New insight into inter-organ crosstalk contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD)
Xu Zhang, Xuetao Ji, Qian Wang, John Zhong Li
New insight into inter-organ crosstalk contributing to the pathogenesis of nonalcoholic fatty liver disease (NAFLD)
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver dysfunction and a significant global health problem with substantial rise in prevalence over the last decades. It is becoming increasingly clear that NALFD is not only predominantly a hepatic manifestation of metabolic syndrome, but also involves extra-hepatic organs and regulatory pathways. Therapeutic options are limited for the treatment of NAFLD. Accordingly, a better understanding of the pathogenesis of NAFLD is critical for gaining new insight into the regulatory network of NAFLD and for identifying new targets for the prevention and treatment of NAFLD. In this review, we emphasize on the current understanding of the inter-organ crosstalk between the liver and peripheral organs that contributing to the pathogenesis of NAFLD.
non-alcoholic fatty liver disease / hepatic lipid metabolism / hypothalamus / gut-liver axis / adipose tissue
[1] |
Adachi M, Brenner DA (2008) High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase. Hepatology 47:677–685
CrossRef
Google scholar
|
[2] |
Agarwal AK, Garg A (2006) Genetic basis of lipodystrophies and management of metabolic complications. Annu Rev Med 57:297–311
CrossRef
Google scholar
|
[3] |
Agarwal AK, Barnes RI, Garg A (2004) Genetic basis of congenital generalized lipodystrophy. Int J Obes Relat Metab Disord 28:336–339
CrossRef
Google scholar
|
[4] |
Alisi A, Ceccarelli S, Panera N, Nobili V (2012) Causative role of gut microbiota in non-alcoholic fatty liver disease pathogenesis. Front Cell Infect Microbiol 2:132
CrossRef
Google scholar
|
[5] |
Aller R, De Luis DA, Izaola O, Gonzalez Sagrado M, Conde R, Pacheco D, Velasco MC, Ovalle HF (2012) Lys656Asn polymorphism of leptin receptor, leptin levels and insulin resistance in patients with non alcoholic fatty liver disease. Eur Rev Med Pharmacol Sci 16:335–341
|
[6] |
Amaro A, Fabbrini E, Kars M, Yue P, Schechtman K, Schonfeld G, Klein S (2010) Dissociation between intrahepatic triglyceride content and insulin resistance in familial hypobetalipoproteinemia. Gastroenterology 139:149–153
CrossRef
Google scholar
|
[7] |
Anstee QDC (2015) The genetics of nonalcoholic fatty liver disease: spotlight on PNPLA3 and TM6SF2. Semin Liver Dis 35:270–290
CrossRef
Google scholar
|
[8] |
Anstee QM, McPherson S, Day CP (2011) How big a problem is non-alcoholic fatty liver disease? BMJ 343:d3897
CrossRef
Google scholar
|
[9] |
Arab JP, Karpen SJ, Dawson PA, Arrese M, Trauner M (2017) Bile acids and nonalcoholic fatty liver disease: molecular insights and therapeutic perspectives. Hepatology 65:350–362
CrossRef
Google scholar
|
[10] |
Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K
CrossRef
Google scholar
|
[11] |
Aron-Wisnewsky J, Gaborit B, Dutour A, Clement K (2013) Gut microbiota and non-alcoholic fatty liver disease: new insights. Clin Microbiol Infect 19:338–348
CrossRef
Google scholar
|
[12] |
Backhed F, Ding H, Wang T, Hooper LV, Koh GY, Nagy A, Semenkovich CF, Gordon JI (2004) The gut microbiota as an environmental factor that regulates fat storage. Proc Natl Acad Sci USA 101:15718–15723
CrossRef
Google scholar
|
[13] |
Baker RA, Herkenham M (1995) Arcuate nucleus neurons that project to the hypothalamic paraventricular nucleus: neuropeptidergic identity and consequences of adrenalectomy on mRNA levels in the rat. J Comp Neurol 358:518–530
CrossRef
Google scholar
|
[14] |
Bandsma RH, Prinsen BH, van Der Velden Mde S, Rake JP, Boer T, Smit GP, Reijngoud DJ, Kuipers F (2008) Increased de novo lipogenesis and delayed conversion of large VLDL into intermediate density lipoprotein particles contribute to hyperlipidemia in glycogen storage disease type 1a. Pediatr Res 63:702–707
CrossRef
Google scholar
|
[15] |
Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, Schoiswohl G, Yang K, Kumari M, Gross RW
CrossRef
Google scholar
|
[16] |
Begriche K, Igoudjil A, Pessayre D, Fromenty B (2006) Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6:1–28
CrossRef
Google scholar
|
[17] |
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001a) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:947–953
CrossRef
Google scholar
|
[18] |
Berg AH, Combs TP, Du X, Brownlee M, Scherer PE (2001b) The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med 7:7
CrossRef
Google scholar
|
[19] |
Bouret SG, Draper SJ, Simerly RB (2004) Formation of projection pathways from the arcuate nucleus of the hypothalamus to hypothalamic regions implicated in the neural control of feeding behavior in mice. J Neurosci 24:2797–2805
CrossRef
Google scholar
|
[20] |
Boursier J, Diehl AM (2015) Implication of gut microbiota in nonalcoholic fatty liver disease. PLoS Pathog 11:e1004559
CrossRef
Google scholar
|
[21] |
Braliou GG, Verga Falzacappa MV, Chachami G, Casanovas G, Muckenthaler MU, Simos G (2008) 2-Oxoglutarate-dependent oxygenases control hepcidin gene expression. J Hepatol 48:801–810
CrossRef
Google scholar
|
[22] |
Bril F, Lomonaco R, Orsak B, Ortiz-Lopez C, Webb A, Tio F, Hecht J, Cusi K (2014) Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis. Hepatology 59:2178–2187
CrossRef
Google scholar
|
[23] |
Broberger C, Johansen J, Johansson C, Schalling M, Hokfelt T (1998) The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamatetreated mice. Proc Natl Acad Sci USA 95:15043–15048
CrossRef
Google scholar
|
[24] |
Brown MS, Goldstein JL (2008) Selective versus total insulin resistance: a pathogenic paradox. Cell Metab 7:95–96
CrossRef
Google scholar
|
[25] |
Bulankina AV, Deggerich A, Wenzel D, Mutenda K, Wittmann JG, Rudolph MG, Burger KN, Honing S (2009) TIP47 functions in the biogenesis of lipid droplets. J Cell Biol 185:641–655
CrossRef
Google scholar
|
[26] |
Burcelin R, Garidou L, Pomie C (2012) Immuno-microbiota cross and talk: the new paradigm of metabolic diseases. Semin Immunol 24:67–74
CrossRef
Google scholar
|
[27] |
Buzzetti E, Pinzani M, Tsochatzis EA (2016) The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). Metabolism 65:1038–1048
CrossRef
Google scholar
|
[28] |
Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE (2005) Local and systemic insulin resistance resulting from hepatic activation of IKK-beta and NF-kappaB. Nat Med 11:183–190
CrossRef
Google scholar
|
[29] |
Carr RM, Reid AE (2015) FXR agonists as therapeutic agents for non-alcoholic fatty liver disease. Curr Atheroscl Rep 17(4):500
CrossRef
Google scholar
|
[30] |
Chang BH, Li L, Saha P, Chan L (2010) 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 51:2132–2142
CrossRef
Google scholar
|
[31] |
Chen Z (2016) Progress and prospects of long noncoding RNAs in lipid homeostasis. Mol Metab 5:164–170
CrossRef
Google scholar
|
[32] |
Chen Y, Huang H, Xu C, Yu C, Li Y (2017) Long non-coding RNA profiling in a non-alcoholic fatty liver disease rodent model: new insight into pathogenesis. Int J Mol Sci.
CrossRef
Google scholar
|
[33] |
Cohen JC, Horton JD, Hobbs HH (2011) Human fatty liver disease: old questions and new insights. Science 332:1519–1523
CrossRef
Google scholar
|
[34] |
Compare D, Coccoli P, Rocco A, Nardone OM, De Maria S, Carteni M, Nardone G (2012) Gut–liver axis: the impact of gut microbiota on non alcoholic fatty liver disease. Nutr Metab Cardiovasc Dis 22:471–476
CrossRef
Google scholar
|
[35] |
Conde-Vancells J, Rodriguez-Suarez E, Embade N, Gil D, Matthiesen R, Valle M, Elortza F, Lu SC, Mato JM, Falcon-Perez JM (2008) Characterization and comprehensive proteome profiling of exosomes secreted by hepatocytes. J Proteome Res 7:5157–5166
CrossRef
Google scholar
|
[36] |
Cone RD, Lu D, Koppula S, Vage DI, Klungland H, Boston B, Chen W, Orth DN, Pouton C, Kesterson RA (1996) The melanocortin receptors: agonists, antagonists, and the hormonal control of pigmentation. Recent Prog Horm Res 51:287–317; discussion 318
|
[37] |
Cook JR, Langlet F, Kido Y, Accili D (2015) Pathogenesis of selective insulin resistance in isolated hepatocytes. J Biol Chem 290:13972–13980
CrossRef
Google scholar
|
[38] |
Coppari R, Ichinose M, Lee CE, Pullen AE, Kenny CD, McGovern RA, Tang V, Liu SM, Ludwig T, Chua SC Jr
CrossRef
Google scholar
|
[39] |
Crunk AE, Monks J, Murakami A, Jackman M, Maclean PS, Ladinsky M, Bales ES, Cain S, Orlicky DJ, McManaman JL (2013) Dynamic regulation of hepatic lipid droplet properties by diet. PLoS ONE 8:e67631
CrossRef
Google scholar
|
[40] |
Cusi K (2012) Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 142(711–725):e716
CrossRef
Google scholar
|
[41] |
Day CP (2006) From fat to inflammation. Gastroenterology 130:207–210
CrossRef
Google scholar
|
[42] |
Day CPJ, James OF (1998) Steatohepatitis: a tale of two “hits”. Gastroenterology 114:842–845
CrossRef
Google scholar
|
[43] |
De Souza CT, Araujo EP S, Bordin EP, Ashimine R, Zollner RL, Boschero AC, Saad MJA, Velloso LA (2005) Consumption of a fat-rich diet activates a proinflammatory response and induces insulin resistance in the hypothalamus. Endocrinology 146:4192–4199
CrossRef
Google scholar
|
[44] |
den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM (2013) The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54:2325–2340
CrossRef
Google scholar
|
[45] |
Deng ZB, Poliakov A, Hardy RW, Clements R, Liu C, Liu Y, Wang J, Xiang X, Zhang S, Zhuang X
CrossRef
Google scholar
|
[46] |
Di Filippo M, Moulin P, Roy P, Samson-Bouma ME, Collardeau-Frachon S, Chebel-Dumont S, Peretti N, Dumortier J, Zoulim F, Fontanges T
CrossRef
Google scholar
|
[47] |
Diehl AM (2004) Tumor necrosis factor and its potential role in insulin resistance and nonalcoholic fatty liver disease. Clin Liver Dis 8:619–638, x
CrossRef
Google scholar
|
[48] |
Diehl AM, Li ZP, Lin HZ, Yang SQ (2005) Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut 54:303–306
CrossRef
Google scholar
|
[49] |
Diehl P, Fricke A, Sander L, Stamm J, Bassler N, Htun N, Ziemann M, Helbing T, El-Osta A, Jowett JB
CrossRef
Google scholar
|
[50] |
DiStefano JK, Gerhard GS (2016) Circulating microRNAs in nonalcoholic fatty liver disease. Expert Rev Gastroenterol Hepatol 10:161–163
CrossRef
Google scholar
|
[51] |
Donnelly KLSC, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ (2005) Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Investig 115:1343–1351
CrossRef
Google scholar
|
[52] |
Drenick EJ, Fisler J, Johnson D (1982) Hepatic steatosis after intestinal bypass–prevention and reversal by metronidazole, irrespective of protein-calorie malnutrition. Gastroenterology 82:535–548
|
[53] |
Duncan SH, Louis P, Thomson JM, Flint HJ (2009) The role of pH in determining the species composition of the human colonic microbiota. Environ Microbiol 11:2112–2122
CrossRef
Google scholar
|
[54] |
Fan JG, Farrell GC (2009) Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol 50:204–210
CrossRef
Google scholar
|
[55] |
Finelli C, Tarantino G (2013) What is the role of adiponectin in obesity related non-alcoholic fatty liver disease? World J Gastroenterol 19:802–812
CrossRef
Google scholar
|
[56] |
Fontana L, Eagon JC, Trujillo ME, Scherer PE, Klein S (2007) Visceral fat adipokine secretion is associated with systemic inflammation in obese humans. Diabetes 56:1010–1013
CrossRef
Google scholar
|
[57] |
Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT, Bihain BE, Lodish HF (2001) Proteolytic cleavage product of 30-kDa adipocyte complement-related protein increases fatty acid oxidation in muscle and causes weight loss in mice. Proc Natl Acad Sci USA 98:2005–2010
CrossRef
Google scholar
|
[58] |
Fuchs CD, Traussnigg SA, Trauner M (2016) Nuclear receptor modulation for the treatment of nonalcoholic fatty liver disease. Semin Liver Dis 36:69–86
CrossRef
Google scholar
|
[59] |
Gabele E, Dostert K, Hofmann C, Wiest R, Scholmerich J, Hellerbrand C, Obermeier F (2011) DSS induced colitis increases portal LPS levels and enhances hepatic inflammation and fibrogenesis in experimental NASH. J Hepatol 55:1391–1399
CrossRef
Google scholar
|
[60] |
Gerhard GS, DiStefano JK (2015) Micro RNAs in the development of non-alcoholic fatty liver disease. World J Hepatol 7:226–234
CrossRef
Google scholar
|
[61] |
Giannini C, Feldstein AE, Santoro N, Kim G, Kursawe R, Pierpont B, Caprio S (2013) Circulating levels of FGF-21 in obese youth: associations with liver fat content and markers of liver damage. J Clin Endocrinol Metab 98:2993–3000
CrossRef
Google scholar
|
[62] |
Gkolfakis P, Dimitriadis G, Triantafyllou K (2015) Gut microbiota and non-alcoholic fatty liver disease. Hepatobiliary Pancreat Dis Int 14:572–581
CrossRef
Google scholar
|
[63] |
Gong J, Sun Z, Wu L, Xu W, Schieber N, Xu D, Shui G, Yang H, Parton RG, Li P (2011) Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites. J Cell Biol 195:953–963
CrossRef
Google scholar
|
[64] |
Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C (1991) Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem 266:11341–11346
|
[65] |
Guan L, Shang XR, Liu FH, Song JY, Ma J, Wang HJ (2014) Association of INSIG2 rs9308762 with ALT level independent of BMI. J Pediatr Gastroenterol Nutr 58:155–159
CrossRef
Google scholar
|
[66] |
Hahn TM, Breininger JF, Baskin DG, Schwartz MW (1998) Coexpression of Agrp and NPY in fasting-activated hypothalamic neurons. Nat Neurosci 1:271–272
CrossRef
Google scholar
|
[67] |
Handy JA, Saxena NK, Fu P, Lin S, Mells JE, Gupta NA, Anania FA (2010) Adiponectin activation of AMPK disrupts leptin-mediated hepatic fibrosis via suppressors of cytokine signaling (SOCS-3). J Cell Biochem 110:1195–1207
CrossRef
Google scholar
|
[68] |
Harte AL, da Silva NF, Creely SJ
CrossRef
Google scholar
|
[69] |
Haupt A, Thamer C, Heni M, Tschritter O, Machann J, Schick F, Machicao F, Haring HU, Staiger H, Fritsche A (2009) Impact of variation near MC4R on whole-body fat distribution, liver fat, and weight loss. Obesity (Silver Spring) 17:1942–1945
CrossRef
Google scholar
|
[70] |
Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ
CrossRef
Google scholar
|
[71] |
Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W, Nelson C, Lowman HB, Wright BD, Skelton NJ
CrossRef
Google scholar
|
[72] |
Holland WL, Bikman BT, Wang LP, Yuguang G, Sargent KM, Bulchand S, Knotts TA, Shui G, Clegg DJ, Wenk MR
CrossRef
Google scholar
|
[73] |
Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM
CrossRef
Google scholar
|
[74] |
Hu E, Liang P, Spiegelman BM (1996) AdipoQ is a novel adiposespecific gene dysregulated in obesity. J Biol Chem 271:10697–10703
CrossRef
Google scholar
|
[75] |
Imai Y, Varela GM, Jackson MB, Graham MJ, Crooke RM, Ahima RS (2007) Reduction of hepatosteatosis and lipid levels by an adipose differentiation-related protein antisense oligonucleotide. Gastroenterology 132:1947–1954
CrossRef
Google scholar
|
[76] |
Itoh M, Suganami T, Nakagawa N, Tanaka M, Yamamoto Y, Kamei Y, Terai S, Sakaida I, Ogawa Y (2011) Melanocortin 4 receptordeficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol 179:2454–2463
CrossRef
Google scholar
|
[77] |
Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, Fang Y, Elariny H, Goodman Z, Chandhoke V
CrossRef
Google scholar
|
[78] |
Jou J, Choi SS, Diehl AM (2008) Mechanisms of disease progression in nonalcoholic fatty liver disease. Semin Liver Dis 28:370–379
CrossRef
Google scholar
|
[79] |
Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792
CrossRef
Google scholar
|
[80] |
Kahn BB, Flier JS (2000) Obesity and insulin resistance. J Clin Invest 106:473–481
CrossRef
Google scholar
|
[81] |
Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, Fukui K, Maeda N, Nishizawa H, Nagaretani H
CrossRef
Google scholar
|
[82] |
Kampf C, Mardinoglu A, Fagerberg L, Hallstrom BM, Edlund K, Lundberg E, Ponten F, Nielsen J, Uhlen M (2014) The human liver-specific proteome defined by transcriptomics and antibodybased profiling. FASEB J 28:2901–2914
CrossRef
Google scholar
|
[83] |
Kleinridders A, Schenten D, Konner AC, Belgardt BF, Mauer J, Okamura T, Wunderlich FT, Medzhitov R, Bruning JC (2009) MyD88 signaling in the CNS is required for development of fatty acid-induced leptin resistance and diet-induced obesity. Cell Metab 10:249–259
CrossRef
Google scholar
|
[84] |
Kornek M, Lynch M, Mehta SH, Lai M, Exley M, Afdhal NH, Schuppan D (2012) Circulating microparticles as diseasespecific biomarkers of severity of inflammation in patients with hepatitis C or nonalcoholic steatohepatitis . Gastroenterology 143:448–458
CrossRef
Google scholar
|
[85] |
Kristensen P, Judge ME, Thim L, Ribel U, Christjansen KN, Wulff BS, Clausen JT, Jensen PB, Madsen OD, Vrang N
CrossRef
Google scholar
|
[86] |
Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ (2003) Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology 38:413–419
CrossRef
Google scholar
|
[87] |
Kwon O, Kim KW, Kim MS (2016) Leptin signalling pathways in hypothalamic neurons. Cell Mol Life Sci 73:1457–1477
CrossRef
Google scholar
|
[88] |
Lambert JE, Ramos-Roman MA, Browning JD, Parks EJ (2014) Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease. Gastroenterology 146:726–735
CrossRef
Google scholar
|
[89] |
Lebensztejn DM, Flisiak-Jackiewicz M, Bialokoz-Kalinowska I, Bobrus-Chociej A, Kowalska I (2016) Hepatokines and nonalcoholic fatty liver disease. Acta Biochim Pol 63:459–467
CrossRef
Google scholar
|
[90] |
Li JZ, Ye J, Xue B, Qi J, Zhang J, Zhou Z, Li Q, Wen Z, Li P (2007) Cideb regulates diet-induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes 56:2523–2532
CrossRef
Google scholar
|
[91] |
Li H, Fang Q, Gao F, Fan J, Zhou J, Wang X, Zhang H, Pan X, Bao Y, Xiang K
CrossRef
Google scholar
|
[92] |
Li S, Brown MS, Goldstein JL (2010b) Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci USA 107:3441–3446
CrossRef
Google scholar
|
[93] |
Li JZ, Huang Y, Karaman R, Ivanova PT, Brown HA, Roddy T, Castro-Perez J, Cohen JC, Hobbs HH (2012) Chronic overexpression of PNPLA3I148M in mouse liver causes hepatic steatosis. J Clin Invest 122:4130–4144
CrossRef
Google scholar
|
[94] |
Li P, Ruan X, Yang L, Kiesewetter K, Zhao Y, Luo H, Chen Y, Gucek M, Zhu J, Cao H (2015) A liver-enriched long non-coding RNA, lncLSTR, regulates systemic lipid metabolism in mice. Cell Metab 21:455–467
CrossRef
Google scholar
|
[95] |
Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N
CrossRef
Google scholar
|
[96] |
Malhotra JD, Kaufman RJ (2007) Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword? Antioxid Redox Signal 9:2277–2293
CrossRef
Google scholar
|
[97] |
Masyuk AI, Masyuk TV, Larusso NF (2013) Exosomes in the pathogenesis, diagnostics and therapeutics of liver diseases. J Hepatol 59:621–625
CrossRef
Google scholar
|
[98] |
Matsuzawa Y (2010) Adiponectin: a key player in obesity related disorders. Curr Pharm Des 16:1896–1901
CrossRef
Google scholar
|
[99] |
Mayer J, Bates MW, Dickie MM (1951) Hereditary diabetes in genetically obese mice. Science 113:746–747
CrossRef
Google scholar
|
[100] |
Mazuy C, Helleboid A, Staels B, Lefebvre P (2015) Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 72:1631–1650
CrossRef
Google scholar
|
[101] |
Miele L, Valenza V, La Torre G, Montalto M, Cammarota G, Ricci R, Masciana R, Forgione A, Gabrieli ML, Perotti G
CrossRef
Google scholar
|
[102] |
Milanski M, Degasperi G, Coope A, Morari J, Denis R, Cintra DE, Tsukumo DML, Anhe G, Amaral ME, Takahashi HK
CrossRef
Google scholar
|
[103] |
Milanski M, Arruda AP, Coope A, Ignacio-Souza LM, Nunez CE, Roman EA, Romanatto T, Pascoal LB, Caricilli AM, Torsoni MA
CrossRef
Google scholar
|
[104] |
Moore DD (2012) Nuclear receptors reverse McGarry’s vicious cycle to insulin resistance. Cell Metab 15:615–622
CrossRef
Google scholar
|
[105] |
Mori K, Emoto M, Inaba M (2011) Fetuin-A: a multifunctional protein. Recent Pat Endocr Metab Immune Drug Discov 5:124–146
CrossRef
Google scholar
|
[106] |
Musso G, Gambino R, Biroli G, Carello M, Faga E, Pacini G, De Michieli F, Cassader M, Durazzo M, Rizzetto M
CrossRef
Google scholar
|
[107] |
Newgard CB (2012) Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab 15:606–614
CrossRef
Google scholar
|
[108] |
Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M
CrossRef
Google scholar
|
[109] |
Ozcan L, Ergin AS, Lu A, Chung J, Sarkar S, Nie D, Myers MG, Ozcan U (2009) Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metab 9:35–51
CrossRef
Google scholar
|
[110] |
Ozcelik F, Yuksel C, Arslan E, Genc S, Omer B, Serdar MA (2013) Relationship between visceral adipose tissue and adiponectin, inflammatory markers and thyroid hormones in obese males with hepatosteatosis and insulin resistance. Arch Med Res 44:273–280
CrossRef
Google scholar
|
[111] |
Pagano C, Soardo G, Pilon C, Milocco C, Basan L, Milan G, Donnini D, Faggian D, Mussap M, Plebani M
CrossRef
Google scholar
|
[112] |
Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S (2012) Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat Med 18:1279–1285
CrossRef
Google scholar
|
[113] |
Pan Q, Ramakrishnaiah V, Henry S, Fouraschen S, de Ruiter PE, Kwekkeboom J, Tilanus HW, Janssen HL, van der Laan LJ (2012) Hepatic cell-to-cell transmission of small silencing RNA can extend the therapeutic reach of RNA interference (RNAi). Gut 61:1330–1339
CrossRef
Google scholar
|
[114] |
Peverill W, Powell LW, Skoien R (2014) Evolving concepts in the pathogenesis of NASH: beyond steatosis and inflammation. Int J Mol Sci 15:8591–8638
CrossRef
Google scholar
|
[115] |
Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B (2003) Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17:259–272
CrossRef
Google scholar
|
[116] |
Pirazzi C, Adiels M, Burza MA, Mancina RM, Levin M, Stahlman M, Taskinen MR, Orho-Melander M, Perman J, Pujia A
CrossRef
Google scholar
|
[117] |
Pirola CJ, Fernandez Gianotti T, Castano GO, Mallardi P, San Martino J, Mora Gonzalez Lopez Ledesma M, Flichman D, Mirshahi F, Sanyal AJ, Sookoian S (2015) Circulating microRNA signature in non-alcoholic fatty liver disease: from serum noncoding RNAs to liver histology and disease pathogenesis. Gut 64:800–812
CrossRef
Google scholar
|
[118] |
Pisetsky D (2011) Cell death in the pathogenesis of immunemediated diseases: the role of HMGB1 and DAMP-PAMP complexes. Swiss Med Wkly 141:w13256
|
[119] |
Poggi M, Bastelica D, Gual P, Iglesias MA, Gremeaux T, Knauf C, Peiretti F, Verdier M, Juhan-Vague I, Tanti JF
CrossRef
Google scholar
|
[120] |
Polyzos SA, Toulis KA, Goulis DG, Zavos C, Kountouras J (2011) Serum total adiponectin in nonalcoholic fatty liver disease: a systematic review and meta-analysis. Metabolism 60:313–326
CrossRef
Google scholar
|
[121] |
Polyzos SA, Aronis KN, Kountouras J, Raptis DD, Vasiloglou MF, Mantzoros CS (2016) Circulating leptin in non-alcoholic fatty liver disease: a systematic review and meta-analysis. Diabetologia 59:30–43
CrossRef
Google scholar
|
[122] |
Posey KA, Clegg DJ, Printz RL, Byun J, Morton GJ, Vivekanandan-Giri A, Pennathur S, Baskin DG, Heinecke JW, Woods SC
CrossRef
Google scholar
|
[123] |
Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118:829–838
CrossRef
Google scholar
|
[124] |
Povero D, Eguchi A, Niesman IR, Andronikou N, de Mollerat du Jeu X, Mulya A, Berk M, Lazic M, Thapaliya S, Parola M
CrossRef
Google scholar
|
[125] |
Povero D, Eguchi A, Li H, Johnson CD, Papouchado BG, Wree A, Messer K, Feldstein AE (2014) Circulating extracellular vesicles with specific proteome and liver microRNAs are potential biomarkers for liver injury in experimental fatty liver disease. PLoS ONE 9:e113651
CrossRef
Google scholar
|
[126] |
Psichas A, Sleeth ML, Murphy KG, Brooks L, Bewick GA, Hanyaloglu AC, Ghatei MA, Bloom SR, Frost G (2015) The short chain fatty acid propionate stimulates GLP-1 and PYY secretion via free fatty acid receptor 2 in rodents. Int J Obes (Lond) 39:424–429
CrossRef
Google scholar
|
[127] |
Puertollano E, Kolida S, Yaqoob P (2014) Biological significance of short-chain fatty acid metabolism by the intestinal microbiome. Curr Opin Clin Nutr Metab Care 17:139–144
CrossRef
Google scholar
|
[128] |
Raposo G, Stoorvogel W (2013) Extracellular vesicles: exosomes, microvesicles, and friends. J Cell Biol 200:373–383
CrossRef
Google scholar
|
[129] |
Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH (2008) Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40:1461–1465
CrossRef
Google scholar
|
[130] |
Ryo M, Nakamura T, Kihara S, Kumada M, Shibazaki S, Takahashi M, Nagai M, Matsuzawa Y, Funahashi T (2004) Adiponectin as a biomarker of the metabolic syndrome. Circ J 68:975–981
CrossRef
Google scholar
|
[131] |
Saberi M,Woods NB, de Luca C, Schenk S, Lu JC, Bandyopadhyay G, Verma IM, Olefsky JM (2009)Hematopoietic cell-specific deletion of toll-like receptor 4 ameliorates hepatic and adipose tissue insulin resistance in high-fat-fed mice. Cell Metab 10:419–429
CrossRef
Google scholar
|
[132] |
Sapru HN (2013) Role of the hypothalamic arcuate nucleus in cardiovascular regulation. Auton Neurosci 175:38–50
CrossRef
Google scholar
|
[133] |
Sato K, Meng F, Glaser S, Alpini G (2016) Exosomes in liver pathology. J Hepatol 65:213–221
CrossRef
Google scholar
|
[134] |
Savkur RS, Bramlett KS, Michael LF, Burris TP (2005) Regulation of pyruvate dehydrogenase kinase expression by the farnesoid X receptor. Biochem Biophys Res Commun 329:391–396
CrossRef
Google scholar
|
[135] |
Schaap FG, Trauner M, Jansen PLM (2014) Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 11:55–67
CrossRef
Google scholar
|
[136] |
Schneider JL, Cuervo AM (2014) Liver autophagy: much more than just taking out the trash. Nat Rev Gastroenterol Hepatol 11:187–200
CrossRef
Google scholar
|
[137] |
Schober F, Neumeier M, Weigert J, Wurm S, Wanninger J, Schaffler A, Dada A, Liebisch G, Schmitz G, Aslanidis C
CrossRef
Google scholar
|
[138] |
Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404:661–671
CrossRef
Google scholar
|
[139] |
Schwiertz A, Taras D, Schafer K, Beijer S, Bos NA, Donus C, Hardt PD (2010) Microbiota and SCFA in lean and overweight healthy subjects. Obesity (Silver Spring) 18:190–195
CrossRef
Google scholar
|
[140] |
Simpson KA, Martin NM, Bloom SR (2009) Hypothalamic regulation of food intake and clinical therapeutic applications. Arq Bras Endocrinol Metabol 53:120–128
CrossRef
Google scholar
|
[141] |
Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ (2000) Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102:731–744
CrossRef
Google scholar
|
[142] |
Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, Cohen JC, Hobbs HH (2015) Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 61:108–118
CrossRef
Google scholar
|
[143] |
Spranger J, Kroke A, Mohlig M, Bergmann MM, Ristow M, Boeing H, Pfeiffer AF (2003) Adiponectin and protection against type 2 diabetes mellitus. Lancet 361:226–228
CrossRef
Google scholar
|
[144] |
Statnick MA, Beavers LS, Conner LJ, Corominola H, Johnson D, Hammond CD, Rafaeloff-Phail R, Seng T, Suter TM, Sluka JP
CrossRef
Google scholar
|
[145] |
Stefan N, Haring HU (2013) Circulating fetuin-A and free fatty acids interact to predict insulin resistance in humans. Nat Med 19:394–395
CrossRef
Google scholar
|
[146] |
Stefan N, Kantartzis K, Haring HU (2008) Causes and metabolic consequences of fatty liver. Endocr Rev 29:939–960
CrossRef
Google scholar
|
[147] |
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312
CrossRef
Google scholar
|
[148] |
Stojsavljevic S, Gomercic Palcic M, Virovic Jukic L, Smircic Duvnjak L, Duvnjak M (2014) Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 20:18070–18091
CrossRef
Google scholar
|
[149] |
Straub BK, Stoeffel P, Heid H, Zimbelmann R, Schirmacher P (2008) Differential pattern of lipid droplet-associated proteins and de novo perilipin expression in hepatocyte steatogenesis. Hepatology 47:1936–1946
CrossRef
Google scholar
|
[150] |
Su W, Wang Y, Jia X, Wu W, Li L, Tian X, Li S, Wang C, Xu H, Cao J
CrossRef
Google scholar
|
[151] |
Thuy S, Ladurner R, Volynets V, Wagner S, Strahl S, Konigsrainer A, Maier KP, Bischoff SC, Bergheim I (2008) Nonalcoholic fatty liver disease in humans is associated with increased plasma endotoxin and plasminogen activator inhibitor 1 concentrations and with fructose intake. J Nutr 138:1452–1455
CrossRef
Google scholar
|
[152] |
Tilg H, Moschen AR (2006) Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6:772–783
CrossRef
Google scholar
|
[153] |
Tremaroli V, Backhed F (2012) Functional interactions between the gut microbiota and host metabolism. Nature 489:242–249
CrossRef
Google scholar
|
[154] |
Tsochatzis E, Papatheodoridis GV, Archimandritis AJ (2006) The evolving role of leptin and adiponectin in chronic liver diseases . Am J Gastroenterol 101:2629–2640
CrossRef
Google scholar
|
[155] |
Tsochatzis E, Papatheodoridis GV, Hadziyannis E, Georgiou A, Kafiri G, Tiniakos DG, Manesis EK, Archimandritis AJ (2008) Serum adipokine levels in chronic liver diseases: association of resistin levels with fibrosis severity. Scand J Gastroenterol 43:1128–1136
CrossRef
Google scholar
|
[156] |
Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI (2006) An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031
CrossRef
Google scholar
|
[157] |
Valdearcos M, Xu AW, Koliwad SK (2015) Hypothalamic inflammation in the control of metabolic function. Annu Rev Physiol 77:131–160
CrossRef
Google scholar
|
[158] |
Van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, London R, Peduto T, Chisholm DJ, George J (2008) Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology 48:449–457
CrossRef
Google scholar
|
[159] |
Vatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK, Bears M, Camporez JP, Cline GW, Jurczak MJ
CrossRef
Google scholar
|
[160] |
Vernon G, Baranova A, Younossi ZM (2011) Systematic review: the epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Aliment Pharmacol Ther 34:274–285
CrossRef
Google scholar
|
[161] |
von Schnurbein J, Heni M, Moss A, Nagel SA, Machann J, Muehleder H, Debatin KM, Farooqi S, Wabitsch M (2013) Rapid improvement of hepatic steatosis after initiation of leptin substitution in a leptin-deficient girl. Horm Res Paediatr 79:310–317
CrossRef
Google scholar
|
[162] |
Vonghia L, Michielsen P, Francque S (2013) Immunological mechanisms in the pathophysiology of non-alcoholic steatohepatitis. Int J Mol Sci 14:19867–19890
CrossRef
Google scholar
|
[163] |
Walther TC, Farese RV Jr (2012) Lipid droplets and cellular lipid metabolism. Annu Rev Biochem 81:687–714
CrossRef
Google scholar
|
[164] |
Wang C, Zhao Y, Gao X, Li L, Yuan Y, Liu F
CrossRef
Google scholar
|
[165] |
Wang Y, Lam KS, Yau MH, Xu A (2008) Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J 409:623–633
CrossRef
Google scholar
|
[166] |
Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J (2004) Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP-1c. J Clin Invest 113:1408–1418
CrossRef
Google scholar
|
[167] |
Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA (2001) Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 86:1930–1935
CrossRef
Google scholar
|
[168] |
Witek RP, Yang L, Liu R, Jung Y, Omenetti A, Syn WK, Choi SS, Cheong Y, Fearing CM, Agboola KM
|
[169] |
Woods SC, Seeley RJ, Porte D Jr, Schwartz MW (1998) Signals that regulate food intake and energy homeostasis. Science 280:1378–1383
CrossRef
Google scholar
|
[170] |
Wynne K, Stanley S, McGowan B, Bloom S (2005) Appetite control. J Endocrinol 184:291–318
CrossRef
Google scholar
|
[171] |
Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ (2003) The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112:91–100
CrossRef
Google scholar
|
[172] |
Xu W, Wu L, Yu M, Chen FJ, Arshad M, Xia X, Ren H, Yu J, Xu L, Xu D
CrossRef
Google scholar
|
[173] |
Yamaguchi K, Yang L, McCall S, Huang J, Yu XX, Pandey SK, Bhanot S, Monia BP, Li YX, Diehl AM (2007) Inhibiting triglyceride synthesis improves hepatic steatosis but exacerbates liver damage and fibrosis in obese mice with nonalcoholic steatohepatitis. Hepatology 45:1366–1374
CrossRef
Google scholar
|
[174] |
Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N
CrossRef
Google scholar
|
[175] |
Ye J, Li JZ, Liu Y, Li X, Yang T, Ma X, Li Q, Yao Z, Li P (2009) Cideb, an ER- and lipid droplet-associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab 9:177–190
CrossRef
Google scholar
|
[176] |
Yilmaz Y, Eren F, Yonal O, Kurt R, Aktas B, Celikel CA, Ozdogan O, Imeryuz N, Kalayci C, Avsar E (2010a) Increased serum FGF21 levels in patients with nonalcoholic fatty liver disease. Eur J Clin Invest 40:887–892
CrossRef
Google scholar
|
[177] |
Yilmaz Y, Yonal O, Kurt R, Ari F, Oral AY, Celikel CA, Korkmaz S, Ulukaya E, Ozdogan O, Imeryuz N
CrossRef
Google scholar
|
[178] |
Yuan A, Farber EL, Rapoport AL, Tejada D, Deniskin R, Akhmedov NB, Farber DB (2009) Transfer of microRNAs by embryonic stem cell microvesicles. PLoS ONE 4:e4722
CrossRef
Google scholar
|
[179] |
Zain SM, Mohamed Z, Mahadeva S, Cheah PL, Rampal S, Chin KF, Mahfudz AS, Basu RC, Tan HL, Mohamed R (2013) Impact of leptin receptor gene variants on risk of non-alcoholic fatty liver disease and its interaction with adiponutrin gene. J Gastroenterol Hepatol 28:873–879
CrossRef
Google scholar
|
[180] |
Zhang X, Zhang G, Zhang H, Karin M, Bai H, Cai D (2008) Hypothalamic IKKbeta/NF-kappaB and ER stress link overnutrition to energy imbalance and obesity. Cell 135:61–73
CrossRef
Google scholar
|
[181] |
Zhang J, Lei T, Chen X, Peng Y, Long H, Zhou L, Huang J, Chen Z, Long Q, Yang Z (2010) Resistin up-regulates COX-2 expression via TAK1-IKK-NF-kappaB signaling pathway. Inflammation 33:25–33
CrossRef
Google scholar
|
[182] |
Zhang X, Wang Y, Liu P (2017) Omic studies reveal the pathogenic lipid droplet proteins in non-alcoholic fatty liver disease. Protein Cell 8:4–13
CrossRef
Google scholar
|
[183] |
Zhu L, Baker RD, Baker SS (2015) Gut microbiome and nonalcoholic fatty liver diseases. Pediatr Res 77:245–251
CrossRef
Google scholar
|
[184] |
Zoccoli G, Amici R, Silvani A (2011) The hypothalamus and its functions. In: Narcolepsy: pathophysiology, diagnosis, and treatment. Springer, New York, pp 191–203
CrossRef
Google scholar
|
[185] |
Zou CC, Liang L, Hong F, Fu JF, Zhao ZY (2005) Serum adiponectin, resistin levels and non-alcoholic fatty liver disease in obese children. Endocr J 52:519–524
CrossRef
Google scholar
|
/
〈 | 〉 |