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Regulation of fatty acid synthesis – A quick revision
The mammalian enzyme is regulated, by two main mechanisms-
A) Short term control
B) Long term control
A) Short term control of fatty acid synthesis includes
a) Allosteric control by local metabolites
Palmitoyl-CoA (or acyl co A) acts as a feedback inhibitor of the enzyme, and citrate is an activator (figure-1).
- When there is an increase in mitochondrial acetyl-CoA and ATP, citrate is transported out of mitochondria
- Citrate becomes both the precursor of cytosolic acetyl-CoA and a signal for the activation of acetyl-CoA carboxylase.
- Conversely , if acyl-CoA accumulates because it is not esterified quickly enough or because of increased lipolysis or an influx of free fatty acids into the tissue, it will automatically reduce the synthesis of new fatty acid.
- Acyl-CoA also inhibits the mitochondrial tricarboxylate transporter, thus preventing activation of the enzyme by egress of citrate from the mitochondria into the cytosol.
Figure-1- Citrate is a positive allosteric modifier, which increases in concentration in the well-fed state and is an indicator of a plentiful supply of acetyl-CoA. Palmitoyl co A or the long chain fatty acids are the negative modifiers of acetyl co A carboxylase (negative feedback inhibition by a product of a reaction).
b) Covalent modification (Phosphorylation and dephosphorylation)
Acetyl-CoA carboxylase is also regulated by hormones such as glucagon, epinephrine, and insulin via changes in its phosphorylation state (figure-2)-
Figure-2- Regulation of acetyl co A carboxylase by covalent modification
Acetyl co A carboxylase exists in two forms-
i) Active (dephosphorylated form)
ii) Inactive (phosphorylated form)
Phosphorylation is brought about by c- AMP mediated phosphorylation cascade. Glucagon (and epinephrine) increase cAMP concentration and inactivate the enzyme by bringing about its phosphorylation.
Dephosphorylation, is brought about by protein phosphatase which is stimulated by insulin. In other words, insulin stimulates this enzyme to promote fatty acid synthesis, while glucagon and catecholamines inactivate this enzyme to inhibit fatty acid synthesis.
c) Conformational changes associated with regulation:
- In the active conformation, Acetyl-CoA Carboxylase associates to form multimeric filamentous complexes. Citrate converts the enzyme from an inactive dimer to an active polymeric form, with a molecular mass of several million.
- Transition to the inactive conformation is associated with dissociation to yield the monomeric form of the enzyme (protomer). Inactivation is promoted by phosphorylation of the enzyme and by long-chain acyl-CoA molecules.
B) Long term control- Additionally, fatty acid synthesis is regulated at the level of gene expression by induction and repression of gene of acetyl co A carboxylase enzyme
Prolonged consumption of high calorie or high carbohydrate diets causes an increase in acetyl co A carboxylase concentration by increasing the gene expression (induction). Conversely, a low-calorie diet or fasting causes a reduction in fatty acid synthesis by decreasing the synthesis of acetyl co A carboxylase(repression) .
Nutritional state regulates lipogenesis- Excess carbohydrates are stored as fat in many animals in anticipation of periods of caloric deficiency such as starvation, hibernation, etc, and to provide energy for use between meals in animals, including humans, that take their food at spaced intervals. The nutritional state of the organism is the main factor regulating the rate of lipogenesis.
Fatty acid synthesis during Fed state
- The rate is higher in the well-fed state if the diet contains a high proportion of carbohydrate
- Lipogenesis converts surplus glucose and intermediates such as pyruvate, lactate, and acetyl-CoA to fat, assisting the anabolic phase of this feeding cycle
- Lipogenesis is increased when sucrose is fed instead of glucose because fructose bypasses the phosphofructokinase control point in glycolysis and floods the lipogenic pathway
Fatty acid synthesis during Fasting
- It is depressed by restricted caloric intake, high fat diet, or a deficiency of insulin, as in diabetes mellitus
- These conditions are associated with increased concentrations of plasma free fatty acids
- An inverse relationship has been demonstrated between hepatic lipogenesis and the concentration of serum-free fatty acids.
Role of Insulin in fatty acid synthesis
- Insulin stimulates lipogenesis by several other mechanisms as well as by increasing acetyl-CoA carboxylase activity.
- It increases the transport of glucose into the cell (e.g., in adipose tissue),
- Increases the availability of both pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the newly formed fatty acids,
- Insulin converts the inactive form of pyruvate dehydrogenase to the active form thus provides more of Acetyl co A
- Insulin also acts by inhibiting c AMP mediated lipolysis in adipose tissue and thereby reduces the concentration of plasma free fatty acids (long-chain fatty acids are inhibitors of lipogenesis.
Note- The fatty acid synthase complex is also similarly regulated.
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