mice. J Nutr Biochem 2007; 18: 86-96.

  33. Patsouris D, Reddy JK, Müller M, Kersten S. Peroxisome Proliferator- Activated Receptor á Mediates the Effects of High- Fat Diet on Hepatic Gene Expression. Endocrinology 2006, 147: 1508-16.

  34. Nakamuta M, Kohjima M, Morizono S, Kotoh K, Yoshimoto T, Miyagi I, Enjoji M. Evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med 2005; 16: 631-5.

  35. Souza-Mello V, Gregório BM, Cardoso-de-Lemos FS, de Carvalho L, Aguila MB, Mandarim-de-Lacerda CA. Comparative effects of telmisartan, sitagliptin and metformin alone or in combination on obesity, insulin resistance, and liver and pancreas remodelling in C57BL/6 mice fed on a very high-fat diet. Clin Sci 2010; 119: 239-50.

  36. Fraulob JC, Souza-Mello V, Aguila MB, Mandarim-de-Lacerda CA. Beneficial effects of rosuvastatin on insulin resistance, adiposity, inflammatory markers and non-alcoholic fatty liver disease in mice fed on a high-fat diet. Clin Sci 2012; 12: 259-70.

  37. Rahimian R, Masih-Khan E, Lo M, van Breemen C, McManus BM, Dube GP. Hepatic over-expression of peroxisome proliferator activated receptor gamma 2 in the ob/ob mouse model of non-insulin dependent diabetes mellitus. Mol Cell Biochem 2001; 224: 29-37.

  38. Pettinelli P, Videla LA. Up-Regulation of PPAR-gamma mRNA Expression in the Liver of Obese Patients: an Additional Reinforcing Lipogenic Mechanism to SREBP-1c Induction. J Clin Endocrinol Metab 2011; 96: 1424-30.

  39. García-Ruiz I, Rodríguez-Juan C, Díaz-Sanjuán T, Martínez MA, Muñoz-Yagüe T, Solís-Herruzo JA. Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ ob mice. Hepatology 2007; 46: 414-23.

  40. Nagasawa T, Inada Y, Nakano S, Tamura T, Takahashi T, Maruyama K, Yamazaki Y, et al. Effects of bezafibrate, PPAR pan-agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine- and choline-deficient diet. Eur J Pharmacol 2006; 536: 182-91.

  41. Dalen KT, Schoonjans K, Ulven SM, Weedon-Fekjaer MS, Bentzen TG, Koutnikova H, Auwerx J, et al. Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma. Diabetes 2004; 53: 1243-52.

  42. Wolins NE, Quaynor BK, Skinner JR, Tzekov A, Croce MA, Gropler MC, Varma V, et al. OXPAT/PAT-1 Is a PPAR-Induced Lipid Droplet Protein That Promotes Fatty Acid Utilization. Diabetes 2006; 55: 3418-28.

  43. Schadinger SE, Bucher NLR, Schreiber BM, Farmer SR. PPARgamma2 regulates lipogenesis and lipid accumulation in steatotic hepatocytes. Am J Physiol Endocrinol Metab 2005; 288: E1195-E1205.

  44. Yamaguchi T, Matsushita S, Motojima K, Hirose F, Osumi T. MLDP, a Novel PAT Family Protein Localized to Lipid Droplets and Enriched in the Heart, Is Regulated by Peroxisome Proliferator- activated Receptor. J Biol Chem 2006; 281: 14232- 40.

  45. Targett-Adams P, McElwee MJ, Ehrenborg E, Gustafsson MC, Palmer CN, McLauchlan J. A PPAR response element regulates transcription of the gene for human adipose differentiation- related protein. Biochim Biophys Acta - Gene Struct Expr 2005; 1728: 95-104.

  46. Kanuri G, Bergheim I. In vitro and in vivo models of non-alcoholic fatty liver disease (NAFLD). Int J Mol Sci 2013; 14: 11963-80.

  47. Kucera O, Cervinkova Z. Experimental models of non-alcoholic fatty liver disease in rats. World J Gastroenterol 2014; 20: 8364-76.

  48. Anstee QM, Goldin RD. Mouse models in non-alcoholic fatty liver disease and steatohepatitis research. Int J Exp Pathol 2006; 87: 1-16.

  49. Machado MV, Michelotti GA, Xie G, Almeida Pereira T, de Almeida TP, Boursier J, Bohnic, B, et al. Mouse models of dietinduced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease. PLoS One 2015; 10: e0127991.

  50. Demori I, Voci A, Fugassa E, Burlando, B. Combined effects of high-fat diet and ethanol induce oxidative stress in rat liver. Alcohol 2006; 40: 185-91.

  51. Grasselli E, Canesi L, Voci A, De Matteis R, Demori I, Fugassa E, Vergani, L. Effects of 3,5-diiodo-L-thyronine administration on the liver of high fat diet-fed rats. Exp Biol Med (Maywood) 2008; 233: 549-57.

  52. Suh HN, Huong HT, Song CH, Lee JH, Han HJ. Linoleic acid stimulates gluconeogenesis via Ca2+/PLC, cPLA2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes. AJP Cell Physiol 2008; 295: C1518-C1527.

  53. Vinciguerra M, Sgroi A, Veyrat-Durebex C, Rubbia-Brandt L, Buhler LH, Foti M. Unsaturated fatty acids inhibit the expression of tumor suppressor phosphatase and tensin homolog (PTEN) via microRNA-21 up-regulation in hepatocytes. Hepatology 2009; 49: 1176-84.

  54. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, Burgart LJ, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-α expression via a lysosomal pathway. Hepatology 2004; 40: 185-94.

  55. Gómez-Lechón MJ, Donato MT, Martínez-Romero A, Jiménez N, Castell JV, O’Connor J-E. A human hepatocellular in vitro model to investigate steatosis. Chem Biol Interact 2007; 165: 106-16.

  56. Hetherington AM, Sawyez CG, Zilberman E, Stoianov AM, Robson DL, Borradaile NM. Differential Lipotoxic Effects of Palmitate and Oleate in Activated Human Hepatic Stellate Cells and Epithelial Hepatoma Cells. Cell Physiol Biochem 2016; 39: 1648-62.

  57. Aaraya J, Rodrigo R, Videla LA, Thielemann L, Orellana M, Pettinelli P, Poniachik J. Increase in long-chain polyunsaturated fatty acid n-6/n-3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci 2004; 106: 635-43.

  58. Leamy AK, Egnatchik RA, Shiota M, Ivanova PT, Myers DS, Brown HA, Young JD. Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitatetreated hepatic cells. J Lipid Res 2014; 55: 1478-88.

  59. Ferrannini E, Barrett EJ, Bevilacqua S, DeFronzo RA. Effect of fatty acids on glucose production and utilization in man. J Clin Invest 1983; 72: 1737-47.

  60. Shulman M, Nahmias Y. Long-term culture and coculture of primary rat and human hepatocytes. Methods Mol Biol 2013; 945: 287-302.

  61. Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells: a biochemical and fine structural study. J Cell Biol 1969; 43: 506-20.

  62. Seglen PO. Preparation of isolated rat liver cells. Methods Cell Biol 1976; 13: 29-83.

  63. Fugassa E, Gallo G, Voci A, Cordone A. RNA synthesis in primary cultures of adult rat hepatocytes. In Vitro 1983; 19: 299-306.

  64. Grasselli E, Voci A, Canesi L, De Matteis R, Goglia F, Cioffi F, Fugassa E, et al. Direct effects of iodothyronines on excess fat storage in rat hepatocytes. J Hepatol 2011; 54: 1230-36.

  65. Clayton DF, Weiss M, Darnell JE. Liver-specific RNA metabolism in hepatoma cells: variations in transcription rates and mRNA levels. Mol Cell Biol 1985; 5: 2633-41.

  66. Spann NJ, Kang S, Li AC, Chen AZ, Newberry EP, Davidson NO, Hui STY, et al. Coordinate transcriptional repression of liver fatty acid-binding protein and microsomal triglyceride transfer protein blocks hepatic very low density lipoprotein secretion without hepatosteatosis. J Biol Chem 2006; 281: 33066-77.

  67. König B, Eder K. Differential action of 13-HPODE on PPARa downstream genes in rat Fao and human HepG2 hepatoma cell lines. J Nutr Biochem 2006; 17: 410-8.

  68. Grasselli E, Voci A, Canesi L, Goglia F, Ravera S, Panfoli I, Gallo G, et al. Non-receptor-mediated actions are responsible for the lipid-lowering effects of iodothyronines in FaO rat hepatoma cells. J Endocrinol 2011; 210: 59-69.

  69. Grasselli E, Voci A, Demori I, Canesi L, De Matteis R, Goglia F, Lanni A, et al. 3,5-Diiodo-L-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver. J Endocrinol 2012; 212: 149-58.

  70. Grasselli E, Voci A, Canesi L, Salis A, Damonte G, Compalati AD, Goglia F, et al. 3,5-diiodo-L-thyronine modifies the lipid droplet composition in a model of hepatosteatosis. Cell Physiol Biochem 2014; 33: 344-56.

  71. Grasselli E, Voci A, Demori I, Vecchione G, Compalati AD, Gallo G, Goglia F, et al. Triglyceride Mobilization from Lipid Droplets Sustains the Anti-Steatotic Action of Iodothyronines in Cultured Rat Hepatocytes. Front Physiol 2016; 6: 1-10.

  72. Pyper SR, Viswakarma N, Yu S, Reddy JK. PPARalpha: energy combustion, hypolipidemia, inflammation and cancer. Nucl Recept Signal 2010; 16: 8:e002.

  73. Lanni A, Moreno M, Lombardi A, de Lange P, Silvestri E, Ragni M, Farina P, et al. 3,5-diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats. FASEB J 2005; 19: 1552-4.

  74. de Lange P, Cioffi F, Senese R, Moreno M, Lombardi A, Silvestri E, De Matteis R, et al. Nonthyrotoxic prevention of dietinduced insulin resistance by 3,5-diiodo-L-thyronine in rats. Diabetes 2011; 60: 2730-9.

  75. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94: 355-82.

  76. Pucci E, Chiovato L, Pinchera A. Thyroid and lipid metabolism. Int J Obes Relat Metab Disord 2000; 24: S109-S112.

  77. Cimmino M, Mion F, Goglia F, Minaire Y, Geloen A. Demonstration of in vivo metabolic effects of 3,5-di-iodothyronine. J Endocrinol 1996; 149: 319-25.

  78. Mollica MP, Lionetti L, Moreno M, Lombardi A, De Lange P, Antonelli A, Lanni A, et al. 3,5-diiodo-l-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet. J Hepatol 2009; 51: 363-70.

  79. Silvestri E, Cioffi F, Glinni D, Ceccarelli M, Lombardi A, de Lange P, Chambery A, et al. Pathways affected by 3,5-diiodo- l-thyronine in liver of high fat-fed rats: evidence from two-dimensional electrophoresis, blue-native PAGE, and mass spectrometry. Mol Biosyst 2010; 6: 2256-71.

  80. Vergani L. Lipid lowering effects of iodothyronines: In vivo and in vitro studies on rat liver. World J Hepatol 2014; 6: 169-77.

  81. Fraczek J, Bolleyn J, Vanhaecke T, Rogiers V, Vinken M. Primary hepatocyte cultures for pharmaco-toxicological studies: at the busy crossroad of various anti-dedifferentiation strategies. Arch Toxicol 2013; 87: 577-610.

  82. Markova M, Pivovarova O, Hornemann S, Sucher S, Frahnow T, Wegner K, Machann J, et al. Isocaloric diets high in animal or plant protein reduce liver fat and inflammation in individuals with type 2 diabetes. Gastroenterology 2017; 152: 571-585 e8.

  83. Schattenberg JM, Galle PR. Animal models of non-alcoholic steatohepatitis: Of mice and man. Dig Dis 2010; 28: 247-54.

  84. Ikura Y, Caldwell SH. Lipid droplet-associated proteins in alcoholic liver disease: a potential linkage with hepatocellular damage. Int J Clin Exp Pathol 2015; 8: 8699-708.

  85. Grygiel-Górniak B. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications-a review. Nutr J 2014; 13: 17.




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