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Technical Report #2 – Metabolism of Fatty Acids: Mitochondria, The Carnitine Shuttle, Beta-Oxidation, and Ketogenesis

Once inside a cell, fatty acids can be oxidized (burned) to release energy. The site of energy production with-in the cell is a membranous organelle called a mito-chondrion. Long chain fatty acids cannot simply enter the mitochondria by themselves; they must be ac-tively transported across the mitochondrial membrane (Record et al, 1986).

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First, the fatty acid is converted to its active form, acyl-CoA. The long chain acyl-CoA is then transesterified to L-carnitine by carnitine acyltransferase I (CAT I), generating acylcarnitine. A protein carrier embed-ded within the mito-chondrial membrane acts as a shuttle to transport the LCFA-carnitine complexes into the inner mito-chondrial space . Once there, carnitine acyl-transferase II (CAT II) releases the fatty acid in its activated form, acyl-CoA (figure 1).The enzymes respon-sible for oxidation of fatty acids are located inside the mitochon-dria. Therefore, if fatty acids are not permitted to enter the mitochondria they cannot be burned for energy. Entry into the mitochon-dria is regulated by the activity of the carnitine shuttle. This transport system is not very active if carbohy-drates are available because carbohydrate metabolism generates malonyl-CoA, which inhibits CAT I. In addition, glucagon (the hormonal antagonist of insu-lin) is involved in stimulating mobilization of body fat stores and use of fat for energy. Following carbo-hydrate ingestion insulin is released and glucagon is suppressed, so very little body fat is used for energy.

After carbohydrate reserves have been diminished, the body releases glucagon as a signal to begin burning fat. These are the reasons why fat stores are drawn upon for energy only after glycogen has been depleted.The inhibition of CAT I by malonyl-CoA represents a regulatory mechanism to prevent the wasteful use of energy substrates. Generally speaking, the body uses carbohydrate fuels first and stores fat as an energy reserve. Fat contains twice the energy density of car-bohydrate (9 calories per gram versus 4 calories per gram) and does not require water for storage, as does carbohydrate. Fat is thus a more efficient molecule for energy storage. Ani-mals are able to store only a small amount of energy as carbohydrate (in the form of liver and muscle glycogen) but can store a virtually unlimited amount of energy as fat.In contrast to long chain fats, MCFAs (includes MCTs) are immediately available for energy. Me-dium chain fatty acids are retained by the liver, where they are rapidly and extensively oxidized (Bach and Babayan, 1982). Medium chain fatty acids can en-ter the mitochondria by passive diffusion and do not require the carnitine transport system (Record et al, 1986; Bach and Babayan, 1982).

MCFAs thus can be used for energy even in the presence of carbohydrates, and in fact have a carbohydrate-sparing effect (Lavau and Hashim, 1978; Cotter et al, 1987). Once inside the mitochondria all fatty acids are burned in a process tion. During beta-oxidation, blocks of two carbon atoms are removed from the activated fatty acid (acyl-CoA) to form acetyl-CoA (figure 2). The intermediate acetyl-CoA can then undergo several metabolic fates: i) it can enter the Krebs cycle to generate ATP; ii) it can be used to generate ketone bodies; iii) it can be used as a substrate for fatty acid synthesis or elonga-tion; or iv) it can be consumed in an energy trans-forming process known as reversed electron transfer (Bach and Babayan, 1982; Berry et al, 1985; Crozier et al, 1987).The vast majority of MCFAs (includes MCTs) are re-tained in the liver where they undergo beta-oxidation, producing acetyl-CoA. To enter the Krebs cycle (the body’s central energy producing pathway) the acetyl-CoA combines with oxaloacetate, producing citrate. Me-dium chain fatty acids are oxidized in the liver so rapidly that the supply of oxaloacetate becomes limiting.

As a result, the capacity of the Krebs cycle is overwhelmed and a large proportion of the acetyl-CoA is directed to-ward the synthesis of ketone bodies (Bach and Babayan, 1982). This process is known as “ketogenesis” (figure 3). Ketone bodies are released from the liver into the blood and are subsequebtly taken up by muscles and used as fuel. LCT ingestion also causes an increase in blood levels of ketone bodies during fasting, but only MCT will still produce ketone bodies if carbohydrates are con-currently ingested (Sucher, 1986). Once inside muscle cells, ketone bodies are converted back to acetyl-CoA, which then enters the Krebs cycle to produce ATP. The conversion of MCFAs to ketone bodies occurs even in the presence of carbohydrates. This additional source of energy decreases glucose uptake and utilization (Lavau and Hashim, 1978) and thus may extend endurance by sparing glycogen (Cotter et al, 1987).

References

Bach and Babayan, Medium chain triglycerides: an update. Am. J. Clin. Nutr. 36:950-962 (1982).

Berry, Clark, Grivell, and Wallace, The contribution of hepatic metabolism to diet-induced thermogenesis. Metab. 34: 141-147 (1985).

Cotter, Taylor, Johnson, and Rowe, A metabolic com-parison of pure long chain triglyceride lipid emulsion (LCT) and various medium chain triglyceride (MCT)

LCT combination emulsions in dogs. Am. J. Clin. Nutr. 45: 927-939 (1987).

Crozier, Bois-Joyeux, Chanez, Girard, and Peret, Metabolic effects induced by long-term feeding of medium chain triglycerides in the rat. Metabolism 36: 807-814 (1987).

Lavau and Hashim, Effect of medium chain triglycer-ide on lipogenesis and body fat in the rat. J. Nutr. 108: 613-620 (1978).

Record, Kolpek, and Rapp, Long chain versus medium chain length triglycerides a review of metabolism and clinical use. Nutr. Clin. Prac. 1:129-135 (1986).

Sucher, Medium chain triglycerides: a review of their enteral use in clinical nutrition. Nutr. Clin. Prac. 44: 146-150 (1986).

2018-03-13T11:10:22-04:00 August 21st, 2009|Medium Chain Triglyceride Technical Reports|

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