Fig. 2.

The Pathway of Mitochondrial Fatty Acid Oxidation in the Liver. Long-chain fatty acids are transported into the liver via a complex of proteins consisting of fatty acid translocase (FAT, aka CD36), liver-fatty acid binding protein (L-FABP), caveolins and phospholipase A2 (PL). In the cytosol fatty acids are activated into fatty acyl-CoA by the actions of long-chain acyl-CoA synthetases (ACSL). Acyl-CoAs are unable to diffuse out of the cell and are committed to different cellular processes such as lipid synthesis or oxidation. The metabolic fate of acyl-CoAs is likely mediated by unique ACSL isoforms. Another pathway that mediates fatty acid import into the hepatocytes is via fatty acid transport protein 5 (FATP5). This enzyme complex additionally contains very long-chain acyl-CoA synthetase 6 (ACSVL6) activity to generate Acyl-CoA. Acyl-CoAs designated for energy production are conjugated to carnitine by carnitine palmitoyltransferase 1 alpha (CPA1a). This is the rate limiting enzyme of fatty acid oxidation accounting for 80% of the control over the pathway. Carnitine is transported into the hepatocytes by OCTN2. Acyl-carnitines can cross outer mitochondrial membrane and are transported across the inner mitochondrial membrane by carnitine-acylcarnitine translocase (CACT) in an exchange for free carnitine transported from mitochondrial matrix into inter membrane space. Inside the mitochondrial matrix carnitine palmitoyltransferase 2 (CPT2) converts acyl-carnitines into free carnitine and acyl-CoA. Beta oxidation involves a four-step process where long chain acyl-CoA are progressively shortened by two carbons to generate acetyl-CoA and two electrons. The first step dehydrogenates acyl-CoA into 2-enoly-CoA, and is mediated by acyl-CoA dehydrogenases (ACADs) of different chain lengths. This dehydrogenation step yields FADH₂, which donates electrons to complex II of the mitochondrial electron transport (ETC) chain for ATP production. The next three steps are mediated by mitochondrial trifunctional protein (MTP). The second step is hydration step and it produces 3-hydroxyacyl-CoA by the action of 2-enoyl-CoA hydratases (ECH). The third step is another dehydrogenation step mediated by 3-hydroxyacyl-CoA dehydrogenase (HADH) to produce 3-ketoacyl-CoA. This dehydrogenation step yields NADH, which donates electrons to complex I of the mitochondrial ETC chain for ATP production. The fourth step is mediated by acetyl-CoA acyltransferase 2 (ACAA2) to produce shortened acyl-CoA chain and acetyl-CoA. Acetyl-CoA can be further reduced in tricarboxylic acid (TCA) cycle and it yields citrate when energy stores are plentifully. During fasting, acetyl-CoA may be converted to ketone bodies that are used during fasting as energy source in other tissue.