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TIP Revista Especializada en Ciencias Químico-Biológicas

2017, Número 1

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TIP Rev Esp Cienc Quim Biol 2017; 20 (1)


Alteraciones en la homeostasis del colesterol hepático y sus implicaciones en la esteatohepatitis no alcohólica

Vega-Badillo J

Idioma: Español
Referencias bibliográficas: 131
Paginas: 50-65
Archivo PDF: 375.88 Kb.


RESUMEN

Diversos estudios han demostrado que el colesterol libre (CL) hepático tiene una participación importante en la patogénesis de la esteatohepatitis no alcohólica (EHNA). Estos estudios han proporcionado evidencias de que la acumulación en el hígado de CL es tóxico a distintos niveles incluyendo: daño oxidativo a la mitocondria, estrés del retículo endoplasmático (RE) y activación de células de Kupffer (CKs) y células estelares hepáticas (CEH). En conjunto, estas evidencias sugieren que el contenido de CL hepático es importante en el inicio, mantenimiento y modulación de la respuesta inflamatoria asociada a la EHNA. En esta revisión, se discuten los distintos mecanismos participantes en la regulación de la homeostasis del colesterol y sus posibles implicaciones en el desarrollo y progresión del hígado graso no alcohólico (HGNA).


REFERENCIAS (EN ESTE ARTÍCULO)

  1. Hamaguchi, M., Kojima, T., Takeda, N., Nakagawa, T., Taniguchi, H., Fujii, K., Omatsu, T., Nakajima, T., Sarui, H., Shimazaki, M., Kato, T., Okuda, J. & Ida, K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann. Intern. Med.143(10): 722-728 (2005).

  2. Fan, J-G., Zhu, J., Li, X-J., Chen, L., Li, L., Dai, F., Li, F. & Chen, S-Y. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J. Hepatol. 43(3): 508-514 (2005). DOI:10.1016/j.jhep.2005.02.042.

  3. Tiniakos, D.G., Vos, M.B. & Brunt, E.M. Nonalcoholic fatty liver disease: pathology and pathogenesis. Annu. Rev. Pathol. 5: 145-171 (2010). DOI:10.1146/annurev-pathol-121808-102132.

  4. Kleiner, D.E., Brunt, E.M., Van Natta, M., Behling, C., Contos, M.J., Cummings, O.W., Ferrell, L.D., Liu, Y-C., Torbenson, M.S., Unalp-Arida, A., Yeh, M., McCullough, A.J. & Sanyal, A.J. Nonalcoholic Steatohepatitis Clinical Research Network. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatol. Baltim. Md. 41(6): 1313-1321 (2005). DOI:10.1002/hep.20701.

  5. Chalasani, N., Younossi, Z., Lavine, J.E., Diehl, A.M., Brunt, E.M., Cusi, K., Charlton, M. & Sanyal, A.J. 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. 55(6): 2005-2023 (2012). DOI:10.1002/hep.25762.

  6. Sharma, M., Mitnala, S., Vishnubhotla, R.K., Mukherjee, R., Reddy, D.N. & Rao, P.N. The Riddle of Nonalcoholic Fatty Liver Disease: Progression From Nonalcoholic Fatty Liver to Nonalcoholic Steatohepatitis. J. Clin. Exp. Hepatol. 5(2):147-158 (2015). DOI:10.1016/j.jceh.2015.02.002.

  7. Speliotes, E.K., Butler, J.L., Palmer, C.D. & Voight, B.F. GIANT Consortium, MIGen Consortium, NASH CRN, Hirschhorn JN. PNPLA3 variants specifically confer increased risk for histologic nonalcoholic fatty liver disease but not metabolic disease. Hepatol. Baltim. Md. 52(3):904-912 (2010). DOI:10.1002/hep.23768.

  8. Lonardo, A., Byrne, C.D., Caldwell, S.H., Cortez-Pinto, H. & Targher, G. Global epidemiology of non-alcoholic fatty liver disease. Meta-analytic assessment of prevalence, incidence and outcomes. Hepatology. Mar 31. (2016). DOI: 10.1002/hep.28584.

  9. Williams, C.D., Stengel, J., Asike, M.I., Torres, D.M., Shaw, J., Contreras, M., Landt, C.L. & Harrison, S.A. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 140(1):124- 131 (2011). DOI:10.1053/j.gastro.2010.09.038.

  10. Charlton, M.R., Burns, J.M., Pedersen, R.A., Watt, K.D., Heimbach, J.K. & Dierkhising, R.A. Frequency and outcomes of liver transplantation for nonalcoholic steatohepatitis in the United States. Gastroenterology 141(4):1249-1253 (2011). DOI:10.1053/j.gastro.2011.06.061.

  11. Wong, R.J., Aguilar, M., Cheung, R., Perumpail, R.B., Harrison, S.A., Younossi, Z.M. & Ahmed, A. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology Figura 3.- Modelo de la participación de los cristales de colesterol en el desarrollo de EHNA y fibrosis. 1) Cristalización de colesterol en hepatocitos, activación del inflamasoma NLRP3 y producción de quimiocinas y citocinas. 2) Formación de estructuras tipo corona (ETC) a través de la agregación de células de Kupffer (CKs). 3) Transformación de las CKs a células espumosas activadas por acumulación de cristales de colesterol. 4) Activación y transformación de células estelares hepáticas a miofibroblastos productores de colágena. Abreviaturas: IL-1ß, interleucina 1 beta; IL18, Interleucina 18; MCP1, proteína quimioatrayente de monocitos 1; TGF-ß, factor de crecimiento transformante beta; NLRP3, inflamasoma que contiene los dominios: LRR (rico en repeticiones de leucina), NOD (domino central de unión a nucleótidos NACHT) y un dominio N-terminal PYD (dominios pirina). Basado en 12,130 148(3):547-555 (2015). DOI:10.1053/j.gastro.2014.11.039.

  12. Ioannou, G.N. The Role of Cholesterol in the Pathogenesis of NASH. Trends Endocrinol. Metab. TEM. 27(2):84-95 (2016). DOI:10.1016/j.tem.2015.11.008.

  13. Day, C.P. & James, O.F. Steatohepatitis: a tale of two “hits”? Gastroenterology 114(4):842-845 (1998).

  14. Neuschwander-Tetri, B.A. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Hepatol. Baltim. Md. 52(2):774-788 (2010). DOI:10.1002/hep.23719.

  15. Browning, J.D. & Horton, J.D. Molecular mediators of hepatic steatosis and liver injury. J. Clin. Invest. 114(2):147-152 (2004). DOI:10.1172/JCI22422.

  16. 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. Hepatol. Baltim. Md. 45(6):1366-1374 (2007). DOI:10.1002/hep.21655.

  17. Peretti, N., Sassolas, A., Roy, C.C., Deslandres, C., Charcosset, M., Castagnetti, J., Pugnet-Chardon, L., Moulin, P., Labarge, S., Bouthillier, L., Lachaux, A. & Levy, E. Department of Nutrition- Hepatogastroenterology, Hôpital Femme Mère Enfant, Bron, Université Lyon 1, Department of Pediatrics, CHU Sainte-Justine Research Center, Université de Montréal. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet. J. Rare Dis. 5:24 (2010). DOI:10.1186/1750-1172-5-24.

  18. Caballero, F., Fernández, A., De Lacy, A.M., Fernández-Checa, J.C., Caballería, J. & García-Ruiz, C. Enhanced free cholesterol, SREBP-2 and StAR expression in human NASH. J. Hepatol. 50(4):789-796 (2009). DOI:10.1016/j.jhep.2008.12.016.

  19. 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. Hepatol. Baltim. Md. 46(4):1081-1090 (2007). DOI:10.1002/hep.21763.

  20. Maldonado Saavedra, O., Ramírez Sánchez, I., García-Sánchez, J.R., Ceballos-Reyes, G.M. & Méndez-Bolaina, E. Colesterol: Función biológica e implicaciones médicas. Rev. Mex. Cienc. Farm. 43(2):7-22 (2012).

  21. Krause, M.R. & Regen, S.L. The structural role of cholesterol in cell membranes: from condensed bilayers to lipid rafts. Acc. Chem. Res. 47(12):3512-3521 (2014). DOI:10.1021/ar500260t.

  22. Ikonen, E. Cellular cholesterol trafficking and compartmentalization. Nat. Rev. Mol. Cell Biol. 9(2):125-138 (2008). DOI:10.1038/ nrm2336.

  23. Grundy, S.M. Absorption and metabolism of dietary cholesterol. Annu. Rev. Nutr. 3:71-96 (1983). DOI:10.1146/annurev. nu.03.070183.000443.

  24. Berg, J.M., Tymoczko, J.L. & Stryer, L. Cholesterol is Synthesized from Acetyl Coenzyme A in Three Stages. (2002). http://www. ncbi.nlm.nih.gov/books/NBK22350/. Accessed July 7, 2016.

  25. Brown, M.S. & Goldstein, J.L. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89(3):331-340 (1997).

  26. Brown, M.S. & Goldstein, J.L. A receptor-mediated pathway for cholesterol homeostasis. Science 232(4746):34-47 (1986).

  27. Radhakrishnan, A., Goldstein, J.L., McDonald, J.G. & Brown, M.S. Switch-like control of SREBP-2 transport triggered by small changes in ER cholesterol: a delicate balance. Cell Metab. 8(6):512-521 (2008). DOI:10.1016/j.cmet.2008.10.008.

  28. Van Rooyen, D.M., Larter, C.Z., Haigh, W.G., Yeh, M.M., Ioannou, G., Kuver, R., Lee, S.P., Teoh, N.C. & Farrell, G.C. Hepatic free cholesterol accumulates in obese, diabetic mice and causes nonalcoholic steatohepatitis. Gastroenterology 141(4):1393-1403 (2011).e1-e5. DOI:10.1053/j.gastro.2011.06.040.

  29. 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. 15(5):665-674 (2012). DOI:10.1016/j.cmet.2012.04.004.

  30. Enjoji, M., Yasutake, K., Kohjima, M. & Nakamuta, M. Nutrition and nonalcoholic Fatty liver disease: the significance of cholesterol. Int. J. Hepatol. 2012:925807 (2012). DOI:10.1155/2012/925807.

  31. Papandreou, D., Karabouta, Z. & Rousso, I. Are dietary cholesterol intake and serum cholesterol levels related to nonalcoholic Fatty liver disease in obese children? Cholesterol 2012:572820 (2012). DOI:10.1155/2012/572820.

  32. Zelber-Sagi, S., Ratziu, V. & Oren, R. Nutrition and physical activity in NAFLD: an overview of the epidemiological evidence. World J. Gastroenterol. 17(29):3377-3389 (2011). DOI:10.3748/ wjg.v17.i29.3377.

  33. Kainuma, M., Fujimoto, M., Sekiya, N., Tsuneyama, K., Cheng, C., Takano, Y., Terasawa, K. & Shimada, Y. Cholesterol-fed rabbit as a unique model of nonalcoholic, nonobese, non-insulin-resistant fatty liver disease with characteristic fibrosis. J. Gastroenterol. 41(10):971-980 (2006). DOI:10.1007/s00535-006-1883-1.

  34. Matsuzawa, N., Takamura, T., Kurita, S., Misu, H., Ota, T., Ando, H., Yokoyama, M., Honda, M., Zen, Y., Nakanuma, Y., Miyamoto, K.-I. & Kaneko, S. Lipid-induced oxidative stress causes steatohepatitis in mice fed an atherogenic diet. Hepatol. Baltim. Md. 46(5):1392-1403 (2007). DOI:10.1002/hep.21874.

  35. Wouters, K., van Gorp, P.J., Bieghs, V., Gijbels, M.J., Duimel, H., Lütjohann, D., Kerksiek, A., van Kruchten, R., Maeda, N., Staels, B., van Bilsen, M., Shiri-Sverdlov, R. & Hofker, M.H. Dietary cholesterol, rather than liver steatosis, leads to hepatic inflammation in hyperlipidemic mouse models of nonalcoholic steatohepatitis. Hepatol. Baltim. Md. 48(2):474-486 (2008). DOI:10.1002/hep.22363.

  36. Ioannou, G.N., Morrow, O.B., Connole, M.L. & Lee, S.P. Association between dietary nutrient composition and the incidence of cirrhosis or liver cancer in the united states population. Hepatology 50(1):175-184 (2009). DOI:10.1002/hep.22941.

  37. Musso, G., Gambino, R., De Michieli, F., Cassader, M., Rizzetto, M., Durazzo, M., Fagà, E., Silli, B. & Pagano, G. Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Hepatol. Baltim. Md. 37(4):909- 916 (2003). DOI:10.1053/jhep.2003.50132.

  38. Yasutake, K., Nakamuta, M., Shima, Y., Ohyama, A., Masuda, K., Haruta, N., Fujino, T., Aoyagi, Y., Fukuizumi, K., Yoshimoto, T., Takemoto, R., Miyahara, T., Harada, N., Hayata, F., Nakashima, M. & Enjoji, M. Nutritional investigation of non-obese patients with non-alcoholic fatty liver disease: the significance of dietary cholesterol. Scand. J. Gastroenterol. 44(4):471-477 (2009). DOI:10.1080/00365520802588133.

  39. Yasutake, K., Kohjima, M., Kotoh, K., Nakashima, M., Nakamuta, M. & Enjoji, M. Dietary habits and behaviors associated with nonalcoholic fatty liver disease. World J. Gastroenterol. 20(7):1756-1767 (2014). DOI:10.3748/wjg.v20.i7.1756.

  40. Musso, G., Cassader, M., Bo, S., De Michieli, F. & Gambino, R. Sterol regulatory element-binding factor 2 (SREBF-2) predicts 7-year NAFLD incidence and severity of liver disease and lipoprotein and glucose dysmetabolism. Diabetes 62(4):1109- 1120 (2013). DOI:10.2337/db12-0858.

  41. Wang, Y., Tong, J., Chang, B., Wang, B.-F., Zhang, D. & Wang, B.-Y. Relationship of SREBP-2 rs2228314 G>C polymorphism with nonalcoholic fatty liver disease in a Han Chinese population. Genet. Test Mol. Biomark. 18(9):653-657 (2014). DOI:10.1089/ gtmb.2014.0116.

  42. Chalasani, N., Guo, X., Loomba, R., Goodarzi, M.O., Haritunians, T., Kwon, S., Cui, J., Taylor, K.D., Wilson, L., Cummings, O.W., Chen, Y.-D.I. & Rotter, J.I. Nonalcoholic Steatohepatitis Clinical Research Network. Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 139(5):1567-1576, 1576 (2010). e1-e6. DOI:10.1053/j.gastro.2010.07.057.

  43. Bernstein, D.L., Hülkova, H., Bialer, M.G. & Desnick, R.J. Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease. J. Hepatol. 58(6):1230-1243 (2013). DOI:10.1016/j.jhep.2013.02.014.

  44. Burton, B.K., Deegan, P.B., Enns, G.M., Guardamagna, O., Horslen, S., Hovingh, G.K., Lobritto, S.J., Malinova, V., McLin, V.A., Raiman, J., Di Rocco, M., Santra, S., Sharma, R., Sykut- Cegielska, J., Whitley, C.B., Eckert, S., Valayannopoulos, V. & Quinn, A.G. Clinical Features of Lysosomal Acid Lipase Deficiency. J. Pediatr. Gastroenterol. Nutr. 61(6):619-625 (2015). DOI:10.1097/MPG.0000000000000935.

  45. Burton, B.K., Balwani, M., Feillet, F., Barić, I., Burrow, T.A., Camarena Grande, C., Coker, M., Consuelo-Sánchez, A., Deegan, P., Di Rocco, M., Enns, G.M., Erbe, R., Ezgu, F., Ficicioglu, C., Furuya, K.N., Kane, J., Laukaitis, C., Mengel, E., Neilan, E.G., Nightingale, S., Peters, H., Scarpa, M., Schwab, K.O., Smolka, V., Valayannopoulos, V., Wood, M., Goodman, Z., Yang, Y., Eckert, S., Rojas-Caro, S. & Quinn, A.G. A Phase 3 Trial of Sebelipase Alfa in Lysosomal Acid Lipase Deficiency. N. Engl. J. Med. 373(11):1010-1020 (2015). DOI:10.1056/NEJMoa1501365.

  46. Sharpe, L.J. & Brown, A.J. Controlling cholesterol synthesis beyond 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). J. Biol. Chem. 288(26):18707-18715 (2013). DOI:10.1074/jbc. R113.479808.

  47. Brundert, M., Heeren, J., Merkel, M., Carambia, A., Herkel, J., Groitl, P., Dobner, T., Ramakrishnan, R., Moore, K.J. & Rinninger, F. Scavenger receptor CD36 mediates uptake of high density lipoproteins in mice and by cultured cells. J. Lipid. Res. 52(4):745-758 (2011). DOI:10.1194/jlr.M011981.

  48. Acton, S., Rigotti, A., Landschulz, K.T., Xu, S., Hobbs, H.H. & Krieger, M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 71(5248):518-520 (1996).

  49. Zhao, L., Chen, Y., Tang, R., Chen, Y., Li, Q., Gong, J., Huang, A., Varghese, Z., Moorhead, J.F. & Ruan, X.Z. Inflammatory stress exacerbates hepatic cholesterol accumulation via increasing cholesterol uptake and de novo synthesis. J. Gastroenterol. Hepatol. 26(5):875-883 (2011). DOI:10.1111/j.1440-1746.2010.06560.x.

  50. Miquilena-Colina, M.E., Lima-Cabello, E., Sánchez-Campos, S., García-Mediavilla, M.V., Fernández-Bermejo, M., Lozano- Rodríguez, T., Vargas-Castrillón, J., Buqué, X., Ochoa, B., Aspichueta, P., González-Gallego, J. & García-Monzón, C. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut. 60(10):1394-1402 (2011). DOI:10.1136/gut.2010.222844.

  51. Zhou, J., Febbraio, M., Wada, T., Zhai, Y., Kuruba, R., He, J., Lee, J.H., Khadem, S., Ren, S., Li, S., Silverstein, R.L. & Xie, W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134(2):556-567 (2008). DOI:10.1053/j.gastro.2007.11.037.

  52. Qiu, Y., Liu, S., Chen, H.-T., Yu, C.-H., Teng, X.-D., Yao, H.-T. & Xu, G.-Q. Upregulation of caveolin-1 and SR-B1 in mice with non-alcoholic fatty liver disease. Hepatobiliary Pancreat. Dis. Int. HBPD INT. 12(6):630-636 (2013).

  53. Tomita, K., Teratani, T., Suzuki, T., Shimizu, M., Sato, H., Narimatsu, K., Okada, Y., Kurihara, C., Irie, R., Yokoyama, H., Shimamura, K., Usui, S, Ebinuma, H., Saito, H., Watanabe, C., Komoto, S., Kawaguchi, A., Nagao, S., Sugiyama, K., Hokari, R., Kanai, T., Miura, S. & Hibi, T. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatol. Baltim. Md. 59(1):154-169 (2014). DOI:10.1002/hep.26604.

  54. Li,T. & Chiang, J.Y.L. Regulation of Bile Acid and Cholesterol Metabolism by PPARs. PPAR Res. 2009;2009. DOI:10.1155/2009/501739.

  55. Baker, A.D., Malur, A., Barna, B.P., Kavuru, M.S., Malur, A.G. & Thomassen, M.J. PPARgamma regulates the expression of cholesterol metabolism genes in alveolar macrophages. Biochem. Biophys. Res. Commun. 393(4):682-687 (2010). DOI:10.1016/j. bbrc.2010.02.056.

  56. Ricote, M. & Glass, C.K. New roles for PPARs in cholesterol homeostasis. Trends Pharmacol. Sci. 22(9):441-443; discussion 444 (2001).

  57. Ma, K.L., Ruan, X.Z., Powis, S.H., Chen, Y., Moorhead, J.F. & Varghese, Z. Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice. Hepatol. Baltim. Md. 48(3):770-781 (2008). DOI:10.1002/ hep.22423.

  58. Montagner, A., Polizzi, A., Fouché, E., Ducheix, S., Lippi, Y., Lasserre, F., Barquissau, V., Régnier, M., Lukowicz, C., Benhamed, F., Iroz, A., Bertrand-Michel, J., Al Saati, T., Cano, P., Mselli-Lakhal, L., Mithieux, G., Rajas, F., Lagarrigue, S., Pineau, T., Loiseau, N., Postic, C., Langin, D., Wahli, W. & Guillou, H. Liver PPARα is crucial for whole-body fatty acid homeostasis and is protective against NAFLD. Gut. 65(7):1202-1214 (2016). DOI:10.1136/gutjnl-2015-310798.

  59. Francque, S., Verrijken, A., Caron, S., Prawitt, J., Paumelle, R., Derudas, B., Lefebvre, P., Taskinen, M.-R., Van Hul, W., Mertens, I., Hubens, G., Van Marck, E., Michielsen, P., Van Gaal, L. & Staels, B. PPARα gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. 63(1):164-173 (2015). DOI:10.1016/j. jhep.2015.02.019.

  60. Arguello, G., Balboa, E., Arrese, M. & Zanlungo, S. Recent insights on the role of cholesterol in non-alcoholic fatty liver disease. Biochim. Biophys. Acta 1852(9):1765-1778 (2015). DOI:10.1016/j.bbadis.2015.05.015.

  61. Musso, G., Gambino, R. & Cassader, M. Cholesterol metabolism and the pathogenesis of non-alcoholic steatohepatitis. Prog. Lipid Res. 52(1):175-191 (2013). DOI:10.1016/j.plipres.2012.11.002.

  62. Fielding, C.J. & Fielding, P.E. Caveolae and intracellular trafficking of cholesterol. Adv. Drug Deliv. Rev. 49(3):251-264 (2001).

  63. Mastrodonato, M., Calamita, G., Rossi, R., Mentino, D., Bonfrate, L., Portincasa, P., Ferri, D. & Liquori, G.E. Altered distribution of caveolin-1 in early liver steatosis. Eur. J. Clin. Invest. 41(6):642- 651 (2011). DOI:10.1111/j.1365-2362.2010.02459.x.

  64. Carstea, E.D., Morris, J.A., Coleman, K.G., Loftus, S.K., Zhang, D., Cummings, C., Gu, J., Rosenfeld, M.A., Pavan, W.J., Krizman, D.B., Nagle, J., Polymeropoulos, M.H., Sturley, S.L., Ioannou, Y.A., Higgins, M.E., Comly, M., Cooney, A., Brown, A., Kaneski, C.R., Blanchette-Mackie, E.J., Dwyer, N.K., Neufeld, E.B., Chang, T.Y., Liscum, L., Strauss, J.F., Ohno, K., Zeigler, M., Carmi, R., Sokol, J., Markie, D., O’Neill, R.R., van Diggelen, O.P., Elleder, M., Patterson, M.C., Brady, R.O., Vanier, M.T., Pentchev, P.G. & Tagle, D.A. Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science277(5323):228-231 (1997).

  65. Klein, A.D., Álvarez, A. & Zanlungo, S. The unique case of the Niemann-Pick type C cholesterol storage disorder. Pediatr. Endocrinol. Rev. PER. 12 Suppl. 1:166-175 (2014).

  66. Carstea, E.D., Polymeropoulos, M.H., Parker, C.C., Detera- Wadleigh, S.D., O’Neill, R.R., Patterson, M.C., Goldin, E., Xiao, H., Straub, R.E. & Vanier, M.T. Linkage of Niemann-Pick disease type C to human chromosome 18. Proc. Natl. Acad. Sci. U.S.A. 90(5):2002-2004 (1993).

  67. Vanier, M.T. Complex lipid trafficking in Niemann-Pick disease type C. J. Inherit. Metab. Dis. 38(1):187-199 (2015). DOI:10.1007/ s10545-014-9794-4.

  68. Jelinek, D., Millward, V., Birdi, A., Trouard, T.P., Heidenreich, R.A. & Garver, W.S. Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance. Hum. Mol. Genet. 20(2):312-321 (2011). DOI:10.1093/hmg/ ddq466.

  69. Soccio, R.E. & Breslow, J.L. StAR-related lipid transfer (START) proteins: mediators of intracellular lipid metabolism. J. Biol. Chem. 278(25):22183-22186 (2003). DOI:10.1074/jbc.R300003200.

  70. Stocco, D.M. The role of the StAR protein in steroidogenesis: challenges for the future. J. Endocrinol. 164(3):247-253 (2000).

  71. Charman, M., Kennedy, B.E., Osborne, N. & Karten, B.. MLN64 mediates egress of cholesterol from endosomes to mitochondria in the absence of functional Niemann-Pick Type C1 protein. J. Lipid Res. 51(5):1023-1034 (2010). DOI:10.1194/jlr.M002345.

  72. Tichauer, J.-E., Morales., M.-G., Amigo, L., Galdames, L., Klein, A., Quinones, V., Ferrada, C., Álvarez, A.-R., Río, M.-C., Miquel, J.-F., Rigotti, A. & Zanlungo, S. Overexpression of the cholesterol-binding protein MLN64 induces liver damage in the mouse. World J. Gastroenterol. 13(22):3071-3079 (2007).

  73. Olkkonen, V.M. OSBP-related proteins: liganding by glycerophospholipids opens new insight into their function. Mol. Basel. Switz. 18(11):13666-13679 (2013). DOI:10.3390/ molecules181113666.

  74. Zhou, T., Li, S., Zhong, W., Vihervaara, T., Béaslas, O., Perttilä, J., Luo, W., Jiang, Y., Lehto, M., Olkkonen, V.M. & Yan, D. OSBP-related protein 8 (ORP8) regulates plasma and liver tissue lipid levels and interacts with the nucleoporin Nup62. PloS One. 6(6):e21078 (2011). DOI:10.1371/journal.pone.0021078.

  75. Joyce, C., Freeman, L., Brewer, H.B. & Santamarina-Fojo, S. Study of ABCA1 function in transgenic mice. Arterioscler. Thromb. Vasc. Biol. 23(6):965-971 (2003). DOI:10.1161/01. ATV.0000055194.85073.FF.

  76. Liu, W., Qin, L., Yu, H., Lv, F. & Wang, Y. Apolipoprotein A-I and adenosine triphosphate-binding cassette transporter A1 expression alleviates lipid accumulation in hepatocytes. J. Gastroenterol. Hepatol. 29(3):614-622 (2014). DOI: 10.1111/jgh.12430.

  77. Yang, Y., Jiang, Y., Wang, Y. & An, W. Suppression of ABCA1 by unsaturated fatty acids leads to lipid accumulation in HepG2 cells. Biochimie. 2010;92(8):958-963 (2013). DOI:10.1016/j. biochi.2010.04.002.

  78. Vega-Badillo, J., Gutiérrez-Vidal, R., Hernández-Pérez, H.A., Villamil-Ramírez, H., León-Mimila, P., Sánchez-Muñoz, F., Morán-Ramos, S., Larrieta-Carrasco, E., Fernández-Silva, I., Méndez-Sánchez, N., Tovar, A.R., Campos-Pérez, F., Villarreal- Molina, T., Hernández-Pando, R., Aguilar-Salinas, C.A. & Canizales-Quinteros, S. Hepatic miR-33a/miR-144 and their target gene ABCA1 are associated with steatohepatitis in morbidly obese subjects. Liver Int. 36(9):1383-1391 (2016). DOI:10.1111/ liv.13109.

  79. Kennedy, M.A., Barrera, G.C., Nakamura, K., Baldán, A., Tarr, P., Fishbein, M.C., Frank, J., Francone, O.L. & Edwards, P.A. ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. Cell Metab. 1(2):121- 131 (2005). DOI:10.1016/j.cmet.2005.01.002.

  80. Terasaka, N., Wang, N., Yvan-Charvet, L. & Tall, A.R. Highdensity lipoprotein protects macrophages from oxidized lowdensity lipoprotein-induced apoptosis by promoting efflux of 7-ketocholesterol via ABCG1. Proc. Natl. Acad. Sci. U.S.A. 104(38):15093-15098 (2007). DOI:10.1073/pnas.0704602104.

  81. Yu, L., Gupta, S., Xu, F., Liverman, A.D.B, Moschetta, A., Mangelsdorf, D.J., Repa, J.J., Hobbs, H.H. & Cohen, J.C. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J. Biol. Chem. 280(10):8742-8747 (2005). DOI:10.1074/jbc.M411080200.

  82. Su, K., Sabeva, N.S., Liu, J., Wang, Y., Bhatnagar, S., van der Westhuyzen, D.R. & Graf, G.A. The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation. J. Biol. Chem. 287(34):28564-28575 (2012). DOI:10.1074/jbc. M112.360081.

  83. Spolding, B., Connor, T., Wittmer, C., Abreu, L.L.F., Kaspi, A., Ziemann, M., Kaur, G., Cooper, A., Morrison, S., Lee, S., Sinclair, A., Gibert, Y., Trevaskis J.L., Roth, J.D., El-Osta, A., Standish, R. & Walder, K. Rapid development of non-alcoholic steatohepatitis in Psammomys obesus (Israeli sand rat). PloS One 9(3):e92656 (2014). DOI:10.1371/journal.pone.0092656.

  84. Savard, C., Tartaglione, E.V., Kuver, R., Haigh, W.G., Farrell G.C., Subramanian, S., Chait, A., Yeh, M.M., Quinn, L.S. &Ioannou, G.N. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology 57(1):81-92 (2013). DOI:10.1002/hep.25789.

  85. Bartel, D.P. MicroRNAs: target recognition and regulatory functions. Cell136(2):215-233 (2009). DOI:10.1016/j. cell.2009.01.002.

  86. Zamore, P.D. & Haley, B. Ribo-gnome: the big world of small RNAs. Science 309(5740):1519-1524 (2005). DOI:10.1126/ science.1111444.

  87. Ambros, V. MicroRNAs and developmental timing. Curr. Opin. Genet. Dev. 21(4):511-517. (2011). DOI:10.1016/j. gde.2011.04.003.

  88. Ceccarelli, S., Panera, N., Gnani, D. & Nobili, V. Dual role of microRNAs in NAFLD. Int. J. Mol Sci. 14(4):8437-8455 (2013). DOI:10.3390/ijms14048437.

  89. Cheung, O., Puri, P., Eicken, C., Contos, M.J., Mirshahi, F., Maher, J.W., Kellum, J.M., Min H., Luketic, V.A. & Sanyal, A.J. Nonalcoholic steatohepatitis is associated with altered hepatic MicroRNA expression. Hepatol. Baltim. Md. 48(6):1810-1820 (2008). DOI:10.1002/hep.22569.

  90. Jin, X., Ye, Y.-F., Chen, S.-H., Yu, C.-H., Liu, J. & Li, Y.-M. MicroRNA expression pattern in different stages of nonalcoholic fatty liver disease. Dig. Liver. Dis. Off J. Ital. Soc. Gastroenterol. Ital. Assoc. Study. Liver. 41(4):289-297 (2009). DOI:10.1016/j. dld.2008.08.008.

  91. Vincent, R. & Sanyal, A. Recent Advances in Understanding of NASH: MicroRNAs as Both Biochemical Markers and Players. Curr. Pathobiol. Rep. 2(3):109-115 (2014). DOI:10.1007/s40139- 014-0049-8.

  92. Braza-Boïls, A., Marí-Alexandre, J., Molina, P., Arnau, M.A., Barceló-Molina, M., Domingo, D., Girbes, J., Giner, J., Martínez- Dolz, L. & Zorio, E. Deregulated hepatic microRNAs underlie the association between non-alcoholic fatty liver disease and coronary artery disease. Liver Int. 36(8):1221-1229. (2016). DOI: 10.1111/ liv.13097.

  93. Lagos-Quintana, M., Rauhut, R., Yalcin, A., Meyer, J., Lendeckel, W. & Tuschl, T. Identification of tissue-specific microRNAs from mouse. Curr. Biol. CB. 12(9):735-739 (2002).

  94. Chang, J., Nicolas, E., Marks, D., Sander, C., Lerro, A., Buendía, M.A., Xu, C., Mason, W.S., Moloshok T., Bort, R., Zaret, K.S. & Taylor, J.M. miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol. 1(2):106-113 (2004).

  95. Esau, C., Davis, S., Murray, S.F., Yu, X.X., Pandey, S.K., Pear, M, Watts, L., Booten, S.L., Graham, M., McKay, R., Subramaniam, A., Propp, S., Lollo, B.A., Freier, S., Bennett, C.F., Bhanot, S. & Monia, B.P. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. ;3(2):87-98 (2006). DOI:10.1016/j.cmet.2006.01.005.

  96. Song, K.-H., Li, T., Owsley, E. & Chiang, J.Y.L. A putative role of micro RNA in regulation of cholesterol 7alpha-hydroxylase expression in human hepatocytes. J. Lipid. Res. 51(8):2223-2233 (2010). DOI:10.1194/jlr.M004531.

  97. Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K.G., Tuschl, T., Manoharan, M. & Stoffel, M. Silencing of microRNAs in vivo with “antagomirs.” Nature 438(7068):685-689 (2005). DOI:10.1038/ nature04303.

  98. Li, S., Chen, X., Zhang, H., Liang, X., Xiang, Y., Yu, C., Zen, K., Li, Y. & Zhang, C.-Y. Differential expression of microRNAs in mouse liver under aberrant energy metabolic status. J. Lipid Res. 50(9):1756-1765 (2009). DOI:10.1194/jlr.M800509-JLR200.

  99. Sun, C., Huang, F., Liu, X., Xiao, X., Yang, M., Hu, G., Liu, H. & Liao, L. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR. Int. J. Mol. Med. 35(3):847-853 (2015). DOI:10.3892/ijmm.2015.2076.

  100. Gerin, I., Clerbaux, L.-A., Haumont, O., Lanthier, N., Das, A.K., Burant, C.F., Leclercq, I.A., MacDougald, O.A. & Bommer, G.T. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J. Biol. Chem. 285(44):33652- 33661 (2010). DOI:10.1074/jbc.M110.152090.

  101. Rayner, K.J., Suárez, Y., Dávalos, A., Parathath, S., Fitzgerald, M.L., Tamehiro, N., Fisher, E.A., Moore, K.J. & Fernández- Hernando, C. MiR-33 contributes to the regulation of cholesterol homeostasis. Science 328(5985):1570-1573 (2010). DOI:10.1126/science.1189862.

  102. Marquart, T.J., Allen, R.M., Ory, D.S. & Baldán, A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc. Natl. Acad. Sci. U.S.A. 107(27):12228-12232 (2010). DOI:10.1073/pnas.1005191107.

  103. Najafi-Shoushtari, S.H., Kristo, F., Li, Y., Shioda, T., Cohen, D.E., Gerszten, R.E. & Näär, A.M. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science 328(5985):1566-1569 (2010). DOI:10.1126/science.1189123.

  104. Horie, T., Ono, K., Horiguchi, M., Nishi, H., Nakamura, T., Nagao, K., Kinoshita, M., Kuwabara, Y., Marusawa, H., Iwanaga, Y., Hasegawa, K., Yokode, M., Kimura, T. & Kita, T. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc. Natl. Acad. Sci. U.S.A. 107(40):17321-17326 (2010). DOI:10.1073/pnas.1008499107.

  105. Rayner, K.J., Esau, C.C., Hussain, F.N., McDaniel, A.L., Marshall, S.M., van Gils, J.M., Ray, T.D., Sheedy, F.J., Goedeke, L., Liu, X., Khatsenko, O.G., Kaimal, V., Lees, C.J., Fernández-Hernando, C., Fisher, E.A., Temel, R.E. & Moore, K.J. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478(7369):404-407 (2011). DOI:10.1038/ nature10486.

  106. Lendvai, G., Jármay, K., Karácsony, G., Halász, T., Kovalszky, I., Baghy, K., Wittmann, T., Schaff, Z. & Kiss, A. Elevated miR-33a and miR-224 in steatotic chronic hepatitis C liver biopsies. World J. Gastroenterol. 20(41):15343-15350 (2014). DOI:10.3748/wjg.v20.i41.15343.

  107. de Aguiar Vallim, T.Q., Tarling, E.J., Kim, T., Civelek, M., Baldán, Á., Esau, C. & Edwards, P.A. MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma highdensity lipoprotein after activation of the nuclear receptor farnesoid X receptor. Circ. Res. 112(12):1602-1612 (2013). DOI:10.1161/CIRCRESAHA.112.300648.

  108. Ramírez, C.M., Rotllan, N., Vlassov, A.V., Dávalos, A., Li M., Goedeke, L., Aranda, J.F., Cirera-Salinas, D., Araldi, E., Salerno, A., Wanschel, A., Zavadil, J., Castrillo, A., Kim, J., Suárez, Y. & Fernández-Hernando, C. Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ. Res. 112(12):1592-1601 (2013). DOI:10.1161/ CIRCRESAHA.112.300626.

  109. Hu, Y.-W., Hu, Y.-R., Zhao, J.-Y., Li, S.-F., Ma, X., Wu, S.- G., Lu, J.-B., Qiu, Y.-R., Sha, Y.-H., Wang, Y.-C., Gao, J.-J., Zheng, L. & Wang, Q. An agomir of miR-144-3p accelerates plaque formation through impairing reverse cholesterol transport and promoting pro-inflammatory cytokine production. PloS One 9(4):e94997 (2014). DOI:10.1371/journal.pone.0094997.

  110. Montero, J., Mari, M., Colell, A., Morales, A., Basáñez, G., García-Ruiz, C. & Fernández-Checa, J.C. Cholesterol and peroxidized cardiolipin in mitochondrial membrane properties, permeabilization and cell death. Biochim. Biophys. Acta 1797(6- 7):1217-1224 (2010). DOI:10.1016/j.bbabio.2010.02.010.

  111. García-Ruiz, C., Mari, M., Colell, A., Morales, A., Caballero, F., Montero, J., Terrones, O., Basáñez, G. & Fernández-Checa, J.C. Mitochondrial cholesterol in health and disease. Histol. Histopathol. 24(1):117-132 (2009).

  112. Tabas, I. Consequences of cellular cholesterol accumulation: basic concepts and physiological implications. J. Clin. Invest. 110(7):905-911 (2002). DOI:10.1172/JCI16452.

  113. Yeagle, P.L. Modulation of membrane function by cholesterol. Biochimie. 73(10):1303-1310 (1991).

  114. Marí, M., Caballero, F., Colell, A., Morales, A., Caballería, J., Fernández, A., Enrich, C., Fernández-Checa, J.C. & García-Ruiz, C. Mitochondrial free cholesterol loading sensitizes to TNF- and Fas-mediated steatohepatitis. Cell Metab. 4(3):185-198 (2006). DOI:10.1016/j.cmet.2006.07.006.

  115. Hager, L., Li, L., Pun, H., Liu, L., Hossain, M.A., Maguire, GF, Naples, M., Baker, C., Magomedova, L., Tam, J., Adeli, K., Cummins, C.L., Connelly, P.W. & Ng, D.S. Lecithin:cholesterol acyltransferase deficiency protects against cholesterol-induced hepatic endoplasmic reticulum stress in mice. J. Biol. Chem. 287(24):20755-20768 (2012). DOI:10.1074/jbc.M112.340919.

  116. Li, L., Hossain, M.A., Sadat, S., Hager, L., Liu, L., Tam, L., Schroer, S., Huogen, L., Fantus, I.G., Connelly, P.W., Woo, M. & Ng, D.S. Lecithin cholesterol acyltransferase null mice are protected from diet-induced obesity and insulin resistance in a gender-specific manner through multiple pathways. J. Biol. Chem. 286(20):17809-17820 (2011). DOI:10.1074/jbc. M110.180893.

  117. Gentile, C.L., Frye, M. & Pagliassotti, M.J. Endoplasmic reticulum stress and the unfolded protein response in nonalcoholic fatty liver disease. Antioxid. Redox Signal. 15(2):505-521 (2011). DOI:10.1089/ars.2010.3790.

  118. Fu, S., Yang, L., Li, P., Hofmann, O., Dicker, L., Hide, W., Lin, X., Watkins, S.M., Ivanov, A.R. & Hotamisligil, G.S. Aberrant lipid metabolism disrupts calcium homeostasis causing liver endoplasmic reticulum stress in obesity. Nature 473(7348):528- 531 (2011). DOI:10.1038/nature09968.

  119. Park, S.W., Zhou, Y., Lee, J., Lee, J. & Ozcan, U. Sarco(endo) plasmic reticulum Ca2+-ATPase 2b is a major regulator of endoplasmic reticulum stress and glucose homeostasis in obesity. Proc. Natl. Acad. Sci. U.S.A. 107(45):19320-19325 (2010). DOI:10.1073/pnas.1012044107.

  120. Leroux, A., Ferrere, G., Godie, V., Cailleux, F., Renoud, M.-L., Gaudin, F., Naveau, S., Prévot, S., Makhzami, S., Perlemuter, G. & Cassard-Doulcier, A.-M. Toxic lipids stored by Kupffer cells correlates with their pro-inflammatory phenotype at an early stage of steatohepatitis. J. Hepatol. 57(1):141-149 (2012). DOI:10.1016/j.jhep.2012.02.028.

  121. Bieghs, V., van Gorp, P.J., Walenbergh, S.M.A., Gijbels, M.J., Verheyen, F., Buurman, W.A., Briles, D.E., Hofker, M.H., Binder, C.J. & Shiri-Sverdlov, R. Specific immunization strategies against oxidized low-density lipoprotein: a novel way to reduce nonalcoholic steatohepatitis in mice. Hepatol. Baltim. Md. 56(3):894-903 (2012). DOI:10.1002/hep.25660.

  122. Hendrikx, T., Bieghs, V., Walenbergh, S.M.A., van Gorp, P.J., Verheyen, F., Jeurissen, M.L.J., Steinbusch, M.M.F., Vaes, N., Binder, C.J., Koek, G.H., Stienstra, R., Netea, M.G., Hofker, M.H. & Shiri-Sverdlov, R. Macrophage specific caspase-1/11 deficiency protects against cholesterol crystallization and hepatic inflammation in hyperlipidemic mice. PloS One. 8(12):e78792 (2013). DOI:10.1371/journal.pone.0078792.

  123. Bieghs, V., Hendrikx, T., van Gorp, P.J., Verheyen, F., Guichot, Y.D., Walenbergh, S.M.A., Jeurissen, M.L.J., Gijbels, M., Rensen, S.S., Bast, A., Plat, J., Kalhan, S.C., Koek, G.H., Leitersdorf, E., Hofker, M.H., Lütjohann, D. & Shiri-Sverdlov, R. The cholesterol derivative 27-hydroxycholesterol reduces steatohepatitis in mice. Gastroenterology 144(1):167-178.e1 (2013). DOI:10.1053/j.gastro.2012.09.062.

  124. Liu, B., Ramírez, C.M., Miller, A.M., Repa, J.J., Turley, S.D. & Dietschy, J.M. Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J. Lipid Res. 51(5):933-944

  125. Fujii, H. & Kawada, N. Inflammation and fibrogenesis in steatohepatitis. J. Gastroenterol. 47(3):215-225 (2012). DOI:10.1007/s00535-012-0527-x.

  126. Teratani, T., Tomita, K., Suzuki, T., Oshikawa, T., Yokoyama, H., Shimamura, K., Tominaga, S., Hiroi, S., Irie, R., Okada, Y., Kurihara, C., Ebinuma, H., Saito, H., Hokari, R., Sugiyama, K., Kanai, T., Miura, S. & Hibi, T. A high-cholesterol diet exacerbates liver fibrosis in mice via accumulation of free cholesterol in hepatic stellate cells. Gastroenterology 142(1):152-164.e10 (2012). DOI:10.1053/j.gastro.2011.09.049.

  127. Tomita, K., Teratani, T., Suzuki, T., Shimizu, M., Sato, H., Narimatsu, K., Usui, S., Furuhashi, H., Kimura, A., Nishiyama, K., Maejima, T., Okada, Y., Kurihara, C., Shimamura, K., Ebinuma, H., Saito, H., Yokoyama, H., Watanabe, C., Komoto, S., Nagao, S., Sugiyama, K., Aosasa, S., Hatsuse, K., Yamamoto, J., Hibi, T., Miura, S., Hokari, R. & Kanai, T. Acyl-CoA:cholesterol acyltransferase 1 mediates liver fibrosis by regulating free cholesterol accumulation in hepatic stellate cells. J. Hepatol. 61(1):98-106 (2014). DOI:10.1016/j.jhep.2014.03.018.

  128. Duewell, P., Kono, H., Rayner, K.J., Sirois, C.M., Vladimer, G., Bauernfeind, F.G., Abela, G.S., Franchi, L., Núñez, G., Schnurr, M., Espevik, T., Lien, E., Fitzgerald, K.A., Rock, K.L., Moore, K.J., Wright, S.D., Hornung, V. & Latz, E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357-1361 (2010). DOI:10.1038/nature08938.

  129. Rajamäki, K., Lappalainen, J., Oörni, K., Välimäki, E., Matikainen, S., Kovanen, P.T. & Eklund, K.K. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PloS One 5(7):e11765 (2010). DOI:10.1371/ journal.pone.0011765.

  130. Ioannou, G.N., Haigh, W.G., Thorning, D. & Savard, C. Hepatic cholesterol crystals and crown-like structures distinguish NASH from simple steatosis. J. Lipid. Res. 54(5):1326-1334 (2013). DOI:10.1194/jlr.M034876.

  131. Ioannou, G.N., Van Rooyen, D.M., Savard, C., Haigh, W.G., Ye, M.M., Teoh, N.C. & Farrell, G.C. Cholesterol-lowering drugs cause dissolution of cholesterol crystals and disperse Kupffer cell crown-like structures during resolution of NASH. J. Lipid. Res. 56(2):277-285 (2015). DOI:10.1194/jlr.M053785.




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