Sunday, December 5, 2021
Mitochondrial Health

Fatty Acid Mobilization and Carnitine Shuttle (Updated)



The free-floating fatty acids, released from adipose tissues to the blood, bind to carrier protein molecule known as serum albumin that carry the fatty acids to the cytoplasm of target cells such as the heart, skeletal muscle, and other tissue cells, where they are used for fuel. But before the target cells can use the fatty acids for ATP production and β oxidation, the fatty acids with chain lengths of 14 or more carbons must be activated and subsequently transported into mitochondrial matrix of the cells in three enzymatic reactions of the carnitine shuttle.
The first reaction of the carnitine shuttle is a two-step process catalyzed by a family of isozymes of acyl-CoA synthetase that are found in the outer mitochondrial membrane, where they promote the activation of fatty acids by forming a thioester bond between the fatty acid carboxyl group and the thiol group of coenzyme A to yield a fatty acyl–CoA.
When low levels of glucose in the blood trigger the release of glucagon, 1 the hormone binds its receptor in the adipocyte membrane and thus stimulates adenylyl cyclase, via a G protein, to produce cAMP. This acti- vates PKA, which phosphorylates the hormone-sensitive lipase (HSL) and perilipin molecules on the surface of the lipid droplet. Phosphoryla- tion of perilipin causes dissociation of the protein CGI from perilipin. CGI then associates with the enzyme adipose triacylglycerol lipase (ATGL), activating it. Active ATGL converts triacylglycerols to diacylglycerols. The phosphorylated perilipin associates with phosphorylated HSL, allowing it access to the surface of the lipid droplet, where it converts diacylglycerols to monoacylglycerols. A third lipase, monoacylglycerol lipase (MGL) , hydrolyzes monoacylglycerols. Fatty acids leave the adipocyte, bind serum albumin in the blood, and are carried in the blood; they are released from the albumin and enter a myocyte via a specific fatty acid transporter. In the myocyte, fatty acids are oxidized to CO2, and the energy of oxidation is conserved in ATP, which fuels muscle contraction and other energy-requiring metabolism in the myocyte.

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