Regulation of glucose entry and utilization in the lactating mammary alveolar cell. (a) Glucose enters the cell via glucose transporter (GLUT)1, a non-insulin sensitive transporter. Free glucose enters the Golgi via GLUT1 where it is combined with UDP-galactose, also derived from glucose to make lactose. Since the Golgi membrane is not permeable to disaccharides, lactose draws water osmotically into the Golgi compartment. Glucose is also converted to glucose-6-PO4 by hexokinase. The glucose-6-PO4 can be isomerized by glucose-6-PO4 isomerase to fructose-6-PO4 from whence it is made into pyruvate or glycerol-3-PO4. Glucose-6-PO4 may also enter the pentose phosphate shunt, a major source of NADPH for lipid synthesis. Pyruvate enters the mitochondrion where two major products are ATP, which provides energy to synthetic processes in the cell, and citrate. Citrate has two fates: it serves as the substrate for fatty acid synthesis by conversion to malonyl-CoA and it can be converted to pyruvate through the malate shunt, which provides additional NADPH. NADPH, glycerol-3-PO4, and pyruvate all contribute to triglyceride (TAG) synthesis. (b) Profile of GLUT1, citrate synthase, the citrate transporter, ATP citrate lyase, and glucose phosphate isomerase showing upregulation of the first four and down regulation of the last. (c) Profile of enzymes whose mammary expression is downregulated by a high fat diet. (d) Profile of enzymes that lead to synthesis of polyunsaturated, long chain fatty acids in the mouse mammary gland. P17, day 17 of pregnancy.