title: Hepatic gene networks in morbidly obese patients with nonalcoholic fatty liver disease.
abstract: BACKGROUND
  Genetic factors alter the risk for nonalcoholic fatty liver disease (NAFLD). We sought to identify NAFLD-associated genes and elucidate gene networks and pathways involved in the pathogenesis of NAFLD.
  
  
  METHODS
  Quantitative global hepatic gene expression analysis was performed on 53 morbidly obese Caucasian subjects undergoing bariatric surgery (27 with NAFLD and 26 controls). After standardization of data, gene expression profiles were compared between patients with NAFLD and controls. The set of genes that significantly correlated with NAFLD was further analyzed by hierarchical clustering and ingenuity pathways analyses.
  
  
  RESULTS
  There were 25,643 quantitative transcripts, of which 108 were significantly associated with NAFLD (p < 0.001). Canonical pathway analysis in the NAFLD-associated gene clusters showed that the hepatic fibrosis signaling was the most significant pathway in the up-regulated NAFLD gene cluster containing three (COL1A1, IL10, IGFBP3) significantly altered genes, whereas the endoplasmic reticulum stress and protein ubiquitination pathways were the most significant pathways in the down-regulated NAFLD gene cluster, with the first pathway containing one (HSPA5) and the second containing two (HSPA5, USP25) significantly altered genes. The four primary gene networks associated with NAFLD were involved in cell death, immunological disease, cellular movement, and lipid metabolism with several significantly altered "hub" genes in these networks.
  
  
  CONCLUSIONS
  This study reveals the canonical pathways and gene networks associated with NAFLD in morbidly obese Caucasians. The application of gene network analysis highlights the transcriptional relationships among NAFLD-associated genes and allows identification of hub genes that may represent high-priority candidates for NAFLD.
authors.affiliation: Department of Medicine, Division of Gastroenterology and Hepatology, Medical College of Wisconsin, Milwaukee, WI 53212, USA. sgawrieh@mcw.edu
authors.forename: Samer
authors.initials: S
authors.lastname: Gawrieh
authors.forename: Tesfaye M
authors.initials: TM
authors.lastname: Baye
authors.forename: Melanie
authors.initials: M
authors.lastname: Carless
authors.forename: James
authors.initials: J
authors.lastname: Wallace
authors.forename: Richard
authors.initials: R
authors.lastname: Komorowski
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.forename: Deborah
authors.initials: D
authors.lastname: Andris
authors.forename: Bassem
authors.initials: B
authors.lastname: Makladi
authors.forename: Regina
authors.initials: R
authors.lastname: Cole
authors.forename: Michael
authors.initials: M
authors.lastname: Charlton
authors.forename: Joanne
authors.initials: J
authors.lastname: Curran
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Dyer
authors.forename: Jac
authors.initials: J
authors.lastname: Charlesworth
authors.forename: Russell
authors.initials: R
authors.lastname: Wilke
authors.forename: John
authors.initials: J
authors.lastname: Blangero
authors.forename: Ahmed H
authors.initials: AH
authors.lastname: Kissebah
authors.forename: Michael
authors.initials: M
authors.lastname: Olivier
mesh_terms: D000328:Adult; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D000091342:Endoplasmic Reticulum Chaperone BiP; D005234:Fatty Liver / Q000453:epidemiology / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000453:epidemiology / Q000235:genetics*; D044465:White People
references.citation: Biochem J. 2000 May 15;348 Pt 1:189-99
references.pmid: 10794731
references.citation: Endocrinology. 2006 Oct;147(10):4553-8
references.pmid: 16709607
references.citation: Hepatology. 2004 Dec;40(6):1387-95
references.pmid: 15565570
references.citation: Am J Physiol Endocrinol Metab. 2009 Apr;296(4):E654-63
references.pmid: 19141684
references.citation: Biomaterials. 2009 Feb;30(6):1113-20
references.pmid: 19046762
references.citation: Mol Genet Metab. 2009 Sep-Oct;98(1-2):203-14
references.pmid: 19546021
references.citation: Obesity (Silver Spring). 2009 Aug;17(8):1563-73
references.pmid: 19265796
references.citation: Gastroenterology. 2003 Aug;125(2):437-43
references.pmid: 12891546
references.citation: J Biol Chem. 2002 Feb 15;277(7):5229-35
references.pmid: 11836260
references.citation: Gastroenterology. 2008 Feb;134(2):568-76
references.pmid: 18082745
references.citation: Nat Rev Drug Discov. 2008 Jun;7(6):489-503
references.pmid: 18511927
references.citation: Cell Metab. 2005 Feb;1(2):107-19
references.pmid: 16054052
references.citation: Hepatology. 2005 Sep;42(3):665-74
references.pmid: 16116632
references.citation: Burns. 2007 Aug;33(5):634-41
references.pmid: 17374457
references.citation: Nature. 2008 Jul 24;454(7203):455-62
references.pmid: 18650916
references.citation: Genes Cells. 2009 Nov;14(11):1209-25
references.pmid: 19849719
references.citation: Semin Liver Dis. 2008 Nov;28(4):339-50
references.pmid: 18956290
references.citation: Am J Med. 2000 Jan;108(1):9-13
references.pmid: 11059435
references.citation: J Gastroenterol Hepatol. 1998 Sep;13(S1):S106-S112
references.pmid: 28976687
references.citation: Nature. 2009 Mar 26;458(7237):453-60
references.pmid: 19325625
references.citation: BMC Genomics. 2009 Aug 27;10:405
references.pmid: 19712483
references.citation: Hepatology. 2005 Jun;41(6):1313-21
references.pmid: 15915461
references.citation: Gastroenterology. 2002 Nov;123(5):1705-25
references.pmid: 12404245
references.citation: Am J Gastroenterol. 2001 Oct;96(10):2957-61
references.pmid: 11693332
references.citation: Genomics. 1999 Dec 15;62(3):395-405
references.pmid: 10644437
references.citation: Hepatology. 2005 Oct;42(4):880-5
references.pmid: 16175608
references.citation: Mol Cell Biochem. 2009 May;325(1-2):69-77
references.pmid: 19184368
references.citation: J Biol Chem. 1993 Jul 15;268(20):14964-71
references.pmid: 7686909
references.citation: Pharmacogenomics J. 2010 Apr;10(2):94-104
references.pmid: 19918261
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 May;294(5):G1281-7
references.pmid: 18388185
references.citation: J Cell Biochem. 2004 Oct 15;93(3):598-608
references.pmid: 15378600
references.citation: Nucleic Acids Res. 2007;35(12):3879-92
references.pmid: 17537817
references.citation: J Clin Invest. 2004 Jul;114(2):147-52
references.pmid: 15254578
references.citation: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17402-7
references.pmid: 17090670
references.citation: Hepatol Res. 2008 Dec;38(12):1204-12
references.pmid: 18637145
references.citation: Biochem J. 2009 Sep 14;423(1):53-9
references.pmid: 19589127
references.citation: Lab Invest. 2006 Feb;86(2):154-65
references.pmid: 16344856
references.citation: Nucleic Acids Symp Ser (Oxf). 2005;(49):295-6
references.pmid: 17150750
references.citation: Biochem Biophys Res Commun. 2002 Sep 13;297(1):105-10
references.pmid: 12220515
references.citation: Hepatology. 2003 Jul;38(1):244-51
references.pmid: 12830008
references.citation: Gastroenterology. 1999 Jun;116(6):1413-9
references.pmid: 10348825
references.citation: Gastroenterology. 2009 May;136(5):1585-92
references.pmid: 19208353
references.citation: Gastroenterology. 2008 Jul;135(1):282-291.e1
references.pmid: 18515091
references.citation: Genome Biol. 2001;2(10):RESEARCH0043
references.pmid: 11597335
references.citation: FEBS Lett. 2007 Jul 31;581(19):3641-51
references.pmid: 17481612
references.citation: Curr Opin Cell Biol. 2009 Feb;21(1):59-67
references.pmid: 19179063
references.citation: J Neurobiol. 2004 Feb 5;58(2):189-200
references.pmid: 14704951
references.citation: J Biol Chem. 2006 Apr 28;281(17):12093-101
references.pmid: 16505490
references.citation: Am J Gastroenterol. 2004 Feb;99(2):292-8
references.pmid: 15046220
references.citation: Pediatrics. 2006 Oct;118(4):1388-93
references.pmid: 17015527
references.citation: Cell Microbiol. 2008 Jul;10(7):1468-77
references.pmid: 18331592
references.citation: Proc Natl Acad Sci U S A. 1998 Dec 8;95(25):14863-8
references.pmid: 9843981
references.citation: J Cell Biochem. 2005 Sep 1;96(1):145-54
references.pmid: 15880694
references.citation: Hepatology. 2004 Aug;40(2):434-41
references.pmid: 15368448
references.citation: J Biol Chem. 2000 Jan 28;275(4):2247-50
references.pmid: 10644669
references.citation: Nat Genet. 2008 Dec;40(12):1461-5
references.pmid: 18820647
references.citation: Gastroenterology. 2001 Jul;121(1):91-100
references.pmid: 11438497
references.citation: Proc Natl Acad Sci U S A. 2006 May 2;103(18):6970-5
references.pmid: 16641093
references.citation: Semin Liver Dis. 2004 Feb;24(1):3-20
references.pmid: 15085483
references.citation: Clin Gastroenterol Hepatol. 2004 Dec;2(12):1048-58
references.pmid: 15625647
references.citation: Nat Genet. 2007 Oct;39(10):1208-16
references.pmid: 17873875
references.citation: Am J Physiol Endocrinol Metab. 2002 Nov;283(5):E937-45
references.pmid: 12376320
references.citation: J Biol Chem. 2009 Feb 20;284(8):5289-98
references.pmid: 19103594
references.citation: Am J Gastroenterol. 2003 May;98(5):960-7
references.pmid: 12809815
references.citation: FEBS Lett. 2004 Aug 13;572(1-3):85-91
references.pmid: 15304329
references.citation: J Biol Chem. 1997 May 2;272(18):12181-8
references.pmid: 9115291
references.citation: Mol Cell Biochem. 2007 Sep;303(1-2):105-13
references.pmid: 17426927
references.citation: J Clin Endocrinol Metab. 2005 Dec;90(12):6588-95
references.pmid: 16189260
references.citation: Hepatology. 2006 Oct;44(4):865-73
references.pmid: 17006923
references.citation: J Clin Invest. 2009 May;119(5):1201-15
references.pmid: 19363290
references.citation: BMC Cell Biol. 2009 Apr 28;10:31
references.pmid: 19400951
references.citation: J Biol Chem. 1998 Jun 19;273(25):15611-20
references.pmid: 9624153
references.citation: BMC Genomics. 2006 Mar 03;7:40
references.pmid: 16515682
references.citation: BMC Gastroenterol. 2008 Jun 27;8:27
references.pmid: 18588668
references.citation: Hepatology. 2004 Sep;40(3):545-54
references.pmid: 15349892
references.citation: J Clin Invest. 2008 Jul;118(7):2640-50
references.pmid: 18551191
references.citation: Exp Mol Pathol. 2006 Dec;81(3):202-10
references.pmid: 16949573
references.citation: J Hepatol. 2002 Jul;37(1):56-62
references.pmid: 12076862