Carnitine homeostasis

Brass EP, Mayer MD, Mulford DJ, Stickler TK, Hoppel CHL. Impact on carnitine homeostasis of short-term treatment with the pivalate prodrug cefditoren pivoxil. Clin Pharmacol Ther 2003 73 338-47. 

Holme E, Jodal U, Linstedt S, Nordin I. Effects of pivahc acid-containing prodrugs on carnitine homeostasis and on response to fasting in children. Scand J Clin Lab Invest... 

Carnitine is present in biological systems as both carnitine and acylcarnitines generated in tissues (see next section). Carnitine deficiency may be a primary defect due to a genetic defect in carnitine transport systems or may be secondary to other metabolic derangements. Normal carnitine homeostasis requires reabsorption of carnitine in the renal tubule via a specific transport protein. This same transport protein is responsible for the accumulation of carnitine in heart and skeletal muscle. If this transport system is not functional, then carnitine cannot reach tissues, and primary carnitine... 

Carnitine supplementation is also critical in these patients. In acute severe metabolic crises, carnitine can be administered intravenously. Oral carnitine supplementation can be used for chronic maintenance therapy. Note that as the primary transport defect will still be present, carnitine supplementation cannot normalize the patient s carnitine homeostasis. 

For more about the toxicity of pivalic acid, another common prodrug byproduct, see Brass, E.P. Pivalate-generating prodrugs and carnitine homeostasis in man. Pharmacol. Rev. 2002, 54, 589-598. 

Roe CR, et al. Carnitine homeostasis in the organic acidemias. In Fatty acid oxidation clinical, biochemical, and molecular aspects. Alan R Liss, Inc., Manhattan 1990. p. 383 02. 

Ringseis, R., G. Wen, and K. Eder. 2012. Regulation of genes involved in carnitine homeostasis by PPARa across different species (rat, mouse, pig, cattle, chicken, and human). PPAR Research 2012 868317. 

As mentioned previously, the diet can provide a significant amount of carnitine, approximately 50% (100 to 300 mg/day) in the form of dther free carnitine or short-and long-chain FAs. This is true for individuals who consume large amounts of beef, pork, and lamb. In addition, this intake is suffident to maintain normal carnitine homeostasis. Vegetarians who consume less than 0.5 /body weight/day must rely on endogenous production of carnitine to maintain homeostasis. " ... 

In general, carnitine homeostasis is maintained several ways, ineluding absorption from dietary sources, modest rates of biosynthesis, and reabsorption, which is very efficient. Carnitine in its esterified forms as short- and long-ehain aeylcanutines is found in several tissues and cellular fluid. In a healthy 70-kg adult the pool of... 

Brass, E.P, Hoppel, C.L., and Hiatt, W.R., Effects of intravenous L-carnitine on carnitine homeostasis and fuel metabolism during exercise in humans. Clin. Pharmacol. Then, 55, 681-692, 1994. 

The second section of the book is Fuel Metabolism and Energetics. Important pathways and enzymes involved in fuel utilization are discussed in the chapters Pyruvate Dehydrogenase Complex Deficiency Mitochondrial En-cephalomyopathy, and Systemic Carnitine Deficiency. The role of gluconeogenesis in glucose homeostasis is illustrated by a discussion in the chapter Neonatal Hypoglycemia. 

As Otto Shape runs, his skeletal muscles increase their use of ATP and their rate of fuel oxidation. Fatty acid oxidation is accelerated by the increased rate of the electron transport chain. As ATP is used and AMP increases, an AMP-dependent protein kinase acts to facilitate fuel utilization and maintain ATP homeostasis. Phosphorylation of acetyl CoA carboxylase results in a decreased level of malonyl CoA and increased activity of carnitine palmitoyl CoA transferase I. At the same time, AMP-dependent protein kinase facilitates the recruitment of glucose transporters into the plasma membrane of skeletal muscle, thereby increasing the rate of glucose uptake. AMP and hormonal signals also increase the supply of glucose 6-P from glycogenoly-sis. Thus, his muscles are supplied with more fuel, and all the oxidative pathways are accelerated. 

Once carnitine is produced, the intracellular homeostasis is controlled by different membrane transporters called organic cation transporters (OCTNs), specifically OCTN2. OCTN2 acts to operate on both the intestinal and renal absorption of L-camitine, in addition to playing a major role in tissue distribution and transport rates within circulation. This transporter has been implieated in the deficiencies mentioned earlier in this chapter, as research has shown that OCTN2 is directly inhibited by various agents and substances identified as eausing systemic carnitine deficiencies. ... 

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