Identification of a gene-pathway associated with non-alcoholic steatohepatitis.
OBJECTIVE
We have integrated gene expression profiling of liver biopsies of NASH patients with liver samples of a mouse model of steatohepatitis (MAT1A-KO) to identify a gene-pathway associated with NASH.


METHODS
Affymetrix U133 Plus 2.0 microarrays were used to evaluate nine patients with NASH, six patients with steatosis, and six control subjects; Affymetrix MOE430A microarrays were used to evaluate wild-type and MAT1A-KO mice at 15 days, 1, 3, 5 and 8 months after birth. Transcriptional profiles of patients with NASH and MAT1A-KO mice were compared with those of their proficient controls.


RESULTS
We identified a gene-pathway associated with NASH, that accurately distinguishes between patients with early-stage NASH and controls. Patients with steatosis have a gene expression pattern intermediate between that of NASH and controls. Promoter analysis revealed that 34 of the genes associated with NASH contained an Sp1 element. We found that Sp1 binding to these genes is increased in MAT1A-KO mice. Sp1 is also hyperphosphorylated in MAT1A-KO as well as in patients with NASH and steatosis.


CONCLUSIONS
A gene-pathway associated with NASH has been identified. We speculate that hyperphosphorylation of Sp1 may be involved in the genesis of steatosis and that other factors, such as oxidative stress, may trigger its progression to NASH.
Rubio
Angel
A
TECNUN, Universidad de Navarra, San Sebastián, Gipuzkoa, Spain.
Guruceaga
Elizabeth
E
Vázquez-Chantada
Mercedes
M
Sandoval
Juan
J
Martínez-Cruz
L Alfonso
LA
Segura
Victor
V
Sevilla
José L
JL
Podhorski
Adam
A
Corrales
Fernando J
FJ
Torres
Luis
L
Rodríguez
Manuel
M
Aillet
Fabienne
F
Ariz
Usue
U
Arrieta
Felix Martínez
FM
Caballería
Juan
J
Martín-Duce
Antonio
A
Lu
Shelly C
SC
Martínez-Chantar
M Luz
ML
Mato
José M
JM
D000328:Adult; D000818:Animals; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D008716:Methionine Adenosyltransferase / Q000172:deficiency; D051379:Mice; D018345:Mice, Knockout; D046228:Microarray Analysis; D008875:Middle Aged; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D016329:Sp1 Transcription Factor / Q000378:metabolism
D016329:Sp1 Transcription Factor; C490703:Mat1a protein, mouse; D008716:Methionine Adenosyltransferase