Regulation of Lipid Metabolism (2 Stages)| Biochemistry

The following points highlight the top two stages for regulation of lipid metabolism. The stages are: 1. Regulation of Lipogenesis 2. Regulation of Ketogenesis.

Regulation of Lipogenesis:

a. Lipogenesis is concerned with the con­version of glucose and intermediate such as pyruvate, lactate and acetyl-CoA to fat.

b. The rate of lipogenesis is high in case of a diet containing a high proportion of carbohydrate. The rate is decreased on a high-fat diet or in the deficiency of insulin as in diabetes mellitus. All these conditions are related to increased concentration of plasma-free fatty acids.

There is an inverse relationship between hepatic lipogenesis and the serum-free fatty acids concentra­tion. Lipogenesis is greatly inhibited over the high range of free fatty acids. Lipo­genesis is depressed by the fat diet in the liver and a little carbohydrate is converted to fat when the fat diet is more than 10%.

c. Lipogenesis is higher when sucrose is fed instead of glucose. It is also blocked in fasting due to the lack of NADPH genera­tion from the HMP shunt pathway.

d. Acetyl-CoA carboxylase is competitively inhibited with the activator citrate by the long chain acyl-CoA molecules. Therefore, if acyl-CoA is accumulated, it will auto­matically reduce the synthesis of new fatty acids.

e. Acyl-CoA may also inhibit the mitochon­drial transport of citrate into the eytosol. Free fatty acids also are inversely related to the proportion of active to inactive pyru­vate dehydrogenase. Acyl-CoA may also inhibit pyruvate dehydrogenase by inhib­iting the ATP-ADP exchange transporter of the inner mitochondrial membrane. As a result, the supply of acetyl-CoA from carbohydrate is blocked.

f. Insulin increases the transport of glucose into the cell making increased availabil­ity of pyruvate for fatty acid synthesis and glycerol 3-phosphate for esterification of the fatty acids. It also converts the inac­tive pyruvate dehydrogenase and acetyl-CoA carboxylase to the active form.

It also depresses the level of intracellular cAMP, inhibits lipolysis and thereby reduces the concentration of long chain acyl-CoA which is an inhibitor of lipogenesis.

Regulation of Ketogenesis:

a. In adipose tissue, very high concentrations of plasma-free fatty acids (FFA) are avail­able as a result of lipolysis of triacylglyce­rol. In fed as well as in fasting conditions, 30% or more of the free fatty acids pass to the liver. After they are activated to acyl- CoA they are either esterified mainly to triacylglycerol and phospholipid or they undergo P-oxidation to form acetyl-CoA.

The acetyl-CoA is either oxidized in the citric acid cycle or used to form ketone bodies (Fig. 19.2).

b. The esterification, which acts as an anti-ketogenic factor, depends on the availability of precursors in the liver to supply sufficient glycerol-3-phosphate. In the liver, anti-ketogenic effects of glycerol and dihydroxyacetone are not correlated with the levels of glycerol 3-phosphate.

c. Phosphatidate phosphohydrolase appears to increase in activity in livers in which extra triacylglycerol synthesis takes place. Insulin increases the activity of glycerol phosphate acyltransferase which cataly­ses the first step in esterification.

d. Carnitine acyltransferase I activity in the mitochondrial membrane regulates the entry of long chain acyl groups into the mitochondria before β-oxidation takes place. In the fed state, fatty acid oxidation is depressed due to its lowered activity; but in fasting, fatty acid oxidation in­creases owing to its increased activity.

This enzyme is inhibited in the fed state by the increased level of malonyl-CoA, the initial intermediate in fatty acid bio­synthesis. Therefore, in the fed state, the active lipogenesis and high malonyl-CoA inhibit carnitine acyltransferase I.

e. Low level of free fatty acids entering the liver cell are nearly all esterified to triacylglycerol’s and transported out of the liver in VLDL. The concentration of free fatty acids increases with the onset of star­vation and acetyl-CoA carboxylase is in­hibited and malonyl-CoA decreases.

Therefore, the inhibition of carnitine acyltransferase I is released with the per­mission of more acyl-CoA to be oxidized. The ratio of the concentrations of insulin and glucagon reinforces these events in starvation causing increased lipolysis in adipose tissue and inhibition of pyruvate kinase and acetyl-CoA carboxylase in the liver.

f. More free fatty acid is converted to ke­tone bodies and less is oxidized to CO₂ via TCA cycle with the increased concen­tration of serum-free fatty acids.

The total free energy as ATP as a result of the oxida­tion of free fatty acids remains constant on the fact that the partition of acetyl-CoA between the ketogenic pathway and the pathway of oxidation to CO₂ is regulated in such a particular manner, on complete oxidation in the Citric acid cycle.

One mol of palmitate yields 129 mols of ATP, whereas this one mol of palmitate pro­duces only 33 mols of ATP when acetoac­etate is the end product. Therefore, ke­togenesis is regarded as a mechanism in which the liver can oxidize large quanti­ties of fatty acids without increasing its total energy expenditure.

g. Reduced level of oxaloacetate within the mitochondria can cause impairment of the TCA cycle to metabolize acetyl-CoA. Krebs has suggested that a fall in the con­centration of oxaloacetate owing to an enhanced gluconeogenesis may be the cause of the severe forms of ketosis found in diabetes and the ketosis of cattle.

It has been assumed that citrate synthase is in­hibited either by long chain acyl-CoA or by increased level of ATP. It has also been shown that pyruvate carboxylase—which converts pyruvate to oxaloacetate—is activated by acetyl-CoA. Therefore, suffi­cient amounts of acetyl-CoA signifies the presence of significant amounts of oxaloacetate to initiate the condensing reaction of TCA cycle.