Lipid Metabolism

What are the roles of the fatty acid oxidation and ketogenic pathways in converting lipids to NADH and FADH2?

● Fatty acyl-CoA synthetases activate short-, medium-, and long-chain fatty acids in the cytosol using an ATP dependent reaction involving formation of a fatty acyl-adenylate intermediate. The spontaneity of this reaction is enhanced by pyrophosphate hydrolysis.

● Fatty acid degradation converts redox energy available in electron-rich fatty acids into ATP by producing acetyl-CoA, which is oxidized by the citrate cycle, as well as FADH2 and NADH, which are oxidized by the electron transport system.

● The β-oxidation pathway of fatty acid degradation involves the sequential thiolytic cleavage of fatty acyl-CoA substrates at the β carbon of the fatty acid, releasing acetyl-CoA and a fatty acyl-CoA product that is two carbons (C2) shorter.

● Each cycle of the β-oxidation pathway involves four reactions: (1) an oxidation catalyzed by acyl-CoA dehydrogenase, (2) a hydration catalyzed by enoyl-CoA hydratase, (3) an oxidation catalyzed by 3-hydroxyacyl-CoA dehydrogenase, and (4) a thiolysis catalyzed by β-ketoacyl-CoA thiolase.

● When carbohydrate sources are limited, ongoing β oxidation in liver cell mitochondria results in the buildup of excess acetyl-CoA. Ketogenesis is a process in liver cell mitochondria that takes this excess acetyl-CoA and converts it to acetoacetate and d-β-hydroxybutyrate, two energy rich compounds known as ketone bodies. Spontaneous decarboxylation of acetoacetate generates acetone.

● Acetoacetate and d-β-hydroxybutyrate are exported from the liver and used by skeletal and heart muscle to generate acetyl-CoA for energy conversion reactions. Even the brain, which prefers glucose as an energy source, can adapt to using ketone bodies as chemical energy during times of extreme starvation.

How does the enzyme fatty acid synthase convert acetyl-CoA into palmitate?

● Each cycle of the fatty acid synthesis pathway involves four reactions: (1) condensation catalyzed by β-ketoacyl-ACP synthase (KS), (2) reduction catalyzed by β-ketoacyl-ACP reductase (KR), (3) dehydration catalyzed by β-hydroxyacyl-ACP dehydratase (DH), and (4) reduction catalyzed by enoyl-ACP reductase (ER).

● Malonyl-CoA is the activated substrate in fatty acid synthesis and is produced by the rate-limiting enzyme acetyl-CoA carboxylase. This is a biotin-dependent enzyme that has three functional activities: a biotin carboxylase, a biotin carboxyl carrier, and a carboxyltransferase.

● The ACP subunit in fatty acid synthase requires an enzyme linked phosphopantetheine coenzyme group derived from vitamin B5 (pantothenate), which provides a sulfhydryl attachment site for the growing hydrocarbon chain.

● The first step in fatty acid synthesis requires malonyl/acetyl-CoA ACP transacylase (MAT) to catalyze the priming reaction, which transfers the acetyl group from acetyl-CoA to the coenzyme sulfhydryl group in ACP and then translocates it to a cysteine residue in the KS domain.

● With substrates attached to both the KS domain (acetyl-S-Cys) and ACP (malonyl-ACP), the four-step reaction sequence of condensation, reduction, dehydration, and reduction repeats seven times to yield palmitoyl-ACP, which is released as palmitate from ACP after hydrolysis by palmitoyl thioesterase (TE).

● Triacylglycerols and glycerophospholipids are derived from diacylglycerol-3-phosphate, also called phosphatidic acid, whereas sphingolipids are derived from ceramide.

● The most abundant membrane lipids in cells are glycerophospholipids, which include phosphatidylserine, phosphatidylethanolamine, and phosphatidylinositol. Phosphatidic acid is the building block for all three of these glycerophospholipids.

What are the reactions in the cholesterol synthesis pathway and how do statin drugs lower serum cholesterol levels?

De novo cholesterol biosynthesis consists of four stages: (1) synthesis of mevalonate, a C6 compound, which is generated by the rate-limiting enzyme HMG-CoA reductase; (2) conversion of mevalonate to isopentenyl pyrophosphate (C5) and dimethylallyl pyrophosphate; (3) formation of squalene (C30) from isopentenyl pyrophosphate and dimethylallyl pyrophosphate; and (4) squalene cyclization to form cholesterol (C27).

● Liver cholesterol has three metabolic fates: (1) it is stored as cholesterol esters in lipid droplets; (2) it is packaged into lipoproteins and exported to the circulatory system; and (3) it is converted into bile acids, which aid in digestion of fatty foods.

● There are five major classes of lipoproteins, which differ in density depending on their size and the ratio of protein to lipid: (1) chylomicrons contain large amounts of dietary triacylglycerols obtained in the small intestine, (2) very low-density lipoproteins (VLDLs) are synthesized in the liver and transport fatty acids in the form of triacylglycerols, (3) intermediate-density lipoproteins (IDLs) are VLDL remnants, (4) low-density lipoproteins (LDLs) transport large amounts of cholesterol esters and are known as “bad cholesterol,” and (5) high-density lipoproteins (HDLs) are cholesterol scavengers and are known as “good cholesterol.”

 ● In addition to de novo cholesterol biosynthesis, liver cholesterol is also obtained by endocytosis of serum LDL, which is initiated by LDL binding to LDL receptors on the cell surface. Low levels of intracellular liver cholesterol stimulate LDL receptor expression, leading to increased LDL endocytosis and decreased serum LDL levels.

● Inhibition of HMG-CoA reductase activity by statin drugs such as simvastatin decreases liver cholesterol and induces LDL receptor expression through proteolytic activation of sterol regulatory element binding proteins (SREBPs). Statin drugs therefore decrease the risk of cardiovascular disease by lowering serum LDL levels.

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