Long- and short-term D-alpha-tocopherol supplementation inhibits liver collagen alpha 1(I) gene expression

We analyzed the role of oxidative stress on liver collagen gene expression in vivo. Long- and short-term supplementation with the lipophilic antioxida nt D-alpha-tocopherol (40 IU/day for 8 wk or 450 IU for 48 h) to normal C57 BL/6 mice selectively decreased liver collagen mRNA by similar to 70 and si milar to 60%, respectively. In transgenic mice, the -0.44 kb of the promote r and the first intron of the human collagen alpha 1(I) gene were sufficien t to confer responsiveness to D-alpha-tocopherol. Inhibition of collagen al pha 1(I) transactivation in primary cultures of quiescent stellate cells fr om these transgenic animals by D-alpha-tocopherol required only -0.44 kb of the 5' regulatory region. This regulation resembled that of the intact ani mal following D-alpha-tocopherol treatment and indicates that D-alpha-tocop herol may act directly on stellate cells. Transfection of stellate cells wi th collagen-LUC chimeric genes allowed localization of an "antioxidant"-res ponsive element to the -0.22 kb of the 5' region excluding the first intron . These findings suggest that oxidative stress, independently of confoundin g variables such as tissue necrosis, inflammation, cell activation, or cell proliferation, modulates in vivo collagen gene expression.