Hepatic gene expression in morbidly obese women: implications for disease susceptibility.
The objective of this study was to determine the molecular bases of disordered hepatic function and disease susceptibility in obesity. We compared global gene expression in liver biopsies from morbidly obese (MO) women undergoing gastric bypass (GBP) surgery with that of women undergoing ventral hernia repair who had experienced massive weight loss (MWL) following prior GBP. Metabolic and hormonal profiles were examined in MO vs. MWL groups. Additionally, we analyzed individual profiles of hepatic gene expression in liver biopsy specimens obtained from MO and MWL subjects. All patients underwent preoperative metabolic profiling. RNAs were extracted from wedge biopsies of livers from MO and MWL subjects, and analysis of mRNA expression was carried out using Affymetrix HG-U133A microarray gene chips. Genes exhibiting greater than twofold differential expression between MO and MWL subjects were organized according to gene ontology and hierarchical clustering, and expression of key genes exhibiting differential regulation was quantified by real-time-polymerase chain reaction (RT-PCR). We discovered 154 genes to be differentially expressed in livers of MWL and MO subjects. A total of 28 candidate disease susceptibility genes were identified that encoded proteins regulating lipid and energy homeostasis (PLIN, ENO3, ELOVL2, APOF, LEPR, IGFBP1, DDIT4), signal transduction (MAP2K6, SOCS-2), postinflammatory tissue repair (HLA-DQB1, SPP1, P4HA1, LUM), bile acid transport (SULT2A, ABCB11), and metabolism of xenobiotics (GSTT2, CYP1A1). Using gene expression profiling, we have identified novel candidate disease susceptibility genes whose expression is altered in livers of MO subjects. The significance of altered expression of these genes to obesity-related disease is discussed.
Elam
Marshall B
MB
Department of Medicine and Research Service, Veterans Affairs Medical Center, Memphis, Tennessee, USA. melam@utmem.edu
Cowan
George S
GS
Rooney
Robert J
RJ
Hiler
M Lloyd
ML
Yellaturu
Chandrahasa R
CR
Deng
Xiong
X
Howell
George E
GE
Park
Edwards A
EA
Gerling
Ivan C
IC
Patel
Divyan
D
Corton
J Christopher
JC
Cagen
Lauren M
LM
Wilcox
Henry G
HG
Gandhi
Malay
M
Bahr
Micheal H
MH
Allan
Micheal C
MC
Wodi
Linus A
LA
Cook
George A
GA
Hughes
Thomas A
TA
Raghow
Rajendra
R
D000328:Adult; D001706:Biopsy; D049109:Cell Proliferation; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D009767:Obesity, Morbid / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D012313:RNA