Sterol regulatory element binding protein and dietary lipid regulation of fatty acid synthesis in the mammary epithelium.
The lactating mammary gland synthesizes large amounts of triglyceride from fatty acids derived from the blood and from de novo lipogenesis. The latter is significantly increased at parturition and decreased when additional dietary fatty acids become available. To begin to understand the molecular regulation of de novo lipogenesis, we tested the hypothesis that the transcription factor sterol regulatory element binding factor (SREBF)-1c is a primary regulator of this system. Expression of Srebf1c mRNA and six of its known target genes increased ≥2.5-fold at parturition. However, Srebf1c-null mice showed only minor deficiencies in lipid synthesis during lactation, possibly due to compensation by Srebf1a expression. To abrogate the function of both isoforms of Srebf1, we bred mice to obtain a mammary epithelial cell-specific deletion of SREBF cleavage-activating protein (SCAP), the SREBF escort protein. These dams showed a significant 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-1α (Acaca) and ATP citrate lyase (Acly) were unchanged. Furthermore, a 46% fat diet significantly decreased de novo fatty acid synthesis and reduced the protein levels of ACACA, ACLY, and FASN significantly, with no change in their mRNA levels. These data lead us to conclude that two modes of regulation exist to control fatty acid synthesis in the mammary gland of the lactating mouse: the well-known SREBF1 system and a novel mechanism that acts at the posttranscriptional level in the presence of SCAP deletion and high-fat feeding to alter enzyme protein.
Rudolph
Michael C
MC
1Department of Physiology and Biophysics, University of Colorado Denver, Aurora, CO, USA.
Monks
Jenifer
J
Burns
Valerie
V
Phistry
Meridee
M
Marians
Russell
R
Foote
Monica R
MR
Bauman
Dale E
DE
Anderson
Steven M
SM
Neville
Margaret C
MC
D000818:Animals; D015153:Blotting, Western; D004041:Dietary Fats / Q000378:metabolism*; D005227:Fatty Acids / Q000032:analysis / Q000096:biosynthesis*; D005260:Female; D015870:Gene Expression; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D007774:Lactation / Q000378:metabolism*; D050155:Lipogenesis / Q000235:genetics; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008892:Milk / Q000737:chemistry; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*
D004041:Dietary Fats; D005227:Fatty Acids; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C102196:SREBP cleavage-activating protein; D051780:Sterol Regulatory Element Binding Protein 1