View source for Fatty acid metabolism

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==Overview==
'''[[Fatty acid]]s''' are an important source of [[energy]] for many organisms. Excess glucose can be stored efficiently as fat. [[Triglyceride]]s yield more than twice as much energy for the same mass as do [[carbohydrate]]s or [[protein]]s. All [[cell membrane]]s 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 [[catabolism|catabolic]] processes which generate energy and [[primary metabolite]]s from fatty acids, and [[anabolic]] processes which create biologically important molecules from fatty acids and other dietary [[carbon]] sources.

== 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 [[Citric acid cycle|TCA cycle]].

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

#Dehydrogenation by [[acyl-CoA dehydrogenase]], yielding 1 [[FAD|FADH<sub>2</sub>]]
#Hydration by [[enoyl-CoA hydratase]]
#Dehydrogenation by [[3-hydroxyacyl-CoA dehydrogenase]], yielding 1 [[NAD|NADH]]
#Cleavage by thiolase, yielding 1 [[acetyl-CoA]] and a fatty acid that has now been shortened by 2 carbons ([[acyl-CoA]])

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 [[redox|reduced]] and [[anhydrous]]. The energy yield from a [[gram]] of fatty acids is approximately 9 [[calorie|Kcal]] (39 kJ), compared to 4 Kcal/g (17 kJ/g) for carbohydrates. Since the [[hydrocarbon]] portion of fatty acids is [[hydrophobic]], these [[molecule]]s, 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 [[pound (mass)|lb]] (31 kg) of hydrated glycogen to have the energy equivalent  to 10 lb (5 kg) of [[fat]].

[[Hibernation|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 [[triglyceride]]s, 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 salt]]s for optimal activity of these enzymes.  People who have had their [[gallbladder]] [[cholecystectomy|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 [[chylomicron]]s or liposomes, which are released into the [[lacteals]], the capillaries of the [[lymph system]] and then into the [[blood]]. Eventually, they bind to the membranes of [[hepatocyte]]s, [[adipocyte]]s or [[muscle fiber]]s, 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 [[Very low density lipoprotein|VLDL]] and  [[Low density lipoprotein|LDL]]. Fatty acids synthesized by the liver are converted to triglyceride and transported to the blood as [[Very low density lipoprotein|VLDL]]. In peripheral tissues, lipoprotein lipase digests part of the VLDL into LDL and free fatty acids, which are taken up for metabolism. This is done by the removal of the triglycerides contained in the VLDL. What is left of the VLDL absorbs cholesterol from other circulating lipoproteins, becoming LDLs. LDL is absorbed via [[LDL receptor]]s. 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. The liver controls the concentration of cholesterol in the blood by removing LDL. Another type of lipoprotein known as [[High-density_lipoprotein|high density lipoprotein, or HDL]] collects cholesterol, glycerol and fatty acids from the blood and transport them to the liver. In summary: 
* Chylomicrons carry diet-derived lipids to body cells
* VLDL's carry lipids synthesized by the liver to body cells
* LDL's carry cholesterol around the body
* HDL's carry cholesterol from the body back to the liver for breakdown and excretion.

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.

==Oxidation==
{{Main|Fatty acid degradation}}
Fatty acid degradation is the process in which [[fatty acids]] are broken down, resulting in release of energy. It includes three major steps: 

*Activation and transport into [[mitochondria]],
*[[β-oxidation]]
*[[Electron transport chain]]

Fatty acids are transported across the [[outer mitochondrial membrane]] by [[carnitine-palmitoyl transferase I]] (CPT-I), and then couriered across the [[inner mitochondrial membrane]] by [[carnitine]]<ref>De Vivo, D. C. ''et al.'' (1998) ''L-Carnitine Supplementation in Childhood Epilepsy: Current Perspectives. ''Epilepsia''. Vol. 39(11), p.1216-1225. [http://www.blackwell-synergy.com/doi/abs/10.1111/j.1528-1157.1998.tb01315.x]</ref>. Once inside the [[mitochondrial matrix]], fatty acyl-carnitine reacts with [[coenzyme A]] to release the fatty acid and produce [[acetyl-CoA]]. CPT-I is believed to be the [[rate limiting step]] in fatty acid oxidation.

Once inside the mitochondrial matrix, fatty acids undergo [[β-oxidation]]. During this process, two-carbon molecules [[acetyl-CoA]] are repeatedly cleaved from the fatty acid. Acetyl-CoA can then enter the [[Citric acid cycle|TCA cycle]], which produces [[NADH]] and [[FADH]]. NADH and FADH are subsequently used in the [[electron transport chain]] to produce [[Adenosine triphosphate|ATP]], the energy currency of the cell.

==Synthesis==
:''See [[Fatty acid]]''
:''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.<ref>Zechner R., Strauss J.G., Haemmerle G., Lass A., Zimmermann R. (2005) Lipolysis: pathway under construction. Curr. Opin. Lipidol. 16, 333-340.</ref>.  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|protein phosphatase 2A]], which dephosphorylates HSL, thereby inhibiting its activity.  Insulin also activates the enzyme [[phosphodiesterase]], which breaks down cAMP and stops 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==
<references/>

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

==External links==
*[http://www2.ufp.pt/~pedros/bq/fatty.htm The chemical logic behind the metabolism of fatty acid]

{{Lipid metabolism}}
{{MetabolismMap}}

[[Category:Metabolism]]
[[Category:Fatty acids]]
[[Category:Hepatology]]

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