Ottey, Karen Angela; (1992) The regulation of fatty acid synthesis in the mammary gland of the lactating rat. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The mammary gland of the lactating rat uses 30 mmol of glucose a day. 70% of this is used for the synthesis of fatty acids which is therefore stringently regulated. This thesis describes investigations designed to elucidate some of the mechanisms of this regulation. Acetyl-CoA carboxylase (ACC) and pyruvate dehydrogenase (PDH) are key regulatory enzymes in the pathway from glucose to fatty acid. Pyruvate dehydrogenase catalyses the oxidative decarboxylation of pyruvate to acetyl-CoA and ACC catalyses the committed step in the synthesis of fatty acids from acetyl-CoA. In lactating rat mammary gland the activities of both enzymes are profoundly inhibited by starvation and rapidly re-activated (within 3 hours) upon refeeding. Unexpectedly during these dietary manipulations the rate of fatty acid synthesis can be more closely correlated with PDH than ACC even though the latter is considered to be the major rate determining enzyme. Perfusion of the mammary gland in situ was performed using known inhibitors of fatty acid synthesis in the perfusate. Palmitic acid inhibited PDH but not ACC; acetoacetate had no effect on either enzyme. In vitro experiments suggest differential effects of palmitate (16:0) and oleate (18:1), palmitate being a less potent inhibitor of fatty acid synthesis and ACC than oleate. ACC in lactating rat mammary gland is phosphorylated and inactivated in response to 24hr starvation. One possible candidate for such phosphorylation is cAMP-dependent protein kinase. This had been purified from lactating mammary gland and its unusual tissue specific properties are described and discussed in relation to the results of in vivo experiments showing that in mammary gland the activity of this kinase does not correlate with the rate of fatty acid synthesis or ACC activity. The partial purification of a kinase capable of phosphorylating and inhibiting ACC in a manner identical to that which occurs during starvation in vivo is described. Its characteristics, regulation and physiological significance are discussed.

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