Formation of milk lipids: a molecular perspective

Abstract

Lipids, primarily triglycerides, are major milk constituents of most mammals, providing a large percentage of calories, essential fatty acids and bioactive lipids required for neonatal growth and development. To meet the caloric and nutritional demands of newborns, the mammary glands of most species have evolved an enormous capacity to synthesize and secrete large quantities of lipids during lactation. Significant information exists regarding the physiological regulation of lipid metabolism in the mammary gland from the study of dairy animals. However, detailed understanding of the molecular mechanisms regulating milk lipid formation is only now coming into focus through advances in mouse genetics, global analysis of mammary gland gene expression, organelle protein properties and the cell biology of lipid metabolism.

Keywords: 1-acylglycerol-3-phosphate O-acyltransferase 6; adipophilin; cytoplasmic lipid droplet; diacylglycerol O-acyltransferase 1; lipogenesis; lipolysis; mammary gland differentiation; milk lipid; protein kinase-B; spot-14.

Figure 1. Lipid accumulation in differentiating milk-secreting cells occurs in phases

The developmental progression of cytoplasmic lipid droplets (CLDs) and their accumulation in milk-secreting cells of differentiating mammary glands are shown in cross-sectional diagrams of alveoli. Small (<1 μm in diameter) CLDs coated with adipophilin (indicated by red dots) are sporadically observed in milk-secreting cells at the beginning of secretory differentiation (phase I), which in mice typically begins at approximately pregnancy day 12 (P12). Between P12 and P14 (phase II) adipophilin CLDs undergo modest increases in size and number in some, but not all, milk-secreting cells. Some CLDs are now large enough that a neutral lipid core (indicated by a yellow sphere) can be seen to be surrounded by adipophilin (shown as a red annulus). Starting at P14 and progressing through P18 (typically the day before parturition) CLDs undergo sharp increases in size and number in all milksecreting cells. In milk-secreting cells of outbred CD1 mice on the day before parturition, CLDs completely fill the cytoplasm and many exceed 10 μm in diameter (phase III). Following parturition and the onset of milk secretion (phase IV), CLD size and number decrease dramatically and they become enriched at the apical border of the cell and are found and secreted in the alveolar lumen. Nuclei are indicated by blue ovals, dotted arrows indicate secretion of CLDs. Lu: Lumen.

Figure 2. Bipartite model of lipogenesis in differentiating milk-secreting cells

Lipogenesis in differentiating milk-secreting cells is proposed to occur in two independently regulated and temporally distinct phases. The first phase is initiated by increased expression of adipophilin (large vertical blue arrows), and possible other molecules that impair triglyceride lipolysis, at the beginning of secretory differentiation. Increased expression of these molecules stabilizes formation of triglycerides that are synthesized at a basal rate resulting in modest increases in the size and number of CLDs (shown as a pink sphere indicating the triglyceride core and a dashed blue line to indicate surface-associated adipophilin). The second phase, induced toward the end of pregnancy, is characterized by dramatic increases in the rate of DGAT-1-dependent triglyceride synthesis (large vertical pink arrows) and further elevation in adipophilin expression. The increase in triglyceride synthesis is mediated by AKT-1-dependent increases in de novo fatty acid and glycerol synthesis and lipoprotein lipase-dependent mobilization of exogenous fatty acids from serum triglycerides. CLD: Cytoplasmic lipid droplet; TAG: Triacylglycerol.