Question 1

Parents of a 3-month-old infant arrive at the ER agitated and frightened by the extreme lethargy and near comatose state of their child. Examination shows the infant to be severely hypoglycemic accompanied by low measurable ketones in the urine and blood. Blood analysis also indicates an elevation in butyric and propionic acids and as well as C8-acylcarnitines. A deficiency in which of the following enzymes is most likely responsible for these observations?

A) CPT-I
B) hormone-sensitive lipase (HSL)
C) lipoprotein lipase (LPL)
D) long-chain acyl-CoA dehydrogenase (LCAD)
E) medium-chain acyl-CoA dehydrogenase (MCAD)

medium-chain acyl-CoA dehydrogenase (MCAD)

Accepted Answer

The symptoms and biochemical findings are indicative of Medium-Chain Acyl-CoA Dehydrogenase (MCAD) deficiency, which leads to hypoglycemia and low ketone levels due to impaired fatty acid oxidation. Elevated C8-acylcarnitines are a hallmark of this condition. In infants, the supply of glycogen lasts less than 6 hours and gluconeogenesis is not sufficient to maintain adequate blood glucose levels. Normally, during periods of fasting (in particular during the night) the oxidation of fatty acids provides the necessary ATP to fuel hepatic gluconeogenesis as well as ketone bodies for nonhepatic tissue energy production. In patients with MCAD deficiency there is a drastically reduced capacity to oxidize fatty acids. This leads to an increase in glucose usage with concomitant hypoglycemia. The deficit in the energy production from fatty acid oxidation, necessary for the liver to use other carbon sources, such as glycerol and amino acids, for gluconeogenesis further exacerbates the hypoglycemia. Normally, hypoglycemia is accompanied by an increase in ketone formation from the increased oxidation of fatty acids. In MCAD deficiency there is a reduced level of fatty acid oxidation, hence near-normal levels of ketones are detected in the serum.

Question 2

Oxidation of fatty acids requires the input of energy in the form of ATP. Which of the following enzyme activities requires this energy input?&#10;A) acyl-CoA dehydrogenases&#10;B) acyl-CoA synthetase&#10;C) CPT-I&#10;D) CPT-II&#10;E) b-ketothiolase

Accepted Answer

Acyl-CoA synthetase catalyzes the activation of fatty acids to form acyl-CoA, a process that requires the input of ATP to form AMP and pyrophosphate. Fatty acids must be activated in the cytoplasm before being oxidized in the mitochondria. Activation is catalyzed by fatty acyl-CoA synthetases (also called acyl-CoA ligases or thiokinases). The net result of this activation process is the consumption of 2 molar equivalents of ATP.

Question 3

Very-long-chain fatty acids (VLCFA) are oxidized in the peroxisomes. The process of oxidation of these fats is referred to as which of the following?&#10;A) &#945;-oxidation&#10;B) b-oxidation&#10;C) d-oxidation&#10;D) g-oxidation&#10;E) w-oxidation

Accepted Answer

Very-long-chain fatty acids undergo β-oxidation in peroxisomes, which is similar to mitochondrial β-oxidation but adapted for very long chains.  Oxidation of fatty acids occurs in the mitochondria and the peroxisomes via similar enzymatic pathways referred to as b-oxidation. Fatty acids of between 4 and 8 and between 6 and 12 carbon atoms in length, referred to as short- and medium-chain fatty acids (SCFAs and MCFAs), respectively, are oxidized exclusively in the mitochondria. Long-chain fatty acids (LCFAs: 10-16 carbons long) are oxidized in both the mitochondria and the peroxisomes with the peroxisomes exhibiting preference for 14-carbon and longer LCFAs. Very-long-chain fatty acids (VLCFAs: 17-26 carbons long) are exclusively oxidized in the peroxisomes

Question 4

Excess delivery of free fatty acids to the pancreas results in progressive damage to the b-cells as these fats are oxidized. The primary cause of this progressive damage is due to which of the following processes?

A) deficiency in peroxisomal oxidative capacity resulting in increased fat droplet production which results in apoptosis
B) excess accumulation of triglycerides derived from the fatty acids
C) increase in ER stress due to incorporation of the fats into membrane lipids triggering apoptosis
D) increased fat oxidation in the peroxisomes results in release of cytochrome c triggering apoptosis
E) limiting levels of catalase resulting in ROS excess leading to membrane lipid damage and mitochondrial dysfunction

Accepted Answer

Excess free fatty acids lead to increased oxidative stress due to limiting levels of catalase, resulting in reactive oxygen species (ROS) accumulation, which damages cellular components and triggers apoptosis. Peroxisomes oxidize long-chain fatty acid via a b-oxidation pathway where the first reaction generates H₂O₂ (a reactive oxygen species [ROS]) instead of FADH₂ as for mitochondrial b-oxidation. High-fat diet results in higher level of peroxisomal fatty acid oxidation resulting in increased levels of H₂O₂ production. Within the b-cells of the pancreas this increased ROS production cannot be tolerated due to low or no catalase production in these cells. The net result is b-cell dysfunction and triggering apoptosis.

Question 5

Polymorphisms in the cytochrome P450 family enzyme, CYP4A11, are associated with hypertension in certain populations, particularly Asian populations. CYP₄A11 belongs to a family of CYP₄A enzymes responsible for the metabolism of arachidonic acid and the leukotriene, LTB₄. Which of the following represents the pathway in which the CYP₄A enzymes functions?

A) a-oxidation
B) b-oxidation
C) d-oxidation
D) g-oxidation
E) w-oxidation

Accepted Answer

CYP4A enzymes, including CYP4A11, are involved in ω-oxidation, which is the oxidation of the terminal methyl group of fatty acids.

Question 6

An individual suffers from a defect in one of the enzymes required for the synthesis of carnitine. If this individual does not have adequate intake of carnitine in the diet and is fasting, which of the following would be the most likely observation in this person compared to conditions of normal carnitine intake?

A) elevated levels of long-chain dicarboxylic acids in the blood
B) elevated very-long-chain fatty acid levels in the blood
C) hyperglycemia
D) increased levels of fatty acid oxidation
E) increased rate of ketogenesis

Accepted Answer

Carnitine is required for the transport of fatty acyl-CoAs from the cytosol into the mitochondria for oxidation. Limiting levels of carnitine would, therefore, result in reduced rates of mitochondrial b-oxidation of fatty acids. A reduced capacity for mitochondrial oxidation would ultimately result in a reduced capacity for cells to take fatty acids from the blood ultimately leading to hyperlipidemia. Since fatty acid oxidation would be impaired there would be reduced ketogenesis occurring and less energy production would restrict gluconeogenesis.

Question 7

Hepatocytes deliver ketone bodies to the circulation because they lack which of the following enzymes?&#10;A) b-hydroxybutyrate dehydrogenase&#10;B) hydroxymethylglutaryl-CoA lyase&#10;C) hydroxymethylglutaryl-CoA synthetase&#10;D) succinyl-CoA: 3-oxoacid-CoA transferase&#10;E) the form of b-ketothiolase necessary to hydrolyze acetoacetyl-CoA

Accepted Answer

Hepatocytes lack succinyl-CoA: 3-oxoacid-CoA transferase, which is necessary for the utilization of ketone bodies. This enzyme is present in peripheral tissues, allowing them to use ketone bodies for energy.  Ketogenesis occurs in the liver from acetyl-CoA during high rates of fatty acid oxidation and during early starvation. The principal ketone bodies are acetoacetate and b-hydroxybutyrate, which are reversibly synthesized in a reaction catalyzed by b-hydroxybutyrate dehydrogenase. The liver delivers b-hydroxybutyrate to the circulation where it is taken up by nonhepatic tissue for use as an oxidizable fuel. The brain will derive much of its energy from ketone body oxidation during fasting and starvation. Within extrahepatic tissues, b-hydroxybutyrate is converted to acetoacetate byb-hydroxybutyrate dehydrogenase. Acetoacetate is reactivated to acetoacetyl-CoA in a reaction catalyzed by succinyl-CoA: 3-oxoacid-CoA-transferase (also called succinyl-CoA-acetoacetate-CoA-transferase or acetoacetate: succinyl-CoA-CoA transferase), which uses succinyl-CoA as the source of CoA. This enzyme is not present in hepatocytes. The acetoacetylCoA is then converted to 2 moles of acetyl-CoA by the thiolase reaction of fatty acid oxidation.

Question 8

Which of the following symptoms can occur frequently in infants suffering from medium-chain acyl-CoA dehydrogenase (MCAD) deficiency if periods between meals are protracted?&#10;A) bone and joint pain and thrombocytopenia&#10;B) hyperammonemia with decreased ketones&#10;C) hyperuricemia and darkening of the urine&#10;D) hypoglycemia and metabolic acidosis with normal levels of ketones&#10;E) metabolic alkalosis with decreased bicarbonate

Accepted Answer

Hypoglycemia and metabolic acidosis with normal levels of ketones are frequent symptoms in infants with MCAD deficiency if periods between meals are protracted.  In infants, the supply of glycogen lasts less than 6 hours and gluconeogenesis is not sufficient to maintain adequate blood glucose levels. Normally, during periods of fasting (in particular during the night) the oxidation of fatty acids provides the necessary ATP to fuel hepatic gluconeogenesis as well as ketone bodies for nonhepatic tissue energy production. In patients with MCAD deficiency there is a drastically reduced capacity to oxidize fatty acids. This leads to an increase in glucose usage with concomitant hypoglycemia. The deficit in the energy production from fatty acid oxidation, necessary for the liver to use other carbon sources, such as glycerol and amino acids, for gluconeogenesis further exacerbates the hypoglycemia. Normally, hypoglycemia is accompanied by an increase in ketone formation from the increased oxidation of fatty acids. In MCAD deficiency there is a reduced level of fatty acid oxidation, hence near-normal levels of ketones are detected in the serum.

Question 9

Following a minor respiratory illness, a seemingly healthy, developmentally normal 15-month-old boy exhibited repeated episodes of severe lethargy and vomiting following periods of fasting, such as during the middle of the night. The parents brought the infant to the ER following a seizure. The child was hypoglycemic and was administered 10% dextrose, but remained lethargic. Blood ammonia was high, liver function tests were slightly elevated, and his serum contained an accumulation of dicarboxylic acids. Only low levels of ketones were detectable in the urine. This infant suffers from which of the following disorders?

A) glutaric acidemia type II
B) Lesch-Nyhan syndrome
C) MCAD deficiency
D) PDH deficiency
E) type III (Cori) glycogen storage disease

Accepted Answer

The symptoms and biochemical findings are consistent with Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, a disorder of fatty acid oxidation. It is characterized by hypoketotic hypoglycemia, elevated dicarboxylic acids, and high blood ammonia levels following fasting or illness.  Deficiency in MCAD is the most common inherited defect in the pathways of mitochondrial fatty acid oxidation. The most common presentation of infants with this disorder is episodic hypoketotic hypoglycemia following periods of fasting. Although the first episode may be fatal, and incorrectly ascribed to sudden infant death syndrome, patients with MCAD deficiency are normal between episodes and are treated by avoidance of fasting and treatment of acute episodes with intravenous glucose. Accumulation of acylcarnitines (dicarboxylic acids) is diagnostic, in particular octanoylcarnitine.

Question 10

A 15-year-old boy has been diagnosed with retinitis pigmentosa, peripheral polyneuropathy, and cerebellar ataxia. Analysis of his cerebrospinal fluid indicated a high protein content but no elevation of cell number. A telling clinical finding was a high level of serum phytanic acid. These findings are indicative of which of the following disorders?

A) carnitine palmitoyltransferase I deficiency
B) fragile X syndrome
C) MCAD deficiency
D) Refsum disease
E) rhizomelic chondrodysplasia punctata

Accepted Answer

Refsum disease is characterized by the accumulation of phytanic acid due to a defect in its metabolism, leading to symptoms such as retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, and elevated protein in cerebrospinal fluid without pleocytosis.  Refsum disease is the result of defects in the oxidation of phytanic acid, a lipid requiring an α-oxidation pathway. As a consequence phytanic acid accumulates in the blood and tissues. The hallmark symptoms of the disease are retinitis pigmentosa, cerebellar ataxia, chronic polyneuropathy, and an elevation in protein in the cerebrospinal fluid with no increase in cell count

Question 11

When fatty acids with odd numbers of carbon atoms are oxidized in the b-oxidation pathway the final product is 1 mole of acetyl-CoA and 1 mole of the 3-carbon molecule, propionyl-CoA. In order to use the propionyl carbons, the molecule is carboxylated and converted ultimately to succinyl-CoA and fed into the TCA cycle. Which of the following represents the vitamin cofactor required in one of the steps of this conversion?

A) cobalamin (B₁₂)
B) pantothenic acid (B₅)
C) pyridoxine (B₆)
D) riboflavin (B₂)
E) thiamine (B₁)

Accepted Answer

The answer of When fatty acids with odd numbers of...

Question 12

The ability of the liver to regulate the level of blood glucose is critical for survival. A number of sources of carbon atoms of nonhepatic origin are used by the liver for gluconeogenesis. However, the net conversion of carbons from fat into carbons of glucose cannot occur in humans because of which of the following?

A) fat oxidation occurs in the mitochondria and gluconeogenesis occurs in the cytosol
B) states of catabolism and anabolism are never concurrently active
C) storage of fats occurs in adipose tissue and gluconeogenesis occurs in liver and kidney
D) the carbons of acetyl-CoA from fat oxidation are lost as CO₂ in the TCA cycle
E) the carbons of acetyl-CoA from fat oxidation inhibit conversion of pyruvate to oxaloacetate

Accepted Answer

The answer of The ability of the liver to regulate...

Question 13

The rate of ketone body production is determined by the relative rate of which of the following key metabolic pathways?&#10;A) gluconeogenesis&#10;B) glycogenolysis (muscle)&#10;C) glycolysis&#10;D) lipolysis&#10;E) proteolysis

Accepted Answer

The answer of The rate of ketone body production is...

Question 14

Serum concentrations of acetoacetate and b-hydroxybutyrate increase dramatically after a 3-day fast primarily because of the increased rate of which of the following?&#10;A) fatty acid oxidation in the liver&#10;B) fatty acid synthesis in the liver&#10;C) glycogenolysis in the liver&#10;D) glycolysis in skeletal muscle&#10;E) protein degradation in skeletal muscle

Accepted Answer

The answer of Serum concentrations of acetoacetate and b-hydroxybutyrate increase...

Question 15

During a period of fasting, the principal precursor of ketone bodies in the blood is most likely to be which of the following?&#10;A) alanine&#10;B) glucose&#10;C) glutamate&#10;D) glycerol&#10;E) palmitate

Accepted Answer

The answer of During a period of fasting, the principal...

Question 16

During prolonged starvation, the brain increases its use of which of the following substrates in blood as an energy source?&#10;A) arachidonic acid&#10;B) glucose&#10;C) glycerol&#10;D) b-hydroxybutyrate&#10;E) palmitic acid

Accepted Answer

The answer of During prolonged starvation, the brain increases its...

Question 17

A 6-year-old boy with progressive muscle weakness is found to have a systemic defect in the production of carnitine. Therefore, this child has a limited ability to produce ATP in skeletal muscle because of a defect in the degradation of long-chain fatty acids via the b-oxidation pathway. Which of the following is the most likely result of this defect in muscle?

A) decreased utilization of lactate
B) increased cholesterol stores
C) increased glycogen stores
D) increased triglyceride stores
E) increased utilization of acetoacetate

Accepted Answer

The answer of A 6-year-old boy with progressive muscle weakness...

Question 18

Synthesis and oxidation of fatty acids take place in the cytoplasm and mitochondria, respectively. Their simultaneous occurrence is prevented by malonyl-CoA, the first intermediate of fatty acid synthesis, because malonyl-CoA inhibits which of the following?

A) acetyl-CoA carboxylase
B) acyl carrier protein
C) carnitine palmitoyltransferase I
D) b-keto-acyl carrier protein reductase
E) b-keto-acyl carrier protein synthase

Accepted Answer

The answer of Synthesis and oxidation of fatty acids take...

Question 19

Which of the following compounds is required for intracellular transport of long-chain fatty acids into mitochondria for oxidation?&#10;A) carnitine&#10;B) ceramide&#10;C) ceruloplasmin&#10;D) citrate&#10;E) cytidine

Accepted Answer

The answer of Which of the following compounds is required...

Question 20

Transport of fatty acids from adipose tissue to other tissues for metabolism is primarily a function of which of the following compounds?&#10;A) chylomicrons&#10;B) &#945;-lipoprotein&#10;C) b-lipoprotein&#10;D) plasmalogens&#10;E) serum albumin

Accepted Answer

The answer of Transport of fatty acids from adipose tissue...

Question 21

During an episode of gastroenteritis that significantly compromises food intake, a 13-month-old girl develops progressive vomiting followed by coma. She is hypoglycemic and no ketone bodies are detected in the urine. A specific defect in the metabolism of which of the following is the most likely cause of these findings?

A) glycine
B) glycogen
C) insulin
D) leucine
E) long-chain fatty acids

Accepted Answer

The answer of During an episode of gastroenteritis that significantly...

Question 22

A 2-year-old boy is admitted to the hospital because of generalized weakness, repeated episodes of vomiting, and coma after several days of reduced food intake because of a minor febrile illness. He is treated successfully with intravenous glucose. After 13 hours of fasting, when the child is well, his serum glucose and b-hydroxybutyrate levels are low while free carnitine concentrations are increased. Triglycerides containing only medium-chain fatty acids are fed, and the serum b-hydroxybutyrate concentration increases to the reference range. Which of the following disorders of fatty acid metabolism is the most likely diagnosis?

A) carnitine palmitoyltransferase I deficiency
B) dietary carnitine deficiency
C) fatty acyl-CoA synthetase deficiency
D) medium-chain acyl-CoA dehydrogenase deficiency
E) peroxisomal

Accepted Answer

The answer of A 2-year-old boy is admitted to the...

Question 23

An 8-month-old female infant is brought to the ER because her parents have been unable to fully rouse her for 3 hours. She had repeated episodes of vomiting and diarrhea the previous day, and she has not eaten for the past 12 hours. Physical examination shows lethargy and mild hepatomegaly. Serum and urine studies show no ketones. There is an abnormally increased ratio of acylcarnitine to free carnitine in urine. Which of the following is the most likely diagnosis?

A) glucose-6-phosphatase deficiency
B) maple syrup urine disease
C) medium-chain acyl-CoA dehydrogenase deficiency
D) tyrosinemia
E) Zellweger syndrome

Accepted Answer

The answer of An 8-month-old female infant is brought to...

Deck 25: Lipids: Lipolysis, Fatty Acid Oxidation, and Ketogenesis