40 Questions
What is the primary treatment for disorders of fatty acid oxidation?
Avoidance of fasting
What is a common feature of defects in fatty acid oxidation?
Hypoketotic hypoglycemia
What is a diagnostic tool for FAO disorders?
All of the above
What is a manifestation of FAO disorders in patients with certain defects?
Cardiac and skeletal muscle weakness
What is the effect of supplementation with carnitine in patients with carnitine transport deficiency?
Improvement in cardiomyopathy
What is a characteristic of hypoglycemia associated with FAO disorders?
Severe and persistent
What is the impact of fasting on patients with FAO disorders?
Fasting exacerbates the clinical features
What is the significance of dicarboxylic aciduria in FAO disorders?
It is an abnormal urine organic acid found in FAO disorders
What happens to malonyl-CoA concentrations during fasting, starvation, exercise, and insulin resistance?
They decrease
What is the role of CPT1 in the regulation of fatty acid β-oxidation?
It promotes fatty acid β-oxidation
What is the end product of each round of the β-oxidation cycle?
Acetyl-CoA and an acyl chain
How many acetyl-CoA molecules are generated during the complete β-oxidation of palmitoyl-CoA?
Eight
What is the fate of the acetyl-CoA produced during β-oxidation?
It is oxidized in the citric acid cycle
What is the net gain of ATP per molecule of palmitic acid oxidized?
129 ATP
What is the purpose of the mitochondrial electron transport chain in β-oxidation?
To pass electrons from FADH2 and NADH
What is the result of the four reactions in the β-oxidation cycle?
The removal of two-carbon units from the fatty acyl-CoA
What enzyme is involved in glyoxylate detoxification in peroxisomes?
Alanine glyoxylate aminotransferase (AGT)
What is the result of electron transfer in various metabolic pathways in peroxisomes?
Generation of hydrogen peroxide
What is the role of long chain fatty acyl-CoA ligase in the FAO pathway?
To attach coenzyme A (CoA) to fatty acids
What is the end product of the FAO pathway?
Acetyl-CoA
What is the byproduct of each cycle of the FAO pathway?
NADH, FADH2, and an acetyl-CoA
What is the role of the citric acid cycle in the FAO pathway?
To convert acetyl-CoA into citrate
What is the net result of the oxidation of each two carbons of a fatty acid in the FAO pathway?
Four NADH and two FADH2
What is the final process that consumes the NADH and FADH2 generated in the FAO pathway?
Oxidative phosphorylation
Where does fatty acid oxidation occur?
In mitochondria, peroxisomes, and ER
What is the main source of energy in fasting conditions?
Fatty acids
What is the result of excessive flux of FFAs and elevated insulin resistance?
Overproduction of ROS and lipotoxicity
What is the principal pathway of fatty acid oxidation?
β-oxidation
What is the function of carnitine palmitoyltransferase (CPT) 1?
To convert acyl-CoA to acylcarnitine
What happens to long-chain fatty acids during β-oxidation?
They are broken down into acetyl-CoA
What is the byproduct of each cycle of β-oxidation?
One acetyl-CoA, one FADH2, and one NADH
Which fatty acids can penetrate the mitochondrial membrane by diffusion?
Short- and medium-chain fatty acids
What is the effect of thyroid hormone on the oxidation of fatty acids in hyperthyroid patients?
It is increased
What is the effect of thyroid hormone on FAO in hypothyroid patients?
It is decreased by 50%
What is the effect of a mutation that causes human generalized thyroid hormone resistance on FAO in mice?
It suppresses FAO
What is the role of thyroid hormone in the regulation of FAO in the adult brain?
It has a critical role
What is the effect of T3 treatment on ATP production and FAO in human and mouse astrocytes?
It increases ATP production and FAO
What is the current understanding of the mechanism by which thyroid hormone alters FAO?
It is not well understood
What is a limitation of studying the mechanism of thyroid hormone on FAO?
The complexity of thyroid hormone signaling pathways
What is the focus of this chapter?
The mechanism by which thyroid hormone alters FAO
Study Notes
Fatty Acid Oxidation and Mitochondrial Transport
- Fatty acid oxidation is a major source of adenosine triphosphate (ATP) in tissues such as liver, skeletal muscle, and heart, especially in fasting conditions where glucose availability is limited.
- The primary treatment of fatty acid oxidation disorders is avoidance of fasting, as conditions that promote a decline in malonyl-CoA concentrations (e.g., fasting, starvation, exercise, and insulin resistance) act to promote fatty acid β-oxidation.
Mitochondrial Fatty Acid Transport
- Carnitine uptake, mitochondrial transport, and oxidation of fatty acids are key steps in fatty acid metabolism.
- The carnitine palmitoyltransferase (CPT) system is responsible for transporting fatty acyl-CoA across the mitochondrial membranes into the matrix prior to β-oxidation.
- Carnitine palmitoyltransferase 1 (CPT 1) converts acyl-CoA (long chain) to acylcarnitine, which is then shuttled inside by carnitine acylcarnitine translocase, and finally reconverted to acyl-CoA by CPT 2.
Fatty Acid β-Oxidation
- Fatty acid β-oxidation is a cyclic process where fatty acids of short, medium, and long chains are broken down within mitochondria.
- Each cycle of β-oxidation removes two carbon atoms from the fatty acid chain, producing acetyl-CoA, FADH2, and NADH.
- The acetyl-CoA produced by β-oxidation is normally oxidized in the citric acid (Krebs) cycle, while the FADH2 and NADH pass their electrons to the mitochondrial electron transport chain.
Oxidation of Fatty Acids and Thyroid Hormone
- Thyroid hormone regulates fatty acid oxidation (FAO) in the brain, which is critical for cognitive function.
- Hyperthyroid patients exhibit an increased oxidation of fatty acids into carbon dioxide or ketone bodies, while FAO in hypothyroid patients is decreased.
- Thyroid hormone rapidly increases ATP production and FAO in astrocytes, demonstrating its importance in brain function.
Obesity and Nonalcoholic Fatty Liver Disease
- Fatty acid oxidation can occur in the mitochondria, peroxisomes, and ER, and is a major source of ATP in tissues such as liver, skeletal muscle, and heart.
- Excessive flux of free fatty acids and elevated insulin resistance lead to an overproduction of ROS and lipotoxicity in peroxisomes and ER.
- β-oxidation is a cyclic process where fatty acids of short, medium, and long chains are broken down within mitochondria, and is necessary for long-chain fatty acids such as palmitoyl-CoA, oleoyl-CoA, and linoleoyl-CoA.
This quiz covers the key steps in carnitine uptake, mitochondrial transport, and oxidation of fatty acids, as well as genetic disorders affecting fatty acid metabolism and mitochondrial function.
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