ADD-1/SREBP-1 is a major determinant of tissue differential lipogenic capacity in mammalian and avian species

Fatty acid synthase (FAS), a key lipogenic enzyme, is expressed in the two major sites of fatty acid production in the body, that is, the liver and th e adipose tissue. Surprisingly, the relative contribution of these sites to lipogenesis is highly variable among species. For example, besides the sit uation in rodents, where liver and fat are equally active, lipogenesis in s ome mammals such as the pig occurs principally in adipose tissue, whereas i n avian species, the liver is the main lipogenic site. We addressed the que stion concerning the factors determining the site of fatty acid synthesis. We show that the expression of adipocyte determination and differentiation- dependent factor 1/sterol regulatory element-binding protein (ADD-1/SREBP-1 ) mRNA, but not SREBP-2, is linked to FAS protein content or activity in ad ipose tissues and livers of pig, chicken, and rabbit. Tissue differences in ADD-1/SREBP-1 mRNA expression between species were paralleled by commensur ate variations in the nuclear concentration of SREBP-1 protein. Moreover, o verexpression of ADD-1/SREBP-1 by adenoviral gene transfer induces FAS in c hicken adipocytes, where lipogenesis is normally low. Conversely, the expre ssion of a dominant negative form of ADD-1/SREBP-1 in pig adipocytes downre gulates FAS expression. These results reinforce the role of ADD-1/SREBP-1 a s a key regulator of lipogenesis, by extending its importance to nonrodent mammals and birds. Furthermore, they establish that differential expression -of ADD-1/SREBP-1 is a key determinant of the site of fatty acid synthesis in the body.