ISOFORM 1C OF STEROL REGULATORY ELEMENT-BINDING PROTEIN IS LESS ACTIVE THAN ISOFORM 1A IN LIVERS OF TRANSGENIC MICE AND IN CULTURED-CELLS

We have produced transgenic mice whose livers express a dominant posit ive NH2-terminal fragment of sterol regulatory element binding protein -1c (SREBP-1c). Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols, We compared SREBP-1c transgenic mice with a line of transgenic mice th at produces an equal amount of the NH2-terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that dif fer in the first exon, which encodes part of an acidic activation doma in. The 1a protein contains a long activation domain with 12 negativel y charged amino acids, whereas the 1c protein contains a short activat ion domain with only 6 such amino acids. As previously reported, liver s of the SREBP-1a transgenic mice were massively enlarged, owing to ac cumulation of triglycerides and cholesterol, SREBP-1c transgenic liver s were only slightly enlarged with only a moderate increase in triglyc erides, but not cholesterol, The mRNAs for the LDL receptor and severa l cholesterol biosynthetic enzymes were elevated in SREBP-1a transgeni c mice, but not in 1c transgenic mice. The mRNAs for fatty acid syntha se and acetyl CoA carboxylase were elevated 9- and 16-fold in 1a anima ls, but only 2- and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcrip tion than SREBP-1a when both are expressed at levels approximating tho se found in nontransfected cells, SREBP-1c became a strong activator o nly when expressed at supraphysiologic levels, We conclude that SREBP- 1a is the most active form of SREBP-1 and that SREBP-1c may be produce d when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism.