Carnitine Shuttle System and Its effects

Free-floating fatty acids released from adipose tissue into the blood bind to a carrier protein molecule called serum albumin,which transports the fatty acids into the cytoplasm of target cells such as heart,skeletal muscle,and other tissue cells,where they for fuel.But before fatty acids can be used by target cells for ATP production and beta oxidation,fatty acids with chain lengths of 14 carbons or more must be activated and then transported into the cell's mitochondrial matrix through three enzymatic reactions of carnitine shuttling.The first reaction of carnitine shuttling is a two-step process catalyzed by a family of isozymes of acyl-CoA synthetases in the outer mitochondrial membrane, which facilitate the activation of fatty acid CoA by forming thioester bonds between fatty acids carboxyl and thiol groups to form acyl-CoA.In the first step of the reaction,acyl-CoA synthetase catalyzes the transfer of an adenosine monophosphate group (AMP) from an ATP molecule to a fatty acid,producing a fatty acyl-adenylate intermediate and a pyrophosphate group (PPi).The pyrophosphate formed by the hydrolysis of two high-energy bonds in ATP is immediately hydrolyzed by inorganic pyrophosphatase into two molecules of Pi.This reaction is highly exothermic,which drives the activation reaction forward and makes it more favorable.In the second step,the thiol group of cytosolic CoA attacks the acyladenylate,displacing AMP to form the thioester acyl-CoA.In the second reaction, acyl-CoA transiently attaches to the hydroxyl group of carnitine to form fatty acylcarnitine.This transesterification is catalyzed by an enzyme in the outer mitochondrial membrane called carnitine acyltransferase 1 (also known as carnitine palmitoyltransferase 1, CPT1).The formed fatty acylcarnitine esters subsequently diffuse across the intermembrane space and into the matrix facilitated by carnitine-acylcarnitine translocase (CACT) located on the inner mitochondrial membrane.For every molecule of fatty acylcarnitine that enters the matrix, this antiporter returns one molecule of carnitine from the matrix to the intermembrane space. 

In the third and final reaction of the carnitine shuttle,the fatty acyl group is transferred from the fatty acylcarnitine to CoA,regenerating the fatty acyl-CoA and free carnitine molecules.This reaction occurs in the mitochondrial matrix and is catalyzed by carnitine acyltransferase 2 (also known as carnitine palmitoyltransferase 2,CPT2) located on the inner surface of the inner mitochondrial membrane.The formed carnitine molecule is then shuttled back to the intermembrane space via the same cotransporter (CACT),while the fatty acyl-CoA enters the β-oxidation.

Regulates fatty acid beta oxidation 

The carnitine-mediated entry process is the rate-limiting factor for fatty acid oxidation and is an important regulatory point.

Suppress

When the liver is supplied with glucose that cannot be oxidized or stored as glycogen,the liver begins to actively manufacture triglycerides from the excess glucose.This increases the concentration of malonyl-CoA,the first intermediate in fatty acid synthesis,leading to inhibition of carnitine acyltransferase 1,which prevents access of fatty acids to the mitochondrial matrix for beta oxidation.This inhibition prevents the breakdown of fatty acids while synthesis occurs.

Activate

Activation of the carnitine shuttle occurs due to the need for fatty acid oxidation required for energy production.During intense muscle contractions or fasting, ATP concentrations decrease and AMP concentrations increase,leading to activation of AMP-activated protein kinase (AMPK).AMPK phosphorylates acetyl-CoA carboxylase,which normally catalyzes malonyl-CoA synthesis.This phosphorylation inhibits acetyl-CoA carboxylase,which in turn reduces malonyl-CoA concentrations.Lower levels of malonyl-CoA inhibit carnitine acyltransferase 1,allowing fatty acids to enter mitochondria and ultimately replenish the supply of ATP.

Transcription factor

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor that functions as a transcription factor.It acts on muscle,adipose tissue,and liver,turning on a set of genes essential for fatty acid oxidation,including the fatty acid transporters carnitine acyltransferase 1 and 2,and short,medium,long, and ultralong fatty acyl-CoA dehydrogenase acyl chains and related enzymes.PPARα acts as a transcription factor in two contexts; as previously described, when the energy demand for fat catabolism increases,such as during fasting between meals or during prolonged starvation. Among other things, the metabolic shift of the heart from fetus to newborn.In the fetus,the fuel sources in the heart muscle are glucose and lactate,but in the neonatal heart,fatty acids are the main fuel needed to activate PPARα,so it can in turn activate genes necessary for fatty acid metabolism at this stage.

Physiological effects

As an example of normal synthesis, a 70 kg (150 lb) person would produce 11-34 mg of carnitine per day.Adults eating a diet mixed with red meat and other animal products consume about 60-180 mg of carnitine per day,while vegans consume about 10-12 mg per day.The majority (54–86%) of carnitine obtained from the diet is absorbed in the small intestine before entering the bloodstream.The total amount of carnitine in a 70 kg (150 lb) human body is approximately 20 g (0.71 oz),almost all of which is contained in skeletal muscle cells.Carnitine is metabolized at a rate of approximately 400 μmol (65mg) per day, less than 1% of total body stores.