Copper deficiency induces hepatic fatty acid synthase gene transcription in rats by increasing the nuclear content of mature sterol regulatory element binding protein 1

and an enhanced rate of hepatic lipid synthesis. Because the nuclear transc ription factor sterol regulatory element binding protein-1 (SREBP-1) is a s trong enhancer of fatty acid synthase promoter activity, it was hypothesize d that Cu deficiency induces fatty acid synthase gene transcription by incr easing the nuclear localization of mature SREBP-1. Male weanling rats were pair-fed a Cu-adequate (6.0 mg/kg) or Cu-deficient (0.6 mg/kg) diet (AIN-93 ) for 28 d. DNase I hypersensitivity site mapping of the hepatic fatty acid synthase gene revealed the presence of four major hypersensitivity sites l ocated at -8700 to -8600, -7300 to -6900, -600 to -400 and -100 to +50. Alt hough Cu deficiency did not change the hypersensitivity site pattern or int ensity, in vitro footprinting of the region between -100 and +50 indicated that Cu deficiency enhanced DNA protein interactions within this region. Th e sequence between -68 and -58 contains the DNA recognition sequence for SR EBP-1 and upstream stimulatory element-1 (USF-1). Western blot analysis rev ealed that the dietary Cu deficiency increased the hepatic nuclear content of mature SREBP-1 by 150% (P < 0.05), and it concomitantly decreased the me mbrane content of precursor SREBP-1 by 45% (P < 0.05). Changes in the hepat ic distribution of SREBP-1 associated with Cu deficiency were not accompani ed by changes in SREBP-1 mRNA. The nuclear content of USF-1 was unaffected by dietary Cu status. The hepatic increase in mature SREBP-1 of Cu-deficien t rats was accompanied by a 400% increase and an 80% decrease in the abunda nce of fatty acid synthase and cholesterol 7-alpha hydroxylase mRNA, respec tively, hepatic These data indicate that a Cu deficiency stimulates hepatic lipogenic gene expression by increasing the hepatic translocation of matur e SREBP-1.