T

Acetoacetyl CoA [4C]

HMG CoA

synthase Hydroxymethyl

HMG CoA lyase

Acetyl-CoA CoA

CoA Acetyl-CoA

Acetoacetate [4C]

Acetase [3C]

p-Hydroxybutyrate dehydrogenase

P-Hydroxybutyrate [4C]

(A) Ketogenesis in the liver from acetyl-CoA

Succinyl CoA

NAD NADH+H

Exported from the liver to other tissues

P-Hydroxybutyrate V À -- Acetoacetate ^^ Acetoacetyl-CoA i

p-Ketothiolase

Succinate p-Hydroxybutyrate Acetoacetyl succinyl CoA dehydrogenase transferase

(B) Extrahepatic metabolism of p-hydroxybutyrate (Ketone bodies) to acetyl-CoA Figure 7 The production (A) and metabolism (B) of ketones produced from acetyl-CoA.

The first step in fatty acid synthesis is the car-boxylation of acetyl-CoA to malonyl-CoA, followed by the addition of a series of malonyl-CoA units by a complex series of reactions via the multienzyme complex fatty acid synthase. The car-boxylation of acetyl-CoA to malonyl-CoA is regulated by the hormones insulin and glucagon, which affect the activity of the enzyme catalyzing this reaction. Hence, in the fed state insulin increases the activity of the enzyme, whereas in the fasting state glucagon decreases its activity. Also, malo-nyl-CoA inhibits the uptake of fatty acids into the mitochondria via acetyl carnitine-CoA so that when fatty acid synthesis is occurring, ^-oxidation is inhibited by limiting the supply of substrate into the mitochondria.

Storage of fatty acids in adipose tissue can only occur when glycolysis is activated in the fed state because the source of glycerol in adipose tissue is blood glucose entering glycolysis and DHA-P removed to be converted to glycerol-3-P.

During fatty acid synthesis, desaturase enzymes can introduce double bonds to make mono- and polyunsaturated fatty acids. However, these enzymes cannot introduce double bonds after C10; this is why there is a requirement for the essential fatty acids linoleic acid (n-6) and linolenic acid (n-3), which can then be converted to the long-chain polyunsaturated fatty acids, arachidonic acid and eicosapentaenoic acid, which are important metabolic precursors.

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