Chapter Summary, Questions Answers - Fatty Acid, Ketone Body, and Triacylglycerol Metabolism

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Chapter: Biochemistry : Fatty Acid, Ketone Body, and Triacylglycerol Metabolism

Generally a linear hydrocarbon chain with a terminal carboxyl group, a fatty acid can be saturated or unsaturated. Two fatty acids are dietary essentials: linoleic and α-linolenic acids.


Generally a linear hydrocarbon chain with a terminal carboxyl group, a fatty acid can be saturated or unsaturated. Two fatty acids are dietary essentials: linoleic and α-linolenic acids. Fatty acids are synthesized in the cytosol of liver following a meal containing excess carbohydrate and protein. Carbons used to synthesize fatty acids are provided by acetyl coenzyme A (CoA), energy by ATP, and reducing equivalents by nicotinamide adenine dinucleotide phosphate ([NADPH]; Figure 16.25) provided by the pentose phosphate pathway and malic enzyme. Citrate carries two-carbon acetyl units from the mitochondrial matrix to the cytosol. The regulated step in fatty acid synthesis is catalyzed by biotin-requiring acetyl CoA carboxylase (ACC) . Citrate allosterically activates ACC and long-chain fatty acyl CoAs inhibit it. ACC can also be activated by insulin and inactivated by adenosine monophosphate–activated protein kinase (AMPK) in response to epinephrine, glucagon, or a rise in AMP. The remaining steps in fatty acid synthesis are catalyzed by the multifunctional enzyme, fatty acid synthase, which produces palmitoyl CoA by adding two-carbon units from malonyl CoA to a series of acyl acceptors. Fatty acids can be elongated and desaturated in the endoplasmic reticulum (ER). When fatty acids are required for energy, adipocyte hormone-sensitive lipase (activated by epinephrine, and inhibited by insulin), along with other lipases, degrades stored triacylglycerol (TAG). The fatty acid products are carried by serum albumin to the liver and peripheral tissues, where oxidation of the fatty acids provides energy. The glycerol backbone of the degraded TAG is carried by the blood to the liver, where it serves as an important gluconeogenic precursor. Fatty acid degradation (β-oxidation) occurs in mitochondria. The carnitine shuttle is required to transport long-chain fatty acids from the cytosol to the mitochondrial matrix. A translocase and the enzymes carnitine palmitoyltransferases (CPT) I and II are required. CPT-I is inhibited by malonyl CoA, thereby preventing simultaneous synthesis and degradation of fatty acids. In the mitochondria, fatty acids are oxidized, producing acetyl CoA, nicotinamide adenine dinucleotide (NADH), and flavin adenine dinucleotide (FADH2). The first step in the β-oxidation pathway is catalyzed by one of four acyl CoA dehydrogenases, each with chain-length specificity. Medium-chain fatty acyl CoA dehydrogenase (MCAD) deficiency causes a decrease in fatty acid oxidation (process stops once a medium chain fatty acid is produced), resulting in hypoketonemia and severe hypoglycemia. Oxidation of fatty acids with an odd number of carbons proceeds two carbons at a time (producing acetyl CoA) until three-carbon propionyl CoA remains. This compound is carboxylated to methylmalonyl CoA (by biotin-requiring propionyl CoA carboxylase), which is then converted to succinyl CoA (a gluconeogenic precursor) by vitamin B2-requiring methylmalonyl CoA mutase. A genetic error in the mutase or vitamin B12 deficiency causes methylmalonic acidemia and aciduria. β-Oxidation of very-long-chain fatty acids and α-oxidation of branched-chain fatty acids occur in the peroxisome. ω-Oxidation, a minor pathway, occurs in the ER. Liver mitochondria can convert acetyl CoA derived from fatty acid oxidation into the ketone bodies acetoacetate and 3-hydroxybutyrate. Peripheral tissues possessing mitochondria can oxidize 3-hydroxybutyrate to acetoacetate, which can be reconverted to acetyl CoA, thereby producing energy for the cell. Unlike fatty acids, ketone bodies are utilized by the brain and, therefore, are important fuels during a fast. Because the liver lacks the ability to degrade ketone bodies, it synthesizes them specifically for the peripheral tissues. Ketoacidosis occurs when the rate of ketone body formation is greater than the rate of use, as is seen in cases of uncontrolled type 1 diabetes mellitus.

Figure 16.25 Key concept map for fatty acid and triacylglycerol metabolism. AMPK = adenosine monophosphate-activated protein kinase; PKA = protein kinase A; CoA = coenzyme A; NADP(H) = nicotinamide adenine dinucleotide phosphate; FAD(H2) = flavin adenine dinucleotide; NAD(H) = nicotinamide adenine dinucleotide; TCA = tricarboxylic acid; VLDL = very-low-density lipoprotein.

Study Questions

Choose the ONE correct answer.


16.1 When oleic acid, 18:1(9), is desaturated at carbon 6 and then elongated, what is the product?

A. 19:2(7,9)

B. 20:2 (n-6)

C. 20:2(6,9)

D. 20:2(8,11)

Correct answer = D. Fatty acids are elongated in the endoplasmic reticulum by adding two carbons at a time to the carboxylate end (carbon 1) of the molecule. This pushes the double bonds at carbon 6 and carbon 9 further away from carbon 1. 20:2(8,11) is an n-9 (ω-9) fatty acid.


16.2 A 4-month-old child is being evaluated for fasting hypoglycemia. Laboratory tests at admission reveal low levels of ketone bodies, free carnitine, and acylcarnitines in the blood. Free fatty acid levels in the blood were elevated. Deficiency of which of the following would best explain these findings?

A. Adipose triglyceride lipase

B. Carnitine transporter

C. Carnitine palmitoyltransferase I

D. Long-chain fatty acid dehydrogenase

Correct answer = B. A defect in the carnitine transporter (primary carnitine deficiency) would result in low levels of carnitine in the blood (as a result of increased urinary loss) and low levels in the tissues. In the liver, this decreases fatty acid oxidation and ketogenesis. Consequently, blood levels of free fatty acids rise. Deficiencies of adipose triglyceride lipase would decrease fatty acid availability.

 Deficiency of carnitine palmitoyltransferase I would result in elevated blood carnitine. Defects in any of the enzymes of β-oxidation would result in secondary carnitine deficiency, with a rise in acylcarnitines.


16.3 A teenager, concerned about his weight, attempts to maintain a fat-free diet for a period of several weeks. If his ability to synthesize various lipids were examined, he would be found to be most deficient in his ability to synthesize:

A. cholesterol.

B. glycolipids.

C. phospholipids.

D. prostaglandins.

E. triacylglycerol.

Correct answer = D. Prostaglandins are synthesized from arachidonic acid. Arachidonic acid is synthesized from linoleic acid, an essential fatty acid obtained by humans from dietary lipids. The teenager would be able to synthesize all other compounds but, presumably, in somewhat decreased amounts.


16.4 A 6-month-old boy was hospitalized following a seizure. History revealed that for several days prior, his appetite was decreased due to a “stomach virus.” At admission, his blood glucose was 24 mg/dl (age-referenced normal is 60–100). His urine was negative for ketone bodies and positive for a variety of dicarboxylic acids. Blood carnitine levels were normal. A tentative diagnosis of medium-chain fatty acyl coenzyme A dehydrogenase (MCAD) deficiency is made. In patients with MCAD deficiency, the fasting hypoglycemia is a consequence of:

A. decreased acetyl coenzyme A production.

B. decreased ability to convert acetyl coenzyme A to glucose.

C. increased conversion of acetyl coenzyme A to acetoacetate.

D. increased production of ATP and nicotinamide adenine dinucleotide.

Correct answer = A. Impaired oxidation of fatty acids less than 12 carbons in length results in decreased production of acetyl coenzyme (CoA), the allosteric activator of pyruvate carboxylase, a gluconeogenic enzyme, and, thus, glucose levels fall. Acetyl CoA can never be used for the net synthesis of glucose. Acetoacetate is a ketone body, and with medium-chain fatty acyl CoA dehydrogenase deficiency, ketogenesis is decreased as a result of decreased production of the substrate, acetyl

CoA. Impaired fatty acid oxidation means that less ATP and nicotinamide adenine dinucleotide are made, and both are needed for gluconeogenesis.


16.5 Explain why with Zellweger syndrome both very-long-chain fatty acids (VLCFAs) and phytanic acid accumulate, whereas with X-linked adrenoleukodystrophy, only VLCFAs accumulate.

Zellweger syndrome is caused by an inability to target matrix proteins to the peroxisome. Therefore, all peroxisomal activities are affected because functional peroxisomes are not able to be formed. In X-linked adrenoleukodystrophy, the defect is an inability to transport very-long-chain fatty acids into the peroxisome, but other peroxisomal functions, such as α-oxidation, are normal.

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