Fatty acid metabolism is stringently controlled so that synthesis and degradation are highly responsive to physiological needs. Fatty acid synthesis is maximal when carbohydrates and energy are plentiful and when fatty acids are scarce. Acetyl CoA carboxylase 1 and 2 play essential roles in regulating fatty acid synthesis and degradation. Recall that acetyl CoA carboxylase 1 catalyzes the committed step in fatty acid synthesis: the production of malonyl CoA (the activated two-carbon donor). This enzyme is subject to both local and hormonal regulation. We will examine each of these levels of regulation in turn.

Acetyl CoA carboxylase 1 responds to changes in its immediate environment, and is switched off by phosphorylation and activated by dephosphorylation (Figure 28.8). AMP-activated protein kinase (AMPK) converts the carboxylase into an inactive form by modifying a single serine residue. AMPK is essentially a fuel gauge; it is activated by AMP and inhibited by ATP. Thus, the carboxylase is inactivated when the energy charge is low. Fats are not synthesized when energy is required.

The carboxylase is also allosterically stimulated by citrate. The level of citrate is high when both acetyl CoA and ATP are abundant, signifying that raw materials and energy are available for fatty acid synthesis. Citrate acts in an unusual manner on inactive acetyl CoA carboxylase, which exists as inactive isolated dimers. Citrate facilitates the polymerization of the dimers into active filaments (Figure 28.9). However, polymerization by citrate alone requires much higher concentrations than are normally present in the cell. Under physiological conditions, citrate-induced polymerization is facilitated by the protein MIG12, which greatly reduces the amount of citrate required. Citrate-induced polymerization can partly reverse the inhibition produced by phosphorylation (Figure 28.10). The level of citrate is high when both acetyl CoA and ATP are abundant, signifying that raw materials and energy are available for fatty acid synthesis. The stimulatory effect of citrate on the carboxylase is counteracted by palmitoyl CoA, which is abundant when there is an excess of fatty acids. Palmitoyl CoA causes the filaments to disassemble into the inactive subunits. Palmitoyl CoA also inhibits the translocase that transports citrate from mitochondria to the cytoplasm, as well as glucose 6-phosphate dehydrogenase, the regulatory enzyme in the oxidative phase of the pentose phosphate pathway.

The isozyme, acetyl CoA carboxylase 2, located in the mitochondria, plays a role in the regulation of fatty acid degradation. Malonyl CoA, the product of the carboxylase reaction, is present at a high level when fuel molecules are abundant. Mitochondrial malonyl CoA inhibits carnitine acyltransferase I, preventing the entry of fatty acyl CoAs into the mitochondrial matrix in times of plenty. Malonyl CoA is an especially effective inhibitor of carnitine acyltransferase I in heart and muscle, tissues that have little fatty-acid-synthesis capacity of their own. In these tissues, acetyl CoA carboxylase may be a purely regulatory enzyme.

Carboxylase is also controlled by the hormones glucagon, epinephrine, and insulin, which indicate the overall energy status of the organism. Insulin stimulates fatty acid synthesis by activating the carboxylase 1, whereas glucagon and epinephrine have the reverse effect.

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Regulation by glucagon and epinephrineConsider, as we did in Chapter 27, a person who has just awakened from a night’s sleep and begins to exercise. Glycogen stores will be low, but lipids are readily available for mobilization. The hormones glucagon and epinephrine, present under conditions of fasting and exercise, will stimulate the mobilization of fatty acids from triacylglycerols in fat cells, which will be released into the blood, and probably in muscle cells, where the fatty acids will be used immediately as fuel. These same hormones will inhibit fatty acid synthesis by inhibiting acetyl CoA carboxylase 1. Although the exact mechanism by which these hormones exert their effects is complex, the net result is to augment the inhibition by the AMP-activated kinase. This result makes sound physiological sense: when the energy level of a cell is low, as signified by a high concentration of AMP, and the energy level of the organism is low, as signaled by glucagon, fats should not be synthesized. Epinephrine, which signals the need for immediate energy, enhances this effect. Hence, these catabolic hormones switch off fatty acid synthesis by keeping the carboxylase in the inactive phosphorylated state.

Regulation by insulinNow consider the situation after the exercise has ended and the exerciser has had a meal. In this case, the hormone insulin inhibits the mobilization of fatty acids and stimulates their accumulation as triacylglycerols by muscle and adipose tissue. Insulin also stimulates fatty acid synthesis by activating acetyl CoA carboxylase 1. Insulin activates the carboxylase by enhancing the phosphorylation of AMPK by Akt, which inhibits AMPK, as well as by stimulating the activity of a protein phosphatase that dephosphorylates and activates acetyl CoA carboxylase. Thus, the signal molecules glucagon, epinephrine, and insulin act in concert on triacylglycerol metabolism and acetyl CoA carboxylase 1 to carefully regulate the utilization and storage of fatty acids.

Response to dietLong-term control is mediated by changes in the rates of synthesis and degradation of the enzymes participating in fatty acid synthesis. Animals that have fasted and are then fed high-carbohydrate, low-fat diets show marked increases in their amounts of acetyl CoA carboxylase 1 and fatty acid synthase within a few days. This type of regulation is known as adaptive control. This regulation, which is mediated both by insulin and by glucose, is at the level of gene transcription.