Sterol regulatory element binding protein and dietary lipid regulation of fattyacid synthesis in the mammary epithelium.

摘要

The lactating mammary gland synthesizes large amounts of triglyceride from fatty acids derived from the blood and from de novo lipogenesis. The latter issignificantly increased at parturition and decreased when additional dietaryfatty acids become available. To begin to understand the molecular regulation of de novo lipogenesis, we tested the hypothesis that the transcription factorsterol regulatory element binding factor (SREBF)-1c is a primary regulator ofthis system. Expression of Srebf1c mRNA and six of its known target genesincreased >=2.5-fold at parturition. However, Srebf1c-null mice showed only minor deficiencies in lipid synthesis during lactation, possibly due to compensation bySrebf1a expression. To abrogate the function of both isoforms of Srebf1, we bred mice to obtain a mammary epithelial cell-specific deletion of SREBFcleavage-activating protein (SCAP), the SREBF escort protein. These dams showed asignificant lactation deficiency, and expression of mRNA for fatty acid synthase (Fasn), insulin-induced gene 1 (Insig1), mitochondrial citrate transporter(Slc25a1), and stearoyl-CoA desaturase 2 (Scd2) was reduced threefold or more;however, the mRNA levels of acetyl-CoA carboxylase-1alpha (Acaca) and ATP citratelyase (Acly) were unchanged. Furthermore, a 46% fat diet significantly decreased de novo fatty acid synthesis and reduced the protein levels of ACACA, ACLY, andFASN significantly, with no change in their mRNA levels. These data lead us toconclude that two modes of regulation exist to control fatty acid synthesis inthe mammary gland of the lactating mouse: the well-known SREBF1 system and anovel mechanism that acts at the posttranscriptional level in the presence ofSCAP deletion and high-fat feeding to alter enzyme protein.