Fatty acid metabolism

Fatty acids are an important source of energy for many organisms. Excess glucose can be stored efficiently as fat. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins. All cell membranes are built up of phospholipids, each of which contains two fatty acids. Fatty acids are also used for protein modification. The metabolism of fatty acids, therefore, consists of catabolic processes which generate energy and primary metabolites from fatty acids, and anabolic processes which create biologically important molecules from fatty acids and other dietary carbon sources.

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Overview

• Lipolysis is carried out by lipases.
• Once freed from glycerol, free fatty acids can enter blood and muscle fiber by diffusion.
• Beta oxidation splits long carbon chains of the fatty acid into acetyl CoA, which can eventually enter the Krebs Cycle.

Briefly, β-oxidation or lipolysis of free fatty acids is as follows:

1. Dehydrogenation by Fatty Acyl-CoA Dehydrogenase, yielding 1 FADH₂
2. Hydration by Enoyl-CoA Hydratase
3. Dehydrogenation by 3-hydroxyacyl-CoA dehydrogenase, yielding 1 NADH
4. Cleavage by thiolase, yielding 1 acetyl-CoA and a fatty acid that has now been shortened by 2 carbons

This cycle repeats until the FFA has been completely reduced to acetyl-CoA or, in the case of fatty acids with odd numbers of carbon atoms, acetyl-CoA and 1 mol of propionyl-CoA per mol of fatty acid.

Fatty acids as an energy source

Fatty acids, stored as triglycerides in an organism, are an important source of energy because they are both reduced and anhydrous. The energy yield from a gram of fatty acids is approximately 9 Kcal (39 kJ), compared to 4 Kcal/g (17 kJ/g) for proteins and carbohydrates. Since fatty acids are non-polar molecules, they can be stored in a relatively anhydrous (water free) environment. Carbohydrates, on the other hand, are more highly hydrated. For example, 1 g of glycogen can bind approximately 2 g of water, which translates to 1.33 Kcal/g (4 Kcal/3 g). This means that fatty acids can hold more than six times the amount of energy. Put another way, if the human body relied on carbohydrates to store energy, then a person would need to carry 67.5 lb (31 kg) of hydrated glycogen to have the energy equivalent to 10 lb (5 kg) of fat.   Hibernating animals provide a good example for utilizing fat reserves as fuel. For example, bears hibernate for about 7 months and during this entire period the energy is derived from degradation of fat stores.

Ruby-throated Hummingbirds fly non-stop between New England and West Indies (approximately 2400 km) at a speed of 40 km/h for 60 hours. This is possible only due to the stored fat.

Digestion and Transport

Fatty acids are usually ingested as triglycerides, which cannot be absorbed by the intestine. They are broken down into free fatty acids and monoglycerides by pancreatic lipase, which forms a 1:1 complex with a protein called colipase which is necessary for its activity. The activated complex can only work at a water-fat interface: it is therefore essential that fatty acids (FA) be emulsified by bile salts for optimal activity of these enzymes. People who have had their gallbladder removed due to gall stones consequently have great difficulty digesting fats. Most are absorbed as free fatty acids and 2-monoglycerides, but a small fraction is absorbed as free glycerol and as diglycerides. Once across the intestinal barrier, they are reformed into triglycerides and packaged into chylomicrons or liposomes, which are released into the lymph system and then into the blood. Eventually, they bind to the membranes of hepatocytes, adipocytes or muscle fibers, where they are either stored or oxidized for energy. The liver acts as a major organ for fatty acid treatment, processing chylomicron remnants and liposomes into the various lipoprotein forms, namely VLDL and LDL. Fatty acids synthesized by the liver are transported in the blood as VLDL. In peripheral tissues, lipoprotein lipase digests part of the VLDL into LDL and free fatty acids, which are taken up for metabolism. LDL is absorbed via LDL receptors. This provides a mechanism for absorption of LDL into the cell, and for its conversion into free fatty acids, cholesterol, and other components of LDL.

When blood sugar is low, glucagon signals the adipocytes to activate hormone sensitive lipase, and to convert triglycerides into free fatty acids. These have very low solubility in the blood, typically about 1 μM. However, the most abundant protein in blood, serum albumin, binds free fatty acids, increasing their effective solubility to ~ 1 mM. Thus, serum albumin transports fatty acids to organs such as muscle and liver for oxidation when blood sugar is low.

Degradation

Main article: Fatty acid degradation

Fatty acid degradation is the process in which fatty acids are broken down into their metabolites, resulting in release of energy to the target cells. It includes three major steps:

• Lipolysis of and release from adipose tissue,
• Activation and transport into mitochondria,
• β-oxidation

Synthesis

See Fatty acid synthesis

Regulation and control

It has long been held that hormone-sensitive lipase (HSL) is the enzyme that hydrolyses triacylglycerides to free fatty acids from fats (lipolysis). However, more recently it has been shown that at most HSL converts triacylglycerides to monoglycerides and free fatty acids. Monoglycerides are hydrolyzed by monoglyceride lipase; adipose triglyceride lipase may have a special role in converting triacylglycerides to diacylglycerides, while diacylglycerides are the best substrate for HSL.^[1]. HSL is regulated by the hormones insulin, glucagon, norepinephrine, and epinephrine.

Glucagon is associated with low blood glucose, and epinephrine is associated with increased metabolic demands. In both situations, energy is needed, and the oxidation of fatty acids is increased to meet that need. Glucagon, norepinephrine, and epinephrine bind to the G protein-coupled receptor, which activates adenylate cyclase to produce cyclic AMP. cAMP consequently activates protein kinase A, which phosphorylates (and activates) hormone-sensitive lipase.

When blood glucose is high, lipolysis is inhibited by insulin. Insulin activates protein phosphatase 2A, which dephosphorylates HSL, thereby inhibiting its activity. Insulin also activates the enzyme phosphodiesterase, which break down cAMP and stop the re-phosphorylation effects of protein kinase A.

For the regulation and control of metabolic reactions involving fat synthesis, see lipogenesis.

See also

• Fatty acid synthase
• Essential fatty acid
• List of fatty acid metabolism disorders

References

1. ^ Zechner R., Strauss J.G., Haemmerle G., Lass A., Zimmermann R. (2005) Lipolysis: pathway under construction. Curr. Opin. Lipidol. 16, 333-340.

Berg, J.M., et al., Biochemistry. 5th ed. 2002, New York: W.H. Freeman. 1 v. (various pagings).