FATTY ACID OXIDATION Occurs inside mitochondria Activation of Fatty acids The first step occurs at the outer mito membrane by the acyl-CoA synthetases. (3 diff isozymes that are specific for short, intermediate and long chain FA exist).

CARNITINE CYCLE The 2nd step is formation of acyl-carnitine by the Carnitine acyltransferase I in the outer mito membrane. The acyl-carnitine diffuses through to the intermembrane space. In the 3rd step, acyl gp from acyl-carnitine is transferred to CoA by the enzyme Carnitine acyltransferase II in the inner mito membrane. Importance of Carnitine shuttle: This carnitine-mediated entry process is the rate limiting step for FA oxidation and is also a regulation point. Malonyl CoA normally inhibits Carnitine acyltransferase I enzyme

FATTY ACID OXIDATION There are basically 4 main rxns Dehydrogenation Hydration Thiolysis The acetyl CoA formed can be oxidized via the TCA cycle.

OXIDATION – UNSATURATED FATTY ACID Two additional enzymes are required Enoyl-CoA isomerase Enoyl-CoA reductase

KETONE BODIES - FORMATION Formed even under normal conditions (from acetyl CoA not oxidized by TCA cycle). Includes acetone, acetoacetate and β-hydroxybutyrate. They are transported to extrahepatic tissues as fuel, converted to acetyl coA & oxidized by TCA cycle. But, in uncontrolled diabetes or severe starvation, an over production of ketone bodies occur leading to acidosis or ketosis. Mechanism: During starvation the body tries to form Glc via gluconeogenesis. This depletes TCA cycle intermediates stopping acetyl CoA oxidation. Likewise, during uncontrolled diabetes (due to insulin deficiency) cells can’t take up glc from blood either to breakdown or convert to fat. Malonyl CoA conc decreases, inhibition of CAT-I is relieved, FA enter into mito & get degraded to acetyl CoA which can’t pass thro TCA cycle because they have been diverted to gluconeogenesis. This excess acetyl CoA results in ketone body formation.