PPARs and nonalcoholic fatty liver disease

Biochimie

Volumn 136, Issue , 2017, Pages 65-74

  Liss, Kim H H ^a   Finck, Brian N ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Fibrates; Liver; NAFLD; NASH; PPAR; Thiazolidinediones

Indexed keywords

GLUCOSE; LIPID; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR AGONIST; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR DELTA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA;

DIET THERAPY; DISEASE COURSE; END STAGE LIVER DISEASE; EXERCISE; HUMAN; INFLAMMATION; LIFESTYLE MODIFICATION; LIPID METABOLISM; LIVER CELL CARCINOMA; LIVER CELL DAMAGE; LIVER FIBROSIS; NONALCOHOLIC FATTY LIVER; PATHOPHYSIOLOGY; REVIEW; TRANSCRIPTION REGULATION; AGONISTS; ANIMAL; METABOLISM; NON-ALCOHOLIC FATTY LIVER DISEASE;

ANIMALS; HUMANS; NON-ALCOHOLIC FATTY LIVER DISEASE; PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS;

EID: 85008145797     PISSN: 03009084     EISSN: 61831638     Source Type: Journal    
DOI: 10.1016/j.biochi.2016.11.009     Document Type: Review

References (127)

1. [1] Brunt, E.M., Wong, V.W., Nobili, V., Day, C.P., Sookoian, S., Maher, J.J., Bugianesi, E., Sirlin, C.B., Neuschwander-Tetri, B.A., Rinella, M.E., Nonalcoholic fatty liver disease. Nat. Rev. Dis. Prim., 1, 2015, 15080.
2. [2] Rinella, M.E., Nonalcoholic fatty liver disease: a systematic review. JAMA 313 (2015), 2263–2273.
3. [3] Schwimmer, J.B., Deutsch, R., Kahen, T., Lavine, J.E., Stanley, C., Behling, C., Prevalence of fatty liver in children and adolescents. Pediatrics 118 (2006), 1388–1393.
4. [4] Younossi, Z.M., Blissett, D., Blissett, R., Henry, L., Stepanova, M., Younossi, Y., Racila, A., Hunt, S., Beckerman, R., The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe. Hepatology 64 (2016), 1577–1586.
5. [5] Adams, L.A., Lymp, J.F., St Sauver, J., Sanderson, S.O., Lindor, K.D., Feldstein, A., Angulo, P., The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129 (2005), 113–121.
6. [6] Ekstedt, M., Franzen, L.E., Mathiesen, U.L., Thorelius, L., Holmqvist, M., Bodemar, G., Kechagias, S., Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 44 (2006), 865–873.
7. [7] 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 (2011), 1249–1253.
8. [8] Adams, L.A., Sanderson, S., Lindor, K.D., Angulo, P., The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J. Hepatol. 42 (2005), 132–138.
9. [9] Patton, H.M., Yates, K., Unalp-Arida, A., Behling, C.A., Huang, T.T., Rosenthal, P., Sanyal, A.J., Schwimmer, J.B., Lavine, J.E., Association between metabolic syndrome and liver histology among children with nonalcoholic Fatty liver disease. Am. J. Gastroenterol. 105 (2010), 2093–2102.
10. [10] 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. Invest 115 (2005), 1343–1351.
11. [11] Day, C.P., James, O.F., Steatohepatitis: a tale of two "hits"?. Gastroenterology 114 (1998), 842–845.
12. [12] Machado, M.V., Diehl, A.M., Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology 150 (2016), 1769–1777.
13. [13] Cusi, K., Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142 (2012), 711–725 e716.
14. [14] 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 45 (2007), 1366–1374.
15. [15] Romeo, S., Kozlitina, J., Xing, C., Pertsemlidis, A., Cox, D., Pennacchio, L.A., Boerwinkle, E., Cohen, J.C., Hobbs, H.H., Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 40 (2008), 1461–1465.
16. [16] Kozlitina, J., Smagris, E., Stender, S., Nordestgaard, B.G., Zhou, H.H., Tybjaerg-Hansen, A., Vogt, T.F., Hobbs, H.H., Cohen, J.C., Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nat. Genet. 46 (2014), 352–356.
17. [17] 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., Rotter, J.I., Nonalcoholic Steatohepatitis Clinical Research, N., Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology, 139, 2010 1567–1576, 1576 e1561–1566.
18. [18] London, R.M., George, J., Pathogenesis of NASH: animal models. Clin. Liver Dis. 11 (2007), 55–74 viii.
19. [19] Hebbard, L., George, J., Animal models of nonalcoholic fatty liver disease. Nat. Rev. Gastroenterol. Hepatol. 8 (2011), 35–44.
20. [20] Maher, J.J., Modeling fatty liver disease in animals: is there an optimal approach, and is the effort worthwhile?. Hepatology 64 (2016), 1398–1400.
21. [21] Vilar-Gomez, E., Martinez-Perez, Y., Calzadilla-Bertot, L., Torres-Gonzalez, A., Gra-Oramas, B., Gonzalez-Fabian, L., Friedman, S.L., Diago, M., Romero-Gomez, M., Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology, 149, 2015 367-378 e365; quiz e314–365.
22. [22] Cave, M.C., Clair, H.B., Hardesty, J.E., Falkner, K.C., Feng, W., Clark, B.J., Sidey, J., Shi, H., Aqel, B.A., McClain, C.J., Prough, R.A., Nuclear receptors and nonalcoholic fatty liver disease. Biochim. Biophys. Acta 1859 (2016), 1083–1099.
23. [23] Tailleux, A., Wouters, K., Staels, B., Roles of PPARs in NAFLD: potential therapeutic targets. Biochim. Biophys. Acta 1821 (2012), 809–818.
24. [24] Pawlak, M., Lefebvre, P., Staels, B., Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J. Hepatol. 62 (2015), 720–733.
25. [25] Motojima, K., Passilly, P., Peters, J.M., Gonzalez, F.J., Latruffe, N., Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J. Biol. Chem. 273 (1998), 16710–16714.
26. [26] Yu, K., Bayona, W., Kallen, C.B., Harding, H.P., Ravera, C.P., McMahon, G., Brown, M., Lazar, M.A., Differential activation of peroxisome proliferator-activated receptors by eicosanoids. J. Biol. Chem. 270 (1995), 23975–23983.
27. [27] Wahli, W., Michalik, L., PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol. Metab. 23 (2012), 351–363.
28. [28] Takeuchi, S., Matsuda, T., Kobayashi, S., Takahashi, T., Kojima, H., In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway. Toxicol. Appl. Pharmacol. 217 (2006), 235–244.
29. [29] Corton, J.C., Evaluation of the role of peroxisome proliferator-activated receptor alpha (PPARalpha) in mouse liver tumor induction by trichloroethylene and metabolites. Crit. Rev. Toxicol. 38 (2008), 857–875.
30. [30] Laughter, A.R., Dunn, C.S., Swanson, C.L., Howroyd, P., Cattley, R.C., Corton, J.C., Role of the peroxisome proliferator-activated receptor alpha (PPARalpha) in responses to trichloroethylene and metabolites, trichloroacetate and dichloroacetate in mouse liver. Toxicology 203 (2004), 83–98.
31. [31] Fisher, C.D., Jackson, J.P., Lickteig, A.J., Augustine, L.M., Cherrington, N.J., Drug metabolizing enzyme induction pathways in experimental non-alcoholic steatohepatitis. Arch. Toxicol. 82 (2008), 959–964.
32. [32] Sznaidman, M.L., Haffner, C.D., Maloney, P.R., Fivush, A., Chao, E., Goreham, D., Sierra, M.L., LeGrumelec, C., Xu, H.E., Montana, V.G., Lambert, M.H., Willson, T.M., Oliver, W.R. Jr., Sternbach, D.D., Novel selective small molecule agonists for peroxisome proliferator-activated receptor delta (PPARdelta)–synthesis and biological activity. Bioorg Med. Chem. Lett. 13 (2003), 1517–1521.
33. [33] Issemann, I., Green, S., Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature 347 (1990), 645–650.
34. [34] Evans, R.M., Barish, G.D., Wang, Y.X., PPARs and the complex journey to obesity. Nat. Med. 10 (2004), 355–361.
35. [35] Desvergne, B., Wahli, W., Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr. Rev. 20 (1999), 649–688.
36. [36] Holden, P.R., Tugwood, J.D., Peroxisome proliferator-activated receptor alpha: role in rodent liver cancer and species differences. J. Mol. Endocrinol. 22 (1999), 1–8.
37. [37] Gonzalez, F.J., Shah, Y.M., PPARalpha: mechanism of species differences and hepatocarcinogenesis of peroxisome proliferators. Toxicology 246 (2008), 2–8.
38. [38] Lee, S.S., Pineau, T., Drago, J., Lee, E.J., Owens, J.W., Kroetz, D.L., Fernandez-Salguero, P.M., Westphal, H., Gonzalez, F.J., Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol. Cell Biol. 15 (1995), 3012–3022.
39. [39] Mandard, S., Muller, M., Kersten, S., Peroxisome proliferator-activated receptor alpha target genes. Cell Mol. Life Sci. 61 (2004), 393–416.
40. [40] Vanden Berghe, W., Vermeulen, L., Delerive, P., De Bosscher, K., Staels, B., Haegeman, G., A paradigm for gene regulation: inflammation, NF-kappaB and PPAR. Adv. Exp. Med. Biol. 544 (2003), 181–196.
41. [41] Patsouris, D., Reddy, J.K., Muller, M., Kersten, S., Peroxisome proliferator-activated receptor alpha mediates the effects of high-fat diet on hepatic gene expression. Endocrinology 147 (2006), 1508–1516.
42. [42] Kim, S., Sohn, I., Ahn, J.I., Lee, K.H., Lee, Y.S., Lee, Y.S., Hepatic gene expression profiles in a long-term high-fat diet-induced obesity mouse model. Gene 340 (2004), 99–109.
43. [43] Gregoire, F.M., Zhang, Q., Smith, S.J., Tong, C., Ross, D., Lopez, H., West, D.B., Diet-induced obesity and hepatic gene expression alterations in C57BL/6J and ICAM-1-deficient mice. Am. J. Physiol. Endocrinol. Metab. 282 (2002), E703–E713.
44. [44] Redonnet, A., Groubet, R., Noel-Suberville, C., Bonilla, S., Martinez, A., Higueret, P., Exposure to an obesity-inducing diet early affects the pattern of expression of peroxisome proliferator, retinoic acid, and triiodothyronine nuclear receptors in the rat. Metabolism 50 (2001), 1161–1167.
45. [45] 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., PPARalpha gene expression correlates with severity and histological treatment response in patients with non-alcoholic steatohepatitis. J. Hepatol. 63 (2015), 164–173.
46. [46] Stienstra, R., Mandard, S., Patsouris, D., Maass, C., Kersten, S., Muller, M., Peroxisome proliferator-activated receptor alpha protects against obesity-induced hepatic inflammation. Endocrinology 148 (2007), 2753–2763.
47. [47] Abdelmegeed, M.A., Yoo, S.H., Henderson, L.E., Gonzalez, F.J., Woodcroft, K.J., Song, B.J., PPARalpha expression protects male mice from high fat-induced nonalcoholic fatty liver. J. Nutr. 141 (2011), 603–610.
48. [48] Stienstra, R., Duval, C., Muller, M., Kersten, S., PPARs, obesity, and inflammation. PPAR Res., 2007, 2007, 95974.
49. [49] Ip, E., Farrell, G.C., Robertson, G., Hall, P., Kirsch, R., Leclercq, I., Central role of PPARalpha-dependent hepatic lipid turnover in dietary steatohepatitis in mice. Hepatology 38 (2003), 123–132.
50. [50] Ip, E., Farrell, G., Hall, P., Robertson, G., Leclercq, I., Administration of the potent PPARalpha agonist, Wy-14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 39 (2004), 1286–1296.
51. [51] Shiri-Sverdlov, R., Wouters, K., van Gorp, P.J., Gijbels, M.J., Noel, B., Buffat, L., Staels, B., Maeda, N., van Bilsen, M., Hofker, M.H., Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates. J. Hepatol. 44 (2006), 732–741.
52. [52] Zhang, N., Lu, Y., Shen, X., Bao, Y., Cheng, J., Chen, L., Li, B., Zhang, Q., Fenofibrate treatment attenuated chronic endoplasmic reticulum stress in the liver of nonalcoholic fatty liver disease mice. Pharmacology 95 (2015), 173–180.
53. [53] Abd El-Haleim, E.A., Bahgat, A.K., Saleh, S., Resveratrol and fenofibrate ameliorate fructose-induced nonalcoholic steatohepatitis by modulation of genes expression. World J. Gastroenterol. 22 (2016), 2931–2948.
54. [54] Laurin, J., Lindor, K.D., Crippin, J.S., Gossard, A., Gores, G.J., Ludwig, J., Rakela, J., McGill, D.B., Ursodeoxycholic acid or clofibrate in the treatment of non-alcohol-induced steatohepatitis: a pilot study. Hepatology 23 (1996), 1464–1467.
55. [55] Fernandez-Miranda, C., Perez-Carreras, M., Colina, F., Lopez-Alonso, G., Vargas, C., Solis-Herruzo, J.A., A pilot trial of fenofibrate for the treatment of non-alcoholic fatty liver disease. Dig. Liver Dis. 40 (2008), 200–205.
56. [56] Basaranoglu, M., Acbay, O., Sonsuz, A., A controlled trial of gemfibrozil in the treatment of patients with nonalcoholic steatohepatitis. J. Hepatol., 31, 1999, 384.
57. [57] Hertz, R., Bar-Tana, J., Peroxisome proliferator-activated receptor (PPAR) alpha activation and its consequences in humans. Toxicol. Lett. 102–103 (1998), 85–90.
58. [58] Palmer, C.N., Hsu, M.H., Griffin, K.J., Raucy, J.L., Johnson, E.F., Peroxisome proliferator activated receptor-alpha expression in human liver. Mol. Pharmacol. 53 (1998), 14–22.
59. [59] Rakhshandehroo, M., Hooiveld, G., Muller, M., Kersten, S., Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. PLoS One, 4, 2009 e6796.
60. [60] Peters, J.M., Shah, Y.M., Gonzalez, F.J., The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention. Nat. Rev. Cancer 12 (2012), 181–195.
61. [61] Tanaka, T., Yamamoto, J., Iwasaki, S., Asaba, H., Hamura, H., Ikeda, Y., Watanabe, M., Magoori, K., Ioka, R.X., Tachibana, K., Watanabe, Y., Uchiyama, Y., Sumi, K., Iguchi, H., Ito, S., Doi, T., Hamakubo, T., Naito, M., Auwerx, J., Yanagisawa, M., Kodama, T., Sakai, J., Activation of peroxisome proliferator-activated receptor delta induces fatty acid beta-oxidation in skeletal muscle and attenuates metabolic syndrome. Proc. Natl. Acad. Sci. U. S. A. 100 (2003), 15924–15929.
62. [62] Mackenzie, L.S., Lione, L., Harnessing the benefits of PPARbeta/delta agonists. Life Sci. 93 (2013), 963–967.
63. [63] Shan, W., Palkar, P.S., Murray, I.A., McDevitt, E.I., Kennett, M.J., Kang, B.H., Isom, H.C., Perdew, G.H., Gonzalez, F.J., Peters, J.M., Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression. Toxicol. Sci. 105 (2008), 418–428.
64. [64] Shan, W., Nicol, C.J., Ito, S., Bility, M.T., Kennett, M.J., Ward, J.M., Gonzalez, F.J., Peters, J.M., Peroxisome proliferator-activated receptor-beta/delta protects against chemically induced liver toxicity in mice. Hepatology 47 (2008), 225–235.
65. [65] Riserus, U., Sprecher, D., Johnson, T., Olson, E., Hirschberg, S., Liu, A., Fang, Z., Hegde, P., Richards, D., Sarov-Blat, L., Strum, J.C., Basu, S., Cheeseman, J., Fielding, B.A., Humphreys, S.M., Danoff, T., Moore, N.R., Murgatroyd, P., O'Rahilly, S., Sutton, P., Willson, T., Hassall, D., Frayn, K.N., Karpe, F., Activation of peroxisome proliferator-activated receptor (PPAR)delta promotes reversal of multiple metabolic abnormalities, reduces oxidative stress, and increases fatty acid oxidation in moderately obese men. Diabetes 57 (2008), 332–339.
66. [66] Bays, H.E., Schwartz, S., Littlejohn, T. 3rd, Kerzner, B., Krauss, R.M., Karpf, D.B., Choi, Y.J., Wang, X., Naim, S., Roberts, B.K., MBX-8025, a novel peroxisome proliferator receptor-delta agonist: lipid and other metabolic effects in dyslipidemic overweight patients treated with and without atorvastatin. J. Clin. Endocrinol. Metab. 96 (2011), 2889–2897.
67. [67] Neuschwander-Tetri, B.A., Brunt, E.M., Wehmeier, K.R., Oliver, D., Bacon, B.R., Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology 38 (2003), 1008–1017.
68. [68] Torres, D.M., Jones, F.J., Shaw, J.C., Williams, C.D., Ward, J.A., Harrison, S.A., Rosiglitazone versus rosiglitazone and metformin versus rosiglitazone and losartan in the treatment of nonalcoholic steatohepatitis in humans: a 12-month randomized, prospective, open- label trial. Hepatology 54 (2011), 1631–1639.
69. [69] Ratziu, V., Giral, P., Jacqueminet, S., Charlotte, F., Hartemann-Heurtier, A., Serfaty, L., Podevin, P., Lacorte, J.M., Bernhardt, C., Bruckert, E., Grimaldi, A., Poynard, T., Group, L.S., Rosiglitazone for nonalcoholic steatohepatitis: one-year results of the randomized placebo-controlled fatty liver improvement with rosiglitazone therapy (FLIRT) trial. Gastroenterology 135 (2008), 100–110.
70. [70] Ratziu, V., Charlotte, F., Bernhardt, C., Giral, P., Halbron, M., Lenaour, G., Hartmann-Heurtier, A., Bruckert, E., Poynard, T., Group, L.S., Long-term efficacy of rosiglitazone in nonalcoholic steatohepatitis: results of the fatty liver improvement by rosiglitazone therapy (FLIRT 2) extension trial. Hepatology 51 (2010), 445–453.
71. [71] Belfort, R., Harrison, S.A., Brown, K., Darland, C., Finch, J., Hardies, J., Balas, B., Gastaldelli, A., Tio, F., Pulcini, J., Berria, R., Ma, J.Z., Dwivedi, S., Havranek, R., Fincke, C., DeFronzo, R., Bannayan, G.A., Schenker, S., Cusi, K., A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N. Engl. J. Med. 355 (2006), 2297–2307.
72. [72] Aithal, G.P., Thomas, J.A., Kaye, P.V., Lawson, A., Ryder, S.D., Spendlove, I., Austin, A.S., Freeman, J.G., Morgan, L., Webber, J., Randomized, placebo-controlled trial of pioglitazone in nondiabetic subjects with nonalcoholic steatohepatitis. Gastroenterology 135 (2008), 1176–1184.
73. [73] Sanyal, A.J., Chalasani, N., Kowdley, K.V., McCullough, A., Diehl, A.M., Bass, N.M., Neuschwander-Tetri, B.A., Lavine, J.E., Tonascia, J., Unalp, A., Van Natta, M., Clark, J., Brunt, E.M., Kleiner, D.E., Hoofnagle, J.H., Robuck, P.R., Nash, C.R.N., Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N. Engl. J. Med. 362 (2010), 1675–1685.
74. [74] Cusi, K., Orsak, B., Bril, F., Lomonaco, R., Hecht, J., Ortiz-Lopez, C., Tio, F., Hardies, J., Darland, C., Musi, N., Webb, A., Portillo-Sanchez, P., Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann. Intern Med. 165 (2016), 305–315.
75. [75] Cariou, B., Hanf, R., Lambert-Porcheron, S., Zair, Y., Sauvinet, V., Noel, B., Flet, L., Vidal, H., Staels, B., Laville, M., Dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 improves hepatic and peripheral insulin sensitivity in abdominally obese subjects. Diabetes Care 36 (2013), 2923–2930.
76. [76] Ratziu, V., Harrison, S.A., Francque, S., Bedossa, P., Lehert, P., Serfaty, L., Romero-Gomez, M., Boursier, J., Abdelmalek, M., Caldwell, S., Drenth, J., Anstee, Q.M., Hum, D., Hanf, R., Roudot, A., Megnien, S., Staels, B., Sanyal, A., Group, G.-I.S., Elafibranor, an agonist of the peroxisome proliferator-activated receptor-alpha and -delta, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology 150 (2016), 1147–1159 e1145.
77. [77] Nagasawa, T., Inada, Y., Nakano, S., Tamura, T., Takahashi, T., Maruyama, K., Yamazaki, Y., Kuroda, J., Shibata, N., 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. 536 (2006), 182–191.
78. [78] Terada, M., Araki, M., Ashibe, B., Motojima, K., GW501516 acts as an efficient PPARalpha activator in the mouse liver. Drug Discov. Ther. 5 (2011), 176–180.
79. [79] Garbacz, W.G., Huang, J.T., Higgins, L.G., Wahli, W., Palmer, C.N., PPARalpha is required for PPARdelta action in regulation of body weight and hepatic steatosis in mice. PPAR Res., 2015, 2015, 927057.
80. [80] Peters, J.M., Gonzalez, F.J., Muller, R., Establishing the role of PPARbeta/delta in carcinogenesis. Trends Endocrinol. Metab. 26 (2015), 595–607.
81. [81] Sahebkar, A., Chew, G.T., Watts, G.F., New peroxisome proliferator-activated receptor agonists: potential treatments for atherogenic dyslipidemia and non-alcoholic fatty liver disease. Expert Opin. Pharmacother. 15 (2014), 493–503.
82. [82] Lee, M.Y., Choi, R., Kim, H.M., Cho, E.J., Kim, B.H., Choi, Y.S., Naowaboot, J., Lee, E.Y., Yang, Y.C., Shin, J.Y., Shin, Y.G., Chung, C.H., Peroxisome proliferator-activated receptor delta agonist attenuates hepatic steatosis by anti-inflammatory mechanism. Exp. Mol. Med. 44 (2012), 578–585.
83. [83] Zhu, Y., Alvares, K., Huang, Q., Rao, M.S., Reddy, J.K., Cloning of a new member of the peroxisome proliferator-activated receptor gene family from mouse liver. J. Biol. Chem. 268 (1993), 26817–26820.
84. [84] Yu, S., Matsusue, K., Kashireddy, P., Cao, W.Q., Yeldandi, V., Yeldandi, A.V., Rao, M.S., Gonzalez, F.J., Reddy, J.K., Adipocyte-specific gene expression and adipogenic steatosis in the mouse liver due to peroxisome proliferator-activated receptor gamma1 (PPARgamma1) overexpression. J. Biol. Chem. 278 (2003), 498–505.
85. [85] Gavrilova, O., Haluzik, M., Matsusue, K., Cutson, J.J., Johnson, L., Dietz, K.R., Nicol, C.J., Vinson, C., Gonzalez, F.J., Reitman, M.L., Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J. Biol. Chem. 278 (2003), 34268–34276.
86. [86] Pettinelli, P., Videla, L.A., 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. 96 (2011), 1424–1430.
87. [87] 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. 16 (2005), 631–635.
88. [88] Moran-Salvador, E., Lopez-Parra, M., Garcia-Alonso, V., Titos, E., Martinez-Clemente, M., Gonzalez-Periz, A., Lopez-Vicario, C., Barak, Y., Arroyo, V., Claria, J., Role for PPARgamma in obesity-induced hepatic steatosis as determined by hepatocyte- and macrophage-specific conditional knockouts. FASEB J. 25 (2011), 2538–2550.
89. [89] Matsusue, K., Haluzik, M., Lambert, G., Yim, S.H., Gavrilova, O., Ward, J.M., Brewer, B. Jr., Reitman, M.L., Gonzalez, F.J., Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J. Clin. Invest 111 (2003), 737–747.
90. [90] Hall, A.M., Soufi, N., Chambers, K.T., Chen, Z., Schweitzer, G.G., McCommis, K.S., Erion, D.M., Graham, M.J., Su, X., Finck, B.N., Abrogating monoacylglycerol acyltransferase activity in liver improves glucose tolerance and hepatic insulin signaling in obese mice. Diabetes 63 (2014), 2284–2296.
91. [91] Maeda, N., Takahashi, M., Funahashi, T., Kihara, S., Nishizawa, H., Kishida, K., Nagaretani, H., Matsuda, M., Komuro, R., Ouchi, N., Kuriyama, H., Hotta, K., Nakamura, T., Shimomura, I., Matsuzawa, Y., PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50 (2001), 2094–2099.
92. [92] Yamauchi, T., Kamon, J., Ito, Y., Tsuchida, A., Yokomizo, T., Kita, S., Sugiyama, T., Miyagishi, M., Hara, K., Tsunoda, M., Murakami, K., Ohteki, T., Uchida, S., Takekawa, S., Waki, H., Tsuno, N.H., Shibata, Y., Terauchi, Y., Froguel, P., Tobe, K., Koyasu, S., Taira, K., Kitamura, T., Shimizu, T., Nagai, R., Kadowaki, T., Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423 (2003), 762–769.
93. [93] Esposito, K., Ciotola, M., Carleo, D., Schisano, B., Saccomanno, F., Sasso, F.C., Cozzolino, D., Assaloni, R., Merante, D., Ceriello, A., Giugliano, D., Effect of rosiglitazone on endothelial function and inflammatory markers in patients with the metabolic syndrome. Diabetes Care 29 (2006), 1071–1076.
94. [94] Esposito, K., Ciotola, M., Merante, D., Giugliano, D., Rosiglitazone cools down inflammation in the metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 26 (2006), 1413–1414.
95. [95] Kawaguchi, K., Sakaida, I., Tsuchiya, M., Omori, K., Takami, T., Okita, K., Pioglitazone prevents hepatic steatosis, fibrosis, and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. Biochem. Biophys. Res. Commun. 315 (2004), 187–195.
96. [96] Nan, Y.M., Fu, N., Wu, W.J., Liang, B.L., Wang, R.Q., Zhao, S.X., Zhao, J.M., Yu, J., Rosiglitazone prevents nutritional fibrosis and steatohepatitis in mice. Scand. J. Gastroenterol. 44 (2009), 358–365.
97. [97] Yu, J., Zhang, S., Chu, E.S., Go, M.Y., Lau, R.H., Zhao, J., Wu, C.W., Tong, L., Zhao, J., Poon, T.C., Sung, J.J., Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro. Int. J. Biochem. Cell Biol. 42 (2010), 948–957.
98. [98] Lehmann, J.M., Moore, L.B., Smith-Oliver, T.A., Wilkison, W.O., Willson, T.M., Kliewer, S.A., An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J. Biol. Chem. 270 (1995), 12953–12956.
99. [99] Garcia-Ruiz, I., Rodriguez-Juan, C., Diaz-Sanjuan, T., Martinez, M.A., Munoz-Yague, T., Solis-Herruzo, J.A., Effects of rosiglitazone on the liver histology and mitochondrial function in ob/ob mice. Hepatology 46 (2007), 414–423.
100. [100] Gupte, A.A., Liu, J.Z., Ren, Y., Minze, L.J., Wiles, J.R., Collins, A.R., Lyon, C.J., Pratico, D., Finegold, M.J., Wong, S.T., Webb, P., Baxter, J.D., Moore, D.D., Hsueh, W.A., Rosiglitazone attenuates age- and diet-associated nonalcoholic steatohepatitis in male low-density lipoprotein receptor knockout mice. Hepatology 52 (2010), 2001–2011.
101. [101] Nan, Y.M., Han, F., Kong, L.B., Zhao, S.X., Wang, R.Q., Wu, W.J., Yu, J., Adenovirus-mediated peroxisome proliferator activated receptor gamma overexpression prevents nutritional fibrotic steatohepatitis in mice. Scand. J. Gastroenterol. 46 (2011), 358–369.
102. [102] Galli, A., Crabb, D.W., Ceni, E., Salzano, R., Mello, T., Svegliati-Baroni, G., Ridolfi, F., Trozzi, L., Surrenti, C., Casini, A., Antidiabetic thiazolidinediones inhibit collagen synthesis and hepatic stellate cell activation in vivo and in vitro. Gastroenterology 122 (2002), 1924–1940.
103. [103] Juurlink, D.N., Gomes, T., Lipscombe, L.L., Austin, P.C., Hux, J.E., Mamdani, M.M., Adverse cardiovascular events during treatment with pioglitazone and rosiglitazone: population based cohort study. BMJ, 339, 2009 b2942.
104. [104] Starner, C.I., Schafer, J.A., Heaton, A.H., Gleason, P.P., Rosiglitazone and pioglitazone utilization from January 2007 through May 2008 associated with five risk-warning events. J. Manag. Care Pharm. 14 (2008), 523–531.
105. [105] Balkrishnan, R., Arondekar, B.V., Camacho, F.T., Shenolikar, R.A., Horblyuk, R., Anderson, R.T., Comparisons of rosiglitazone versus pioglitazone monotherapy introduction and associated health care utilization in medicaid-enrolled patients with type 2 diabetes mellitus. Clin. Ther. 29 Spec No (2007), 1306–1315.
106. [106] Beysen, C., Murphy, E.J., Nagaraja, H., Decaris, M., Riiff, T., Fong, A., Hellerstein, M.K., Boyle, P.J., A pilot study of the effects of pioglitazone and rosiglitazone on de novo lipogenesis in type 2 diabetes. J. Lipid Res. 49 (2008), 2657–2663.
107. [107] de Vries, C.S., Russell-Jones, D.L., Rosiglitazone or pioglitazone in type 2 diabetes?. BMJ, 339, 2009, b3076.
108. [108] Uto, H., Nakanishi, C., Ido, A., Hasuike, S., Kusumoto, K., Abe, H., Numata, M., Nagata, K., Hayashi, K., Tsubouchi, H., The peroxisome proliferator-activated receptor-gamma agonist, pioglitazone, inhibits fat accumulation and fibrosis in the livers of rats fed a choline-deficient, l-amino acid-defined diet. Hepatol. Res. 32 (2005), 235–242.
109. [109] Hsiao, P.J., Hsieh, T.J., Kuo, K.K., Hung, W.W., Tsai, K.B., Yang, C.H., Yu, M.L., Shin, S.J., Pioglitazone retrieves hepatic antioxidant DNA repair in a mice model of high fat diet. BMC Mol. Biol., 9, 2008, 82.
110. [110] Leclercq, I.A., Lebrun, V.A., Starkel, P., Horsmans, Y.J., Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. Lab. Invest 87 (2007), 56–65.
111. [111] Leclercq, I.A., Sempoux, C., Starkel, P., Horsmans, Y., Limited therapeutic efficacy of pioglitazone on progression of hepatic fibrosis in rats. Gut 55 (2006), 1020–1029.
112. [112] Boettcher, E., Csako, G., Pucino, F., Wesley, R., Loomba, R., Meta-analysis: pioglitazone improves liver histology and fibrosis in patients with non-alcoholic steatohepatitis. Aliment. Pharmacol. Ther. 35 (2012), 66–75.
113. [113] Polyzos, S.A., Mantzoros, C.S., Adiponectin as a target for the treatment of nonalcoholic steatohepatitis with thiazolidinediones: a systematic review. Metabolism 65 (2016), 1297–1306.
114. [114] Chen, Z., Vigueira, P.A., Chambers, K.T., Hall, A.M., Mitra, M.S., Qi, N., McDonald, W.G., Colca, J.R., Kletzien, R.F., Finck, B.N., Insulin resistance and metabolic derangements in obese mice are ameliorated by a novel peroxisome proliferator-activated receptor gamma-sparing thiazolidinedione. J. Biol. Chem. 287 (2012), 23537–23548.
115. [115] McCommis, K.S., Chen, Z., Fu, X., McDonald, W.G., Colca, J.R., Kletzien, R.F., Burgess, S.C., Finck, B.N., Loss of mitochondrial pyruvate carrier 2 in the liver leads to defects in gluconeogenesis and compensation via pyruvate-alanine cycling. Cell Metab. 22 (2015), 682–694.
116. [116] Brand, C.L., Sturis, J., Gotfredsen, C.F., Fleckner, J., Fledelius, C., Hansen, B.F., Andersen, B., Ye, J.M., Sauerberg, P., Wassermann, K., Dual PPARalpha/gamma activation provides enhanced improvement of insulin sensitivity and glycemic control in ZDF rats. Am. J. Physiol. Endocrinol. Metab. 284 (2003), E841–E854.
117. [117] Harrity, T., Farrelly, D., Tieman, A., Chu, C., Kunselman, L., Gu, L., Ponticiello, R., Cap, M., Qu, F., Shao, C., Wang, W., Zhang, H., Fenderson, W., Chen, S., Devasthale, P., Jeon, Y., Seethala, R., Yang, W.P., Ren, J., Zhou, M., Ryono, D., Biller, S., Mookhtiar, K.A., Wetterau, J., Gregg, R., Cheng, P.T., Hariharan, N., Muraglitazar, a novel dual (alpha/gamma) peroxisome proliferator-activated receptor activator, improves diabetes and other metabolic abnormalities and preserves beta-cell function in db/db mice. Diabetes 55 (2006), 240–248.
118. [118] Ye, J.M., Iglesias, M.A., Watson, D.G., Ellis, B., Wood, L., Jensen, P.B., Sorensen, R.V., Larsen, P.J., Cooney, G.J., Wassermann, K., Kraegen, E.W., PPARalpha/gamma ragaglitazar eliminates fatty liver and enhances insulin action in fat-fed rats in the absence of hepatomegaly. Am. J. Physiol. Endocrinol. Metab. 284 (2003), E531–E540.
119. [119] Nissen, S.E., Wolski, K., Topol, E.J., Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 294 (2005), 2581–2586.
120. [120] Henry, R.R., Lincoff, A.M., Mudaliar, S., Rabbia, M., Chognot, C., Herz, M., Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 374 (2009), 126–135.
121. [121] Hamren, B., Ohman, K.P., Svensson, M.K., Karlsson, M.O., Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J. Clin. Pharmacol. 52 (2012), 1317–1327.
122. [122] Peters, J.M., Aoyama, T., Burns, A.M., Gonzalez, F.J., Bezafibrate is a dual ligand for PPARalpha and PPARbeta: studies using null mice. Biochim. Biophys. Acta 1632 (2003), 80–89.
123. [123] Nakano, S., Nagasawa, T., Ijiro, T., Inada, Y., Tamura, T., Maruyama, K., Kuroda, J., Yamazaki, Y., Kusama, H., Shibata, N., Bezafibrate prevents hepatic stellate cell activation and fibrogenesis in a murine steatohepatitis model, and suppresses fibrogenic response induced by transforming growth factor-beta1 in a cultured stellate cell line. Hepatol. Res. 38 (2008), 1026–1039.
124. [124] Staels, B., Rubenstrunk, A., Noel, B., Rigou, G., Delataille, P., Millatt, L.J., Baron, M., Lucas, A., Tailleux, A., Hum, D.W., Ratziu, V., Cariou, B., Hanf, R., Hepatoprotective effects of the dual peroxisome proliferator-activated receptor alpha/delta agonist, GFT505, in rodent models of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Hepatology 58 (2013), 1941–1952.
125. [125] Cariou, B., Zair, Y., Staels, B., Bruckert, E., Effects of the new dual PPAR alpha/delta agonist GFT505 on lipid and glucose homeostasis in abdominally obese patients with combined dyslipidemia or impaired glucose metabolism. Diabetes Care 34 (2011), 2008–2014.
126. [126] Angulo, P., Kleiner, D.E., Dam-Larsen, S., Adams, L.A., Bjornsson, E.S., Charatcharoenwitthaya, P., Mills, P.R., Keach, J.C., Lafferty, H.D., Stahler, A., Haflidadottir, S., Bendtsen, F., Liver fibrosis, but No other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 149 (2015), 389–397 e310.
127. [127] Ekstedt, M., Hagstrom, H., Nasr, P., Fredrikson, M., Stal, P., Kechagias, S., Hultcrantz, R., Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 61 (2015), 1547–1554.