Ketogenesis

Information about Ketogenesis

Ketogenesis Pathway

Ketogenesis is the process by which ketone bodies are produced as a result of fatty acid breakdown.

Production

Ketone bodies are produced mainly in the mitochondria of liver cells. Its synthesis occurs in response to low carbohydrate levels in the blood, and after exhaustion of cellular carbohydrate stores, such as glycogen. The production of ketone bodies is then initiated to make available energy that is stored as fatty acids also known as lipids. Fatty acids are enzymatically broken down in β-oxidation to form acetyl-CoA. Normally, acetyl-CoA is further oxidized and its energy transferred as electrons to NADH, FADH₂, and GTP in the citric acid cycle (TCA cycle). However, if the amounts of acetyl-CoA generated in fatty-acid β-oxidation challenge the processing capacity of the TCA cycle or if activity in the TCA cycle is low due to low amounts of intermediates such as oxaloacetate, acetyl-CoA is then used instead in biosynthesis of ketone bodies via acetoacyl-CoA and β-hydroxy-β-methylglutaryl-CoA (HMG-CoA).

Besides its role in the synthesis of ketone bodies, HMG-CoA is also an intermediate in the synthesis of cholesterol.

Types of ketone bodies

The three ketone bodies are:

Acetoacetate; if not oxidized to form usable energy, it is the source of the two other ketone bodies below.
Acetone; is not used as an energy source, but is instead exhaled or excreted as waste.
β-hydroxybutyrate; it is not technically a ketone according to IUPAC nomenclature.

Each of these compounds are synthesized from acetyl-CoA molecules.

Regulation

Ketogenesis may or may not occur, depending on levels of available carbohydrates in the cell or body. This is closely related to the paths of acetyl-CoA:

When the body has ample carbohydrates available as energy source, glucose is completely oxidized to CO₂; acetyl-CoA is formed as an intermediate in this process, first entering the citric acid cycle followed by complete conversion of its chemical energy to ATP in oxidative phosporylation.
When the body has excess carbohydrates available, some glucose is fully metabolized, and some of it is stored by using acetyl-CoA to create fatty acids. (CoA is also recycled here.)
When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.

Pathology

Ketone bodies are created at moderate levels in everyone's bodies, such as during sleep and other times when no carbohydrates are available. However, when ketogenesis is happening at higher than normal levels, the body is said to be in a state of ketosis. It is unknown whether ketosis has negative long-term effects or not.

Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these ketone bodies are too high, the pH of the blood drops, resulting in ketoacidosis. This is very rare, and, in general, happens only in untreated Type I diabetes (see diabetic ketoacidosis) and in alcoholics after binge drinking and subsequent starvation (see alcoholic ketoacidosis).

External links

Fat metabolism at University of South Australia
James Baggott. (1998) Synthesis and Utilization of Ketone Bodies at University of Utah Retrieved 23 May 2005.
Musa-Veloso K, Likhodii SS, Cunnane SC (2002). "Breath acetone is a reliable indicator of ketosis in adults consuming ketogenic meals". Am. J. Clin. Nutr. 76 (1): 65-70. PMID 12081817.
Richard A. Paselk. (2001) Fat Metabolism 2: Ketone Bodies at Humboldt State University Retrieved 23 May 2005.

• • [ e] Metabolism: lipid metabolism
Lipid production	Acetyl-CoA carboxylase - Fatty acid synthesis: Beta-ketoacyl-ACP synthase - Β-Ketoacyl ACP reductase - 3-Hydroxyacyl ACP dehydrase - Enoyl ACP reductase unsaturated (Enoyl CoA isomerase, 2,4 Dienoyl-CoA reductase) - odd chain (Propionyl-CoA carboxylase) - Fatty acid synthase - Long fatty acyl CoA synthetase
Lipid degradation	Acyl transport: Carnitine palmitoyltransferase I - Carnitine-acylcarnitine translocase - Carnitine palmitoyltransferase II Beta oxidation: Acyl CoA dehydrogenase (ACADL, ACADM, ACADS, ACADVL) - Enoyl-CoA hydratase - 3-Hydroxyacyl CoA dehydrogenase - Acetyl-CoA C-acyltransferase - Mitochondrial trifunctional protein Ketogenesis: HMG-CoA synthase - HMG-CoA lyase - Other: Malonyl-CoA decarboxylase
Phospholipids	Diacylglycerol kinase
Steroids	HMG-CoA reductase - Farnesyl-diphosphate farnesyltransferase - Squalene monooxygenase - Lanosterol synthase - CYP51A1
Prostanoids	Cyclooxygenase - Thromboxane-A synthase - Prostacyclin synthase - Prostaglandin E synthase - Prostaglandin D2 synthase
Leukotrienes	Arachidonate 5-lipoxygenase - 5-Lipoxygenase activating protein - Leukotriene A4 hydrolase - Leukotriene C4 synthase
Bile acids	Cholesterol 7 alpha-hydroxylase

Ketone bodies are three water soluble compounds that are produced as by-products when fatty acids are broken down for energy. They are used as a source of energy in the heart and brain. In the brain, they are a vital source in fasting.
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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.
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liver is an organ present in vertebrates and some other animals. It plays a major role in metabolism and has a number of functions in the body, including glycogen storage, decomposition of red blood cells, plasma protein synthesis, and detoxification.
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Glycogen is a polysaccharide of glucose (Glc) which functions as the primary short term energy storage in animal cells. It is made primarily by the liver and the muscles, but can also be made by the brain, uterus, and the vagina.
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Types of Fats in Food

Unsaturated fat
Monounsaturated fat
Polyunsaturated fat
Trans fat
Omega: 3, 6, 9

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Lipids can be broadly defined as any fat-soluble (hydrophobic), naturally-occurring molecules. The term is more-specifically used to refer to fatty-acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids) as well as other fat-soluble sterol-containing
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Acetyl-CoA is an important molecule in metabolism, used in many biochemical reactions. Its main use is to convey the carbon atoms within the acetyl group to Krebs Cycle to be oxidized for energy production.
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FADH2 (or 1,5-dihydro-FAD) is a derivative of FAD.

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