MCAT Biochemistry
Triglyceride catabolism involves the breakdown of stored fatty acids, which serve as a primary fuel source for tissues. Most fatty acids undergo beta-oxidation within the mitochondria, while very long-chain fatty acids are oxidized within peroxisomes. Stored as triglycerides in adipose tissue, fatty acids are released into the bloodstream through the action of hormone-sensitive lipase, which hydrolyzes triglycerides into glycerol and free fatty acids.
Long-chain fatty acyl-CoAs require the carnitine shuttle to cross the mitochondrial membrane, with the involvement of three proteins: CAT-1, CACT, and CAT-2. Once inside the mitochondria, beta-oxidation proceeds through a four-step process involving acyl-CoA dehydrogenase, enoyl CoA hydratase, 3-hydroxyacyl CoA dehydrogenase, and thiolase. The end product of beta-oxidation, acetyl-CoA, can either enter the TCA cycle or be used to make ketone bodies, depending on the body's needs and energy status.
Lesson Outline
<ul> <li>Fatty acids are part of the family of lipids</li> <li>Main storage of fuel</li> <li>Most tissues can oxidize fatty acids for energy</li> <ul> <li>Exceptions: red blood cells and central nervous system</li> </ul> <li>Cardiac muscle uses fatty acids as primary fuel source</li> <li>Understanding triglyceride catabolism and beta-oxidation of even-chain fatty acids</li> <li>Occurs in mitochondria and peroxisomes (for very long chain fats)</li> <li>Most fatty acids stored as triglycerides in adipose tissue</li> <li>Hormone-sensitive lipase hydrolyzes triglycerides into glycerol and free fatty acids</li> <ul> <li>Regulated by insulin, glucagon, and epinephrine</li> </ul> <li>Glycerol can feed into gluconeogenesis</li> <li>Fatty acids must be activated before entering mitochondria</li> <ul> <li>Acyl-CoA synthetase uses ATP to make fatty acyl-CoA from a free fatty acid and CoA</li> </ul> <li>Carnitine shuttle transports long-chain fatty acids into mitochondrial matrix</li> <ul> <li>Contains 3 proteins: CAT-1, CACT, and CAT-2</li> <li>Malonyl CoA inhibits CAT-1</li> </ul> <li>Once inside mitochondria, beta oxidation begins</li> <li>Beta oxidation broken into 4 steps:</li> <ul> <li>1. Acyl-CoA dehydrogenase oxidizes fatty acyl CoA to enoyl CoA, making 1 FADH2</li> <li>2. Enoyl CoA hydratase adds water to enoyl CoA, making 3-hydroxyacyl CoA</li> <li>3. 3-Hydroxyacyl CoA dehydrogenase oxidizes 3-hydroxyacyl CoA to 3-ketoacyl CoA, making 1 NADH</li> <li>4. Thiolase cuts 3-ketoacyl CoA into 2-carbon acetyl CoA and a smaller acyl CoA with 2 fewer carbons</li> </ul> <li>These steps are repeated as necessary until all carbons are used</li> <li>Acetyl-CoA can enter TCA cycle or be used to make ketone bodies</li> </ul>
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FAQs
The initial step in triglyceride catabolism is the hydrolysis of triglycerides into free fatty acids and glycerol by lipases, specifically hormone-sensitive lipase (HSL). This process is regulated by hormones like insulin (which inhibits HSL) and glucagon, epinephrine, and norepinephrine (which activate HSL).
Fatty acids are transported into the mitochondria using the carnitine shuttle system. First, the fatty acid is activated by acyl-CoA synthetase, converting it to fatty acyl-CoA. Then, carnitine palmitoyltransferase I (CPT I) exchanges CoA for carnitine, forming fatty acyl-carnitine. The fatty acyl-carnitine is transported across the mitochondrial membrane by a carnitine-acylcarnitine translocase. Once inside the mitochondria, CPT II reattaches CoA, forming fatty acyl-CoA and freeing carnitine to be transported back to the cytosol.
Beta oxidation of even chain fatty acids involves four main steps: (1) Dehydrogenation: Removal of hydrogen atoms from the α and β carbons of fatty acyl-CoA, catalyzed by acyl-CoA dehydrogenase enzymes, to create a double bond and transferring the electrons to FAD, producing FADH₂. (2) Hydration: Addition of water across the double bond, converting the β carbon into a hydroxyl group, catalyzed by enoyl-CoA hydratase. (3) Dehydrogenation again: Conversion of the hydroxyl group into a ketone, catalyzed by hydroxyacyl-CoA dehydrogenase, and transferring the electrons to NAD⁺, producing NADH. (4) Thiolysis: Cleavage of the fatty acyl-CoA, catalyzed by β-ketothiolase, resulting in the release of acetyl-CoA and a fatty acyl-CoA that is shortened by two carbons.
Acetyl-CoA is the end product of each round of beta oxidation and serves as the key molecule connecting fatty acid catabolism with the TCA cycle. It enters the TCA cycle by combining with oxaloacetate to form citrate, and it is subsequently oxidized in the cycle to generate ATP, NADH, and FADH₂, which are used for energy production in the cell.
Ketone bodies are water-soluble molecules produced from fatty acids during periods of low glucose availability, such as fasting, prolonged exercise, or low carbohydrate diets. They are synthesized in the liver from excess acetyl-CoA that cannot enter the TCA cycle due to a shortage of oxaloacetate. The three main ketone bodies are acetone, acetoacetate, and beta-hydroxybutyrate. They can be transported to peripheral tissues and converted back to acetyl-CoA to generate ATP in a process called ketolysis.
