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2014 ; 60
(3
): 919-30
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E2F1 is a novel fibrogenic gene that regulates cholestatic liver fibrosis through
the Egr-1/SHP/EID1 network
#MMPMID24619556
Zhang Y
; Xu N
; Xu J
; Kong B
; Copple B
; Guo GL
; Wang L
Hepatology
2014[Sep]; 60
(3
): 919-30
PMID24619556
show ga
E2F transcription factor 1 (E2F1) is an important regulator of metabolic
diseases; however, its role in liver function remains elusive. This study
unraveled a regulatory cascade involving E2F1, early growth response-1 (Egr-1),
nuclear receptor small heterodimer partner (SHP, NR0B2), and EIA-like inhibitor
of differentiation 1 (EID1) in cholestatic liver fibrosis. Liver E2F1 messenger
RNA (mRNA) and protein expression was strongly up-regulated in human nonalcoholic
steatohepatitis (NASH) and alcohol cirrhosis; the latter was inversely correlated
with diminished SHP expression. E2F1 was also highly induced by
3,5-diethoxycarbonyl-1, 4-dihydrocollidine (DDC) feeding and bile-duct ligation
(BDL) in mice. E2F1-/- mice exhibited reduced biliary fibrosis by DDC as
determined by Masson Trichrome and Picro Sirius red staining, and decreased serum
bile acid (BA), BA pool size, and fecal BA excretion. In addition, cholestatic
liver fibrosis induced by BDL, as determined by immunohistochemistry analysis of
a1 collagen expression, was increased in SHP-/- mice but attenuated in hepatocyte
SHP-overexpressed transgenic (STG) mice. Egr-1 exhibited marked induction in
livers of SHP-/- mice compared to the wild-type mice in both sham and BDL groups,
and reduction in STG livers. Egr-1 promoter was activated by E2F1, and the
activation was abrogated by expression of SHP and its co-repressor EID1 in
hepatoma cells Huh7, Hepa1, and stellate cells LX2. Chromatin immunoprecipitation
assays further confirmed the association of E2F1, SHP, and EID1 proteins with the
Egr-1 promoter, and their direct protein interactions were determined by
glutathione S-transferase pull-down assays. Interestingly, E2F1 activated Egr-1
expression in a biphasic fashion as described in both human and mouse
hepatocytes. CONCLUSION: E2F1 is a fibrogenic gene and could serve as a potential
new diagnostic marker for nonalcoholic and alcoholic liver fibrosis/cirrhosis.