Fatty acid synthesis regulation

Secondary signals Citrate activates (acetyl-CoA carboxylase). 

The major control point for fatty acid synthesis is acetyl-CoA carboxylase. The enzyme is inactivated by phosphorylation and activated by high concentrations of citrate. 

Calculating energy costs for the synthesis of a Cig fatty acid from acetyl-CoA is not as simple as you might first think. The major complication is that acetyl-CoA is made in the mitochondria, but fatty acid synthesis occurs in the cytosol—acetyl-CoA can t cross the mitochondrial membrane. Acetyl-CoA gets out of the mitochondria disguised as citrate. The acetyl-CoA is condensed with oxaloacetate to give citrate, and the citrate leaves the mitochondria. In the cytosol, the citrate is cleaved by an ATP-dependent citrate lyase into acetyl-CoA and oxaloacetate  

This reaction and the reactions required to get oxaloacetate back into the mitochondria set up the cycle shown in Fig. 13-2. 

Another point that you should appreciate is that in cycles like this, writing a balanced equation for the reaction is terribly easy. You just write the stuff that goes into the cycle on the left and the stuff that comes out on the right. It s not necessary to write down all the individual reactions that make up the cycle itself. The compounds that are members of the cycle itself (such as oxaloacetate or citrate shown earlier) will not show up in the final balanced equation. The balanced equation for Fig. 13-2 is 

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Fatty Acid Synthesis Function Fatty Acid Synthesis Location Fatty Acid Synthesis Connections Fatty Acid Synthesis Regulation Fatty Acid Synthesis ATP Costs (for C16)... 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

FIGURE 25.16 Regulation of fatty acid synthesis and fatty acid oxidation are conpled as shown. Malonyl-CoA, produced during fatty acid synthesis, inhibits the uptake of fatty acylcarnitine (and thus fatty acid oxidation) by mitochondria. When fatty acyl CoA levels rise, fatty acid synthesis is inhibited and fatty acid oxidation activity increases. Rising citrate levels (which reflect an abundance of acetyl-CoA) similarly signal the initiation of fatty acid synthesis. 

FIGURE 25.17 Hormonal signals regulate fatty acid synthesis, primarily through actions on acetyl-CoA carboxylase. Availability of fatty acids also depends upon hormonal activation of triacylglycerol lipase. 

NADPH is a reducing agent that is reserved for biosynthetic pathways—notably fatty acid synthesis. Thus, the HMP pathway is called upon when reducing equivalents and fatty acid synthesis are turned on. Primarily, the regulation of the pathway is through the supply and demand of NADPH. 

The regulation of fat metabolism is relatively simple. During fasting, the rising glucagon levels inactivate fatty acid synthesis at the level of acetyl-CoA carboxylase and induce the lipolysis of triglycerides in the adipose tissue by stimulation of a hormone-sensitive lipase. This hormone-sensitive lipase is activated by glucagon and epinephrine (via a cAMP mechanism). This releases fatty acids into the blood. These are transported to the various tissues, where they are used. 

The activity of carnitine palmitoyltransferase-I plays an important role in the regulation of fatty acid oxidation malonyl-CoA is an allosteric exhibitor of the enzyme. Malonyl-CoA is a key intermediate in fatty acid synthesis, which ensures that fatty acid oxidation is decreased when synthesis is taking place. Nonetheless, malonyl-CoA has a major role in the control of fatty acid oxidation in all tissues in which fatty acid oxidation occurs, even if no synthesis takes place. 

As indicated above, the flux-generating step for fatty acid synthesis is the conversion of acetyl-CoA to malonyl-CoA, catalysed by acetyl-CoA carboxylase. Consequently, regulation of the rate of synthesis is achieved via changes in the activity of this enzyme. The properties of the carboxylase identify three mechanisms for regulation allosteric regulation, reversible phosphorylation (an interconversion cycle) and changes in the concentration of the enzyme. (The principles underlying the first two mechanisms are discussed in Chapter 3.)... 

Finally, a high carbohydrate diet results in activation of a protein that regulates transcription of genes that express enzymes involved in the process of fatty acid synthesis (Figure 11.8(c)). 

Figure 8-1. Hormonal regulation of fat metabolism. A Control of fatty acid synthesis by reversible phosphorylation of acetyl CoA carboxylase. B Regulation of tri-acylglycerol degradation by reversible phosphorylation of hormone-sensitive lipase. cAMP, cyclic adenosine monophosphate HS, hormone-sensitive.

Insulin is a polypeptide hormone that consists of two peptide chains bonded by two disulfide bonds. The two chains are designated A and B. The A chain consists of 21 amino acids with a third internal disulfide bond, and the chain contains the remaining 30 amino acids. All vertebrates produce insulin and the structure is similar in these species. For example, the insulin produced in humans and porcine species differs by only one amino acid, and humans and bovine insulin differ by three amino acids. Insulin plays a crucial role in several physiological processes. These include the regulation of sugar in the body, fatty acid synthesis, formation of triglycerides, and amino acid synthesis. 

PPAR is a nuclear receptor-transcription factor and is ligand-dependent and expressed in several tissues. It is initially involved in adipocyte differentiation and fatty acid synthesis. Fatty acid and eicosanoids bind to PPAR and regulate transcription. PPAR activation inhibits monocyte differentiation and expression of several pro-inflammatory genes such as iNOS, TNF, etc. PPAR activation inhibits tumor cell proliferation (epithelial, colon, prostate). PPAR is involved in angiogenesis. 

We focus first on the pathway of fatty acid synthesis, then turn our attention to regulation of the pathway and to the biosynthesis of longer-chain fatty acids, unsaturated fatty acids, and their eicosanoid derivatives. 

Acetyl-CoA carboxylase is also regulated by covalent modification. Phosphorylation, triggered by the hormones glucagon and epinephrine, inactivates the enzyme and reduces its sensitivity to activation by citrate, thereby slowing fatty acid synthesis. In its active (dephosphorylated) form, acetyl-CoA carboxylase polymerizes into long filaments (Fig. 21-1 lb) phosphorylation is accompanied by dissociation into monomeric subunits and loss of activity. 

FIGURE 21-11 Regulation of fatty acid synthesis. (a) In the cells of vertebrates, both allosteric regulation and hormone-dependent covalent modification influence the flow of precursors into malonyl-CoA. In plants, acetyl-CoA carboxylase is activated by the changes in [Mg2+] and pH that accompany illumination (not shown here), (b) Filaments of acetyl-CoA carboxylase (the active, dephosphorylated form) as seen with the electron microscope. 

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