The genetic architecture of NAFLD among inbred strains of mice

eLife

Volumn 4, Issue JUNE2015, 2015, Pages

  Hui, Simon T ^a   Parks, Brian W ^a   Org, Elin ^a   Norheim, Frode ^b   Che, Nam ^a   Pan, Calvin ^a   Castellani, Lawrence W ^a   Charugundla, Sarada ^a   Dirks, Darwin L ^a   Psychogios, Nikolaos ^c   Neuhaus, Isaac ^d   Gerszten, Robert E ^c   Kirchgessner, Todd ^d   Gargalovic, Peter S ^d   Lusis, Aldons J ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b UNIVERSITY OF OSLO   (Norway)

^c MASSACHUSETTS GENERAL HOSPITAL   (United States)

^d BRISTOL MYERS SQUIBB   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ALANINE AMINOTRANSFERASE; GLYCEROPHOSPHATE; PHOSPHODIESTERASE; SHORT HAIRPIN RNA; TRIACYLGLYCEROL; GLYCEROPHOSPHODIESTER PHOSPHODIESTERASE;

ADENOVIRIDAE; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CHOLESTEROL BLOOD LEVEL; CHROMOSOME 7; CONTROLLED STUDY; ENVIRONMENTAL FACTOR; FATTY LIVER; GENE EXPRESSION; GENE LOCUS; GENE OVEREXPRESSION; GENETIC ASSOCIATION; GENETIC TRAIT; GENETIC TRANSCRIPTION; GENETIC TRANSDUCTION; GENETIC VARIABILITY; GENOME ANALYSIS; HISTOLOGY; INSULIN RESISTANCE; INTESTINE FLORA; METABOLIC SYNDROME X; METABOLISM; METABOLITE; METABOLOMICS; MOUSE; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; RNA ISOLATION; ADIPOSE TISSUE; ANIMAL; GENE EXPRESSION PROFILING; GENE SILENCING; GENETICS; GENOME-WIDE ASSOCIATION STUDY; INBRED MOUSE STRAIN; LIVER; PATHOLOGY; RODENT DISEASE; VETERINARY;

MUS;

ADIPOSE TISSUE; ANIMALS; GENE EXPRESSION; GENE EXPRESSION PROFILING; GENE KNOCKDOWN TECHNIQUES; GENOME-WIDE ASSOCIATION STUDY; LIVER; MICE, INBRED STRAINS; NON-ALCOHOLIC FATTY LIVER DISEASE; PHOSPHORIC DIESTER HYDROLASES; RODENT DISEASES; TRIGLYCERIDES;

EID: 84937046632     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.05607     Document Type: Article

References (100)

1. Adams LA, White SW, Marsh JA, Lye SJ, Connor KL, Maganga R, Ayonrinde OT, Olynyk JK, Mori TA, Beilin LJ, Palmer LJ, Hamdorf JM, Pennell CE. 2013. Association between liver-specific gene polymorphisms and their expression levels with nonalcoholic fatty liver disease. Hepatology 57:590-600. doi: 10.1002/hep.26184.
2. Anstee QM, Daly AK, Day CP. 2011. Genetic modifiers of non-alcoholic fatty liver disease progression. Biochimica et Biophysica Acta 1812:1557-1566. doi: 10.1016/j.bbadis.2011.07.017.
3. Bennett BJ, Farber CR, Orozco L, Kang HM, Ghazalpour A, Siemers N, Neubauer M, Neuhaus I, Yordanova R, Guan B, Truong A, Yang WP, He A, Kayne P, Gargalovic P, Kirchgessner T, Pan C, Castellani LW, Kostem E, Furlotte N, Drake TA, Eskin E, Lusis AJ. 2010.A high-resolution association mapping panel for the dissection of complex traits in mice. Genome Research 20:281-290. doi: 10.1101/gr.099234.109.
4. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. 2013. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metabolism 17:49-60. doi: 10.1016/j.cmet.2012.12.011.
5. Bokulich NA, Subramanian S, Faith JJ, Gevers D, Gordon JI, Knight R, Mills DA, Caporaso JG. 2013. Qualityfiltering vastly improves diversity estimates from Illumina amplicon sequencing. Nature Methods 10:57-59. doi: 10.1038/nmeth.2276.
6. Brown MS, Goldstein JL. 2008. Selective versus total insulin resistance: a pathogenic paradox. Cell Metabolism 7: 95-96. doi: 10.1016/j.cmet.2007.12.009.
7. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. 2004. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 40: 1387-1395. doi: 10.1002/hep.20466.
8. Caporaso JG, Kuczynski J, Stombaugh J, Bittinger K, Bushman FD, Costello EK, Fierer N, Peña AG, Goodrich JK, Gordon JI, Huttley GA, Kelley ST, Knights D, Koenig JE, Ley RE, Lozupone CA, McDonald D, Muegge BD, Pirrung M, Reeder J, Sevinsky JR, Turnbaugh PJ, Walters WA, Widmann J, Yatsunenko T, Zaneveld J, Knight R. 2010.QIIME allows analysis of high-throughput community sequencing data. Nature Methods 7:335-336. doi: 10.1038/nmeth.f.303.
9. Caporaso JG, Lauber CL, Walters WA, Berg-Lyons D, Huntley J, Fierer N, Owens SM, Betley J, Fraser L, Bauer M, Gormley N, Gilbert JA, Smith G, Knight R. 2012. Ultra-high-throughput microbial community analysis on the Illumina HiSeq and MiSeq platforms. The ISME Journal 6:1621-1624. doi: 10.1038/ismej.2012.8.
10. Chalasani N, Guo X, Loomba R, Goodarzi MO, Haritunians T, Kwon S, Cui J, Taylor KD, Wilson L, Cummings OW, Chen YD, Rotter JI, Nonalcoholic Steatohepatitis Clinical Research Network. 2010.Genome-wide association study identifies variants associated with histologic features of nonalcoholic Fatty liver disease. Gastroenterology 139:1567-1576. 76 e1-6. doi: 10.1053/j.gastro.2010.07.057.
11. Chambers JC, Zhang W, Sehmi J, Li X, Wass MN, Van der Harst P, Holm H, Sanna S, Kavousi M, Baumeister SE, Coin LJ, Deng G, Gieger C, Heard-Costa NL, Hottenga JJ, Kühnel B, Kumar V, Lagou V, Liang L, Luan J, Vidal PM, Mateo Leach I, O’Reilly PF, Peden JF, Rahmioglu N, Soininen P, Speliotes EK, Yuan X, Thorleifsson G, Alizadeh BZ, Atwood LD, Borecki IB, Brown MJ, Charoen P, Cucca F, Das D, de Geus EJ, Dixon AL, Döring A, Ehret G, Eyjolfsson GI, Farrall M, Forouhi NG, Friedrich N, Goessling W, Gudbjartsson DF, Harris TB, Hartikainen AL, Heath S, Hirschfield GM, Hofman A, Homuth G, Hyppönen E, Janssen HL, Johnson T, Kangas AJ, Kema IP, Kühn JP, Lai S, Lathrop M, Lerch MM, Li Y, Liang TJ, Lin JP, Loos RJ, Martin NG, Moffatt MF, Montgomery GW, Munroe PB, Musunuru K, Nakamura Y, O’Donnell CJ, Olafsson I, Penninx BW, Pouta A, Prins BP, Prokopenko I, Puls R, Ruokonen A, Savolainen MJ, Schlessinger D, Schouten JN, Seedorf U, Sen-Chowdhry S, Siminovitch KA, Smit JH, Spector TD, Tan W, Teslovich TM, Tukiainen T, Uitterlinden AG, Van der Klauw MM, Vasan RS, Wallace C, Wallaschofski H, Wichmann HE, Willemsen G, Würtz P, Xu C, Yerges-Armstrong LM, Alcohol Genome-wide Association (AlcGen) Consortium, Diabetes Genetics Replication and Meta-analyses (DIAGRAM+) Study, Genetic Investigation of Anthropometric Traits (GIANT) Consortium, Global Lipids Genetics Consortium, Genetics of Liver Disease (GOLD) Consortium, International Consortium for Blood Pressure (ICBP-GWAS), Meta-analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), Abecasis GR, Ahmadi KR, Boomsma DI, Caulfield M, Cookson WO, van Duijn CM, Froguel P, Matsuda K, McCarthy MI, Meisinger C, Mooser V, Pietiläinen KH, Schumann G, Snieder H, Sternberg MJ, Stolk RP, Thomas HC, Thorsteinsdottir U, Uda M, Waeber G, Wareham NJ, Waterworth DM, Watkins H, Whitfield JB, Witteman JC, Wolffenbuttel BH, Fox CS, Ala-Korpela M, Stefansson K, Vollenweider P, Völzke H, Schadt EE, Scott J, Järvelin MR, Elliott P, Kooner JS. 2011. Genome-wide association study identifies loci influencing concentrations of liver enzymes in plasma. Nature Genetics 43: 1131-1138. doi: 10.1038/ng.970.
12. Chavin KD, Yang S, Lin HZ, Chatham J, Chacko VP, Hoek JB, Walajtys-Rode E, Rashid A, Chen CH, Huang CC, Wu TC, Lane MD, Diehl AM. 1999. Obesity induces expression of uncoupling protein-2 in hepatocytes and promotes liver ATP depletion. The Journal of Biological Chemistry 274:5692-5700. doi: 10.1074/jbc.274.9.5692.
13. Choi Y, Chan AP. 2015. PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels. Bioinformatics.
14. Civelek M, Lusis AJ. 2014. Systems genetics approaches to understand complex traits. Nature Reviews. Genetics 15:34-48. doi: 10.1038/nrg3575.
15. Clugston RD, Yuen JJ, Hu Y, Abumrad NA, Berk PD, Goldberg IJ, Blaner WS, Huang LS. 2014. CD36-deficient mice are resistant to alcohol-and high-carbohydrate-induced hepatic steatosis. Journal of Lipid Research 55:239-246. doi: 10.1194/jlr.M041863.
16. Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R. 2009. Bacterial community variation in human body habitats across space and time. Science 326:1694-1697. doi: 10.1126/science.1177486.
17. Dankel SN, Fadnes DJ, Stavrum AK, Stansberg C, Holdhus R, Hoang T, Veum VL, Christensen BJ, Våge V, Sagen JV, Steen VM, Mellgren G. 2010.Switch from stress response to homeobox transcription factors in adipose tissue after profound fat loss. PLOS ONE 5:e11033. doi: 10.1371/journal.pone.0011033.
18. Day CP, James OF. 1998. Steatohepatitis: a tale of two "hits"? Gastroenterology 114:842-845. doi: 10.1016/S0016-5085(98)70599-2.
19. Day CP. 2002. Pathogenesis of steatohepatitis. Best Practice & Research. Clinical Gastroenterology 16:663-678. doi: 10.1053/bega.2002.0333.
20. Diehl AM, Goodman Z, Ishak KG. 1988. Alcohollike liver disease in nonalcoholics. A clinical and histologic comparison with alcohol-induced liver injury. Gastroenterology 95:1056-1062.
21. Donnelly KL, Smith CI, 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. The Journal of Clinical Investigation 115:1343-1351. doi: 10.1172/JCI23621.
22. Dorn C, Engelmann JC, Saugspier M, Koch A, Hartmann A, Müller M, Spang R, Bosserhoff A, Hellerbrand C. 2014. Increased expression of c-Jun in nonalcoholic fatty liver disease. Laboratory Investigation 94:394-408. doi: 10.1038/labinvest.2014.3.
23. Dumas ME, Barton RH, Toye A, Cloarec O, Blancher C, Rothwell A, Fearnside J, Tatoud R, Blanc V, Lindon JC, Mitchell SC, Holmes E, McCarthy MI, Scott J, Gauguier D, Nicholson JK. 2006. Metabolic profiling reveals a contribution of gut microbiota to fatty liver phenotype in insulin-resistant mice. Proceedings of the National Academy of Sciences of USA 103:12511-12516. doi: 10.1073/pnas.0601056103.
24. Dumas ME, Kinross J, Nicholson JK. 2014. Metabolic phenotyping and systems biology approaches to understanding metabolic syndrome and fatty liver disease. Gastroenterology 146:46-62. doi: 10.1053/j.gastro.2013.11.001.
25. Eccleston HB, Andringa KK, Betancourt AM, King AL, Mantena SK, Swain TM, Tinsley HN, Nolte RN, Nagy TR, Abrams GA, Bailey SM. 2011. Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice. Antioxidants & Redox Signaling 15:447-459. doi: 10.1089/ars.2010.3395.
26. Farrell GC, Larter CZ. 2006. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology 43:S99-S112. doi: 10.1002/hep.20973.
27. Folch J, Lees M, Sloane Stanley GH. 1957. A simple method for the isolation and purification of total lipides from animal tissues. The Journal of Biological Chemistry 226:497-509.
28. Guerrero R, Vega GL, Grundy SM, Browning JD. 2009. Ethnic differences in hepatic steatosis: an insulin resistance paradox? Hepatology 49:791-801. doi: 10.1002/hep.22726.
29. Gustavsson N, Lao Y, Maximov A, Chuang JC, Kostromina E, Repa JJ, Li C, Radda GK, Südhof TC, Han W. 2008. Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice. Proceedings of the National Academy of Sciences of USA 105:3992-3997. doi: 10.1073/pnas.0711700105.
30. Gustavsson N, Wei SH, Hoang DN, Lao Y, Zhang Q, Radda GK, Rorsman P, Südhof TC, Han W. 2009. Synaptotagmin-7 is a principal Ca2+ sensor for Ca2+-induced glucagon exocytosis in pancreas. The Journal of Physiology 587:1169-1178. doi: 10.1113/jphysiol.2008.168005.
31. Haas JT, Biddinger SB. 2009. Dissecting the role of insulin resistance in the metabolic syndrome. Current Opinion in Lipidology 20:206-210.doi: 10.1097/MOL.0b013e32832b2024.
32. Haas BE, Horvath S, Pietilainen KH, Cantor RM, Nikkola E, Weissglas-Volkov D, Rissanen A, Civelek M, Cruz-Bautista I, Riba L, Kuusisto J, Kaprio J, Tusie-Luna T, Laakso M, Aguilar-Salinas CA, Pajukanta P. 2012. Adipose co-expression networks across Finns and Mexicans identify novel triglyceride-associated genes. BMC Medical Genomics 5:61. doi: 10.1186/1755-8794-5-61.
33. Hamady M, Walker JJ, Harris JK, Gold NJ, Knight R. 2008. Error-correcting barcoded primers for pyrosequencing hundreds of samples in multiplex. Nature Methods 5:235-237. doi: 10.1038/nmeth.1184.
34. Hasenfuss SC, Bakiri L, Thomsen MK, Williams EG, Auwerx J, Wagner EF. 2014. Regulation of steatohepatitis and PPARgamma signaling by distinct AP-1 dimers. Cell Metabolism 19:84-95. doi: 10.1016/j.cmet.2013.11.018.
35. Hill-Baskin AE, Markiewski MM, Buchner DA, Shao H, DeSantis D, Hsiao G, Subramaniam S, Berger NA, Croniger C, Lambris JD, Nadeau JH. 2009. Diet-induced hepatocellular carcinoma in genetically predisposed mice. Human Molecular Genetics 18:2975-2988. doi: 10.1093/hmg/ddp236.
36. Hindorff LA, Sethupathy P, Junkins HA, Ramos EM, Mehta JP, Collins FS, Manolio TA. 2009. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proceedings of the National Academy of Sciences of USA 106:9362-9367. doi: 10.1073/pnas.0903103106.
37. Huang da W, Sherman BT, Lempicki RA. 2009. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4:44-57. doi: 10.1038/nprot.2008.211.
38. Huang da W, Sherman BT, Lempicki RA. 2009. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Research 37:1-13. doi: 10.1093/nar/gkn923.
39. Huang W, Bansode R, Mehta M, Mehta KD. 2009. Loss of protein kinase Cbeta function protects mice against dietinduced obesity and development of hepatic steatosis and insulin resistance. Hepatology 49:1525-1536. doi: 10.1002/hep.22815.
40. Huang W, Bansode RR, Bal NC, Mehta M, Mehta KD. 2012. Protein kinase Cbeta deficiency attenuates obesity syndrome of ob/ob mice by promoting white adipose tissue remodeling. Journal of Lipid Research 53:368-378. doi: 10.1194/jlr.M019687.
41. Ito S, Tsukada K. 2002. Matrix effect and correction by standard addition in quantitative liquid chromatographicmass spectrometric analysis of diarrhetic shellfish poisoning toxins. Journal of Chromatography A 943:39-46. doi: 10.1016/S0021-9673(01)01429-7.
42. Kahle M, Horsch M, Fridrich B, Seelig A, Schultheiß J, Leonhardt J, Irmler M, Beckers J, Rathkolb B, Wolf E, Franke N, Gailus-Durner V, Fuchs H, de Angelis MH, Neschen S. 2013. Phenotypic comparison of common mouse strains developing high-fat diet-induced hepatosteatosis. Molecular Metabolism 2:435-446. doi: 10.1016/j.molmet.2013.07.009.
43. Kopec KL, Burns D. 2011. Nonalcoholic fatty liver disease: a review of the spectrum of disease, diagnosis, and therapy. Nutrition in Clinical Practice 26:565-576. doi: 10.1177/0884533611419668.
44. Kozlitina J, Smagris E, Stender S, Nordestgaard BG, Zhou HH, Zhou HH, Tybjærg-Hansen A, Vogt TF, Hobbs HH, Cohen JC. 2014. Exome-wide association study identifies a TM6SF2 variant that confers susceptibility to nonalcoholic fatty liver disease. Nature Genetics 46:352-356. doi: 10.1038/ng.2901.
45. Kuczynski J, Stombaugh J, Walters WA, Gonzalez A, Caporaso JG, Knight R. 2011. Using QIIME to analyze 16S rRNA gene sequences from microbial communities. Current Protocols in Bioinformatics. Chapter 10Unit 10 7. doi: 10.1002/0471250953.bi1007s36.
46. Kumazawa M, Kobayashi M, Io F, Kawai T, Nishimura M, Ohno T, Horio F. 2007. Searching for genetic factors of fatty liver in SMXA-5 mice by quantitative trait loci analysis under a high-fat diet. Journal of Lipid Research 48: 2039-2046. doi: 10.1194/jlr.M700222-JLR200.
47. Lam YY, Ha CW, Campbell CR, Mitchell AJ, Dinudom A, Oscarsson J, Cook DI, Hunt NH, Caterson ID, Holmes AJ, Storlien LH. 2012. Increased gut permeability and microbiota change associate with mesenteric fat inflammation and metabolic dysfunction in diet-induced obese mice. PLOS ONE 7:e34233. doi: 10.1371/journal.pone.0034233.
48. Lazo M, Clark JM. 2008. The epidemiology of nonalcoholic fatty liver disease: a global perspective. Seminars in Liver Disease 28:339-350. doi: 10.1055/s-0028-1091978.
49. Leavens KF, Birnbaum MJ. 2011. Insulin signaling to hepatic lipid metabolism in health and disease. Critical Reviews in Biochemistry and Molecular Biology 46:200-215. doi: 10.3109/10409238.2011.562481.
50. Lee YH, Petkova AP, Mottillo EP, Granneman JG. 2012. In vivo identification of bipotential adipocyte progenitors recruited by beta3-adrenoceptor activation and high-fat feeding. Cell Metabolism 15:480-491. doi: 10.1016/j.cmet.2012.03.009.
51. Lepage P, Hasler R, Spehlmann ME, Rehman A, Zvirbliene A, Begun A, Ott S, Kupcinskas L, Dore´ J, Raedler A, Schreiber S. 2011. Twin study indicates loss of interaction between microbiota and mucosa of patients with ulcerative colitis. Gastroenterology 141:227-236. doi: 10.1053/j.gastro.2011.04.011.
52. Ley RE, Turnbaugh PJ, Klein S, Gordon JI. 2006. Microbial ecology: human gut microbes associated with obesity. Nature 444:1022-1023. doi: 10.1038/4441022a.
53. Li S, Brown MS, Goldstein JL. 2010.Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proceedings of the National Academy of Sciences of USA 107:3441-3446. doi: 10.1073/pnas.0914798107.
54. Listgarten J, Lippert C, Kadie CM, Davidson RI, Eskin E, Heckerman D. 2012. Improved linear mixed models for genome-wide association studies. Nature Methods 9:525-526. doi: 10.1038/nmeth.2037.
55. Mantena SK, Vaughn DP, Andringa KK, Eccleston HB, King AL, Abrams GA, Doeller JE, Kraus DW, Darley-Usmar VM, Bailey SM. 2009. High fat diet induces dysregulation of hepatic oxygen gradients and mitochondrial function in vivo. The Biochemical Journal 417:183-193. doi: 10.1042/BJ20080868.
56. Marc Rhoads J, Wu G. 2009. Glutamine, arginine, and leucine signaling in the intestine. Amino Acids 37:111-122. doi: 10.1007/s00726-008-0225-4.
57. Marchesini G, Brizi M, Morselli-Labate AM, Bianchi G, Bugianesi E, McCullough AJ, Forlani G, Melchionda N. 1999. Association of nonalcoholic fatty liver disease with insulin resistance. The American Journal of Medicine 107: 450-455. doi: 10.1016/S0002-9343(99)00271-5.
58. Marchesini G, Bugianesi E, Forlani G, Cerrelli F, Lenzi M, Manini R, Natale S, Vanni E, Villanova N, Melchionda N, Rizzetto M. 2003. Nonalcoholic fatty liver, steatohepatitis, and the metabolic syndrome. Hepatology 37:917-923. doi: 10.1053/jhep.2003.50161.
59. Mato JM, Martinez-Chantar ML, Lu SC. 2014. Systems biology for hepatologists. Hepatology 60:736-743. doi: 10.1002/hep.27023.
60. Mills AL, Wassel RA. 1980. Aspects of diversity measurement for microbial communities. Applied and Environmental Microbiology 40:578-586.
61. Millward CA, Burrage LC, Shao H, Sinasac DS, Kawasoe JH, Hill-Baskin AE, Ernest SR, Gornicka A, Hsieh CW, Pisano S, Nadeau JH, Croniger CM. 2009. Genetic factors for resistance to diet-induced obesity and associated metabolic traits on mouse chromosome 17. Mammalian Genome 20:71-82. doi: 10.1007/s00335-008-9165-2.
62. Milner JA, Hassan AS. 1981. Species specificity of arginine deficiency-induced hepatic steatosis. The Journal of Nutrition 111:1067-1073.
63. Minkina O, Cheverud JM, Fawcett G, Semenkovich CF, Kenney-Hunt JP. 2012. Quantitative trait loci affecting liver fat content in mice. G3 2:1019-1025. doi: 10.1534/g3.112.003343.
64. Moghadam PK, Jackson MB. 2013. The functional significance of synaptotagmin diversity in neuroendocrine secretion. Frontiers in Endocrinology 4:124. doi: 10.3389/fendo.2013.00124.
65. Montgomery MK, Hallahan NL, Brown SH, Liu M, Mitchell TW, Cooney GJ, Turner N. 2013. Mouse straindependent variation in obesity and glucose homeostasis in response to high-fat feeding. Diabetologia 56: 1129-1139. doi: 10.1007/s00125-013-2846-8.
66. Mouzaki M, Comelli EM, Arendt BM, Bonengel J, Fung SK, Fischer SE, McGilvray ID, Allard JP. 2013. Intestinal microbiota in patients with nonalcoholic fatty liver disease. Hepatology 58:120-127. doi: 10.1002/hep.26319.
67. Nair S, Lee YH, Rousseau E, Cam M, Tataranni PA, Baier LJ, Bogardus C, Permana PA. 2005. Increased expression of inflammation-related genes in cultured preadipocytes/stromal vascular cells from obese compared with nonobese Pima Indians. Diabetologia 48:1784-1788. doi: 10.1007/s00125-005-1868-2.
68. Okazaki Y, Ohshima N, Yoshizawa I, Kamei Y, Mariggio S, Okamoto K, Maeda M, Nogusa Y, Fujioka Y, Izumi T, Ogawa Y, Shiro Y, Wada M, Kato N, Corda D, Yanaka N. 2010.A novel glycerophosphodiester phosphodiesterase, GDE5, controls skeletal muscle development via a non-enzymatic mechanism. The Journal of Biological Chemistry 285:27652-27663. doi: 10.1074/jbc.M110.106708.
69. Onn I, Aono N, Hirano M, Hirano T. 2007. Reconstitution and subunit geometry of human condensin complexes. The EMBO Journal 26:1024-1034. doi: 10.1038/sj.emboj.7601562.
70. Orozco LD, Bennett BJ, Farber CR, Ghazalpour A, Pan C, Che N, Wen P, Qi HX, Mutukulu A, Siemers N, Neuhaus I, Yordanova R, Gargalovic P, Pellegrini M, Kirchgessner T, Lusis AJ. 2012. Unraveling inflammatory responses using systems genetics and gene-environment interactions in macrophages. Cell 151:658-670. doi: 10.1016/j.cell.2012.08.043.
71. Parks BW, Nam E, Org E, Kostem E, Norheim F, Hui ST, Pan C, Civelek M, Rau CD, Bennett BJ, Mehrabian M, Ursell LK, He A, Castellani LW, Zinker B, Kirby M, Drake TA, Drevon CA, Knight R, Gargalovic P, Kirchgessner T, Eskin E, Lusis AJ. 2013. Genetic control of obesity and gut microbiota composition in response to high-fat, highsucrose diet in mice. Cell Metabolism 17:141-152. doi: 10.1016/j.cmet.2012.12.007.
72. Parks BW, Sallam T, Mehrabian M, Psychogios N, Hui ST, Norheim F, Castellani LW, Rau CD, Pan C, Phun J, Zhou Z, Yang WP, Neuhaus I, Gargalovic PS, Kirchgessner TG, Graham M, Lee R, Tontonoz P, Gerszten RE, Hevener AL, Lusis AJ. 2015. Genetic architecture of insulin resistance in the mouse. Cell Metabolism 21:334-346. doi: 10.1016/j.cmet.2015.01.002.
73. Plourde M, Vohl MC, Bellis C, Carless M, Dyer T, Dolley G, Marette A, Despre´ s JP, Bouchard C, Blangero J, Pe´ russe L. 2013. A variant in the LRRFIP1 gene is associated with adiposity and inflammation. Obesity 21: 185-192. doi: 10.1002/oby.20242.
74. Qin J, Li Y, Cai Z, Li S, Zhu J, Zhang F, Liang S, Zhang W, Guan Y, Shen D, Peng Y, Zhang D, Jie Z, Wu W, Qin Y, Xue W, Li J, Han L, Lu D, Wu P, Dai Y, Sun X, Li Z, Tang A, Zhong S, Li X, Chen W, Xu R, Wang M, Feng Q, Gong M, Yu J, Zhang Y, Zhang M, Hansen T, Sanchez G, Raes J, Falony G, Okuda S, Almeida M, LeChatelier E, Renault P, Pons N, Batto JM, Zhang Z, Chen H, Yang R, Zheng W, Li S, Yang H, Wang J, Ehrlich SD, Nielsen R, Pedersen O, Kristiansen K, Wang J. 2012. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490:55-60. doi: 10.1038/nature11450.
75. Rangnekar AS, Lammert F, Igolnikov A, Green RM. 2006. Quantitative trait loci analysis of mice administered the methionine-choline deficient dietary model of experimental steatohepatitis. Liver International 26:1000-1005. doi: 10.1111/j.1478-3231.2006.01314.x.
76. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. 2010.A position statement on NAFLD/NASH based on the EASL 2009 special conference. Journal of Hepatology 53:372-384. doi: 10.1016/j.jhep.2010.04.008.
77. Roberts LD, Souza AL, Gerszten RE, Clish CB. 2012. Targeted metabolomics. Current Protocols in Molecular Biology 1-24. Chapter 30Unit 30 2. doi: 10.1002/0471142727.mb3002s98.
78. 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. Nature Genetics 40: 1461-1465. doi: 10.1038/ng.257.
79. Schreuder TC, Verwer BJ, van Nieuwkerk CM, Mulder CJ. 2008. Nonalcoholic fatty liver disease: an overview of current insights in pathogenesis, diagnosis and treatment. World Journal of Gastroenterology 14:2474-2486. doi: 10.3748/wjg.14.2474.
80. Schwimmer JB, Celedon MA, Lavine JE, Salem R, Campbell N, Schork NJ, Shiehmorteza M, Yokoo T, Chavez A, Middleton MS, Sirlin CB. 2009. Heritability of nonalcoholic fatty liver disease. Gastroenterology 136:1585-1592. doi: 10.1053/j.gastro.2009.01.050.
81. Shockley KR, Witmer D, Burgess-Herbert SL, Paigen B, Churchill GA. 2009. Effects of atherogenic diet on hepatic gene expression across mouse strains. Physiological Genomics 39:172-182. doi: 10.1152/physiolgenomics.90350.2008.
82. Simon GM, Cravatt BF. 2010.Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence for multiple pathways that contribute to endocannabinoid production in vivo. Molecular Biosystems 6:1411-1418. doi: 10.1039/c000237b.
83. Speliotes EK, Yerges-Armstrong LM, Wu J, Hernaez R, Kim LJ, Palmer CD, Gudnason V, Eiriksdottir G, Garcia ME, Launer LJ, Nalls MA, Clark JM, Mitchell BD, Shuldiner AR, Butler JL, Tomas M, Hoffmann U, Hwang SJ, Massaro JM, O’Donnell CJ, Sahani DV, Salomaa V, Schadt EE, Schwartz SM, Siscovick DS, NASH CRN, GIANT Consortium, MAGIC Investigators, Voight BF, Carr JJ, Feitosa MF, Harris TB, Fox CS, Smith AV, Kao WH, Hirschhorn JN, Borecki IB, GOLD Consortium. 2011. Genome-wide association analysis identifies variants associated with nonalcoholic fatty liver disease that have distinct effects on metabolic traits. PLOS Genetics 7: e1001324. doi: 10.1371/journal.pgen.1001324.
84. Storey JD, Tibshirani R. 2003. Statistical significance for genomewide studies. Proceedings of the National Academy of Sciences of USA 100:9440-9445. doi: 10.1073/pnas.1530509100.
85. Struben VM, Hespenheide EE, Caldwell SH. 2000. Nonalcoholic steatohepatitis and cryptogenic cirrhosis within kindreds. The American Journal of Medicine 108:9-13. doi: 10.1016/S0002-9343(99)00315-0.
86. Teli MR, James OF, Burt AD, Bennett MK, Day CP. 1995. The natural history of nonalcoholic fatty liver: a follow-up study. Hepatology 22:1714-1719. doi: 10.1002/hep.1840220616.
87. Tilg H, Moschen AR. 2010.Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology 52:1836-1846. doi: 10.1002/hep.24001.
88. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. 2009. A core gut microbiome in obese and lean twins. Nature 457:480-484. doi: 10.1038/nature07540.
89. Vernon G, Baranova A, Younossi ZM. 2011. Systematic review: the epidemiology and natural history of nonalcoholic fatty liver disease and non-alcoholic steatohepatitis in adults. Alimentary Pharmacology & Therapeutics 34:274-285. doi: 10.1111/j.1365-2036.2011.04724.x.
90. Walker AW, Ince J, Duncan SH, Webster LM, Holtrop G, Ze X, Brown D, Stares MD, Scott P, Bergerat A, Louis P, McIntosh F, Johnstone AM, Lobley GE, Parkhill J, Flint HJ. 2011. Dominant and diet-responsive groups of bacteria within the human colonic microbiota. The ISME Journal 5:220-230. doi: 10.1038/ismej.2010.118.
91. Wang WY, Barratt BJ, Clayton DG, Todd JA. 2005. Genome-wide association studies: theoretical and practical concerns. Nature Reviews. Genetics 6:109-118. doi: 10.1038/nrg1522.
92. Wang Q, Garrity GM, Tiedje JM, Cole JR. 2007. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Applied and Environmental Microbiology 73:5261-5267. doi: 10.1128/AEM.00062-07.
93. Wang TJ, Larson MG, Vasan RS, Cheng S, Rhee EP, McCabe E, Lewis GD, Fox CS, Jacques PF, Fernandez C, O’Donnell CJ, Carr SA, Mootha VK, Florez JC, Souza A, Melander O, Clish CB, Gerszten RE. 2011. Metabolite profiles and the risk of developing diabetes. Nature Medicine 17:448-453. doi: 10.1038/nm.2307.
94. Willner IR, Waters B, Patil SR, Reuben A, Morelli J, Riely CA. 2001. Ninety patients with nonalcoholic steatohepatitis: insulin resistance, familial tendency, and severity of disease. The American Journal of Gastroenterology 96:2957-2961. doi: 10.1111/j.1572-0241.2001.04667.x.
95. Wu G, Bazer FW, Davis TA, Kim SW, Li P, Marc Rhoads J, Carey Satterfield M, Smith SB, Spencer TE, Yin Y. 2009. Arginine metabolism and nutrition in growth, health and disease. Amino Acids 37:153-168. doi: 10.1007/s00726-008-0210-y.
96. 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. doi: 10.1002/hep.21655.
97. Yang H, Ding Y, Hutchins LN, Szatkiewicz J, Bell TA, Paigen BJ, Graber JH, de Villena FP, Churchill GA. 2009. A customized and versatile high-density genotyping array for the mouse. Nature Methods 6:663-666. doi: 10.1038/nmeth.1359.
98. Yue F, Cheng Y, Breschi A, Vierstra J, Wu W, Ryba T, Sandstrom R, Ma Z, Davis C, Pope BD, Shen Y, Pervouchine DD, Djebali S, Thurman RE, Kaul R, Rynes E, Kirilusha A, Marinov GK, Williams BA, Trout D, Amrhein H, Fisher-Aylor K, Antoshechkin I, DeSalvo G, See LH, Fastuca M, Drenkow J, Zaleski C, Dobin A, Prieto P, Lagarde J, Bussotti G, Tanzer A, Denas O, Li K, Bender MA, Zhang M, Byron R, Groudine MT, McCleary D, Pham L, Ye Z, Kuan S, Edsall L, Wu YC, Rasmussen MD, Bansal MS, Kellis M, Keller CA, Morrissey CS, Mishra T, Jain D, Dogan N, Harris RS, Cayting P, Kawli T, Boyle AP, Euskirchen G, Kundaje A, Lin S, Lin Y, Jansen C, Malladi VS, Cline MS, Erickson DT, Kirkup VM, Learned K, Sloan CA, Rosenbloom KR, Lacerda de Sousa B, Beal K, Pignatelli M, Flicek P, Lian J, Kahveci T, Lee D, Kent WJ, Ramalho Santos M, Herrero J, Notredame C, Johnson A, Vong S, Lee K, Bates D, Neri F, Diegel M, Canfield T, Sabo PJ, Wilken MS, Reh TA, Giste E, Shafer A, Kutyavin T, Haugen E, Dunn D, Reynolds AP, Neph S, Humbert R, Hansen RS, De Bruijn M, Selleri L, Rudensky A, Josefowicz S, Samstein R, Eichler EE, Orkin SH, Levasseur D, Papayannopoulou T, Chang KH, Skoultchi A, Gosh S, Disteche C, Treuting P, Wang Y, Weiss MJ, Blobel GA, Cao X, Zhong S, Wang T, Good PJ, Lowdon RF, Adams LB, Zhou XQ, Pazin MJ, Feingold EA, Wold B, Taylor J, Mortazavi A, Weissman SM, Stamatoyannopoulos JA, Snyder MP, Guigo R, Gingeras TR, Gilbert DM, Hardison RC, Beer MA, Ren B, Mouse ENCODE Consortium. 2014. A comparative encyclopedia of DNA elements in the mouse genome. Nature 515:355-364. doi: 10.1038/nature13992.
99. Zheng B, Chen D, Farquhar MG. 2000. MIR16, a putative membrane glycerophosphodiester phosphodiesterase, interacts with RGS16. Proceedings of the National Academy of Sciences of USA 97:3999-4004. doi: 10.1073/pnas.97.8.3999.
100. Zhu L, Baker SS, Gill C, Liu W, Alkhouri R, Baker RD, Gill SR. 2013. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology 57:601-609. doi: 10.1002/hep.26093.