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-tocopherol
supplementation inhibits liver collagen 1(I) gene
expression
Department of Medicine, Veterans Affairs Medical Center, and Center for Molecular Genetics, University of California, San Diego, California 92161
We analyzed the
role of oxidative stress on liver collagen gene expression in vivo.
Long- and short-term supplementation with the lipophilic antioxidant
D-
-tocopherol (40 IU/day for
8 wk or 450 IU for 48 h) to normal C57BL/6 mice selectively decreased liver collagen mRNA by ~70 and ~60%, respectively. In transgenic mice, the 
0.44 kb of the promoter and the first intron of the human collagen 1(I) gene were sufficient to confer responsiveness to D--tocopherol. Inhibition
of collagen 1(I) transactivation in primary cultures of quiescent
stellate cells from these transgenic animals by
D--tocopherol required only
0.44 kb of the 5' regulatory region. This regulation
resembled that of the intact animal following D--tocopherol treatment and
indicates that D--tocopherol
may act directly on stellate cells. Transfection of stellate cells with
collagen-LUC chimeric genes allowed
localization of an "antioxidant"-responsive element to the
0.22 kb of the 5' region excluding the first intron. These
findings suggest that oxidative stress, independently of confounding
variables such as tissue necrosis, inflammation, cell activation, or
cell proliferation, modulates in vivo collagen gene expression.
liver fibrosis; antioxidants; transcription; stellate cells
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