Author
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MOHAMMAD, MAHMOUD - Children'S Nutrition Research Center (CNRC) |
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HAYMOND, MOREY - Children'S Nutrition Research Center (CNRC) |
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Submitted to: American Journal of Physiology - Endocrinology and Metabolism
Publication Type: Peer Reviewed Journal Publication Acceptance Date: 7/22/2013 Publication Date: 9/1/2013 Citation: Mohammad, M.A., Haymond, M.W. 2013. Regulation of lipid synthesis genes and milk fat production in human mammary epithelial cells during secretory activation. American Journal of Physiology - Endocrinology and Metabolism. 305(6):E700-E716. Interpretive Summary: Breastmilk fat consists of 98% triglycerides and provides the infants with more than half of their energy needs. As the name indicates, the triglycerides molecule is composed of three fatty acid molecules bound to a glycerol molecule. Thus, it is extremely important to understand how the breasts form milk triglycerides and to define the genetic message (mRNA) that control milk fat production in the cells that make the milk fat (mammary epithelial cells or MECs). In this study, mRNA was purified from milk fat droplets and the composition of milk fatty acids was measured in 7 healthy lactating women 6h following delivery and throughout the first 42 days of lactation. The results showed that over the first 4 days following delivery daily milk fat production increased several fold and paralleled the expression of genes involved in all aspects of fat metabolism and fatty acid production. This study enabled us to identify genes that are required for breakdown of lipids ("lipolysis") either at the membrane of the milk producing cell or within the cell and the metabolism of fatty acids such as uptake from blood, intracellular transport, synthesis, triglycerides synthesis, cholesterol synthesis and transport, and lipid droplet formation. The study highlights the complexity and the orchestration of a wide variety of pathways which are required for milk lipid synthesis and secretion processes in humans. Technical Abstract: Expression of genes for lipid biosynthetic enzymes during initiation of lactation in humans is unknown. Our objective was to study mRNA expression of lipid metabolic enzymes in human mammary epithelial cell (MEC) in conjunction with the measurement of milk fatty acid (FA) composition during secretory activation. Gene expression from mRNA isolated from milk fat globule (MFG) and milk FA composition were measured from 6h to 42 days postpartum in 7 normal women. Over the first 96h postpartum, daily milk fat output increased several fold and mirrored expression of genes for all aspects of lipid metabolism and milk FA production including: lipolysis at the MEC membrane, FA uptake from blood, intracellular FA transport, de novo FA synthesis, FA and glycerol activation, FA elongation, FA desaturation, triglyceride synthesis, cholesterol synthesis, and lipid droplet formation. Expression of the gene for a key lipid synthesis regulator, sterol regulatory element-binding transcription factor1 (SREBF1), increased 2.0 fold by 36h and remained elevated over the study duration. Expression of genes for estrogen receptor1 (ESR1), thyroid hormone responsive protein (THRSP) and insulin-induced2 (INSIG2) increased progressively to plateau by 96h. In contrast, mRNA of peroxisome proliferator-activated receptor gamma (PPARG) decreased several fold. With the onset of lactation, increased de novo synthesis of FAs was the most prominent change in milk FA composition and mirrored the expression of FA synthesis genes. We concluded milk lipid synthesis and secretion in humans is a complex process requiring the orchestration of a wide variety of pathways of which SREBF1 may play a primary role. |
