Fatty Acid Metabolism and Disorders

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Questions and Answers

During peroxisomal beta-oxidation of very-long-chain fatty acids, which of the following is produced?

Acetyl CoA and NADH (correct)

Lactate and NADPH

Pyruvate and FADH2

Succinate and GTP

What enzyme is responsible for the initial dehydrogenation step in peroxisomal beta-oxidation?

Acyl CoA dehydrogenase (NAD+)

Beta-ketothiolase

Enoyl CoA hydratase

Acyl CoA oxidase (FAD) (correct)

In Zellweger syndrome, the primary metabolic defect is the inability to oxidize which?

Very-long-chain fatty acids (correct)

Short chain fatty acids

Odd chain fatty acids

Medium chain fatty acids

Beta-oxidation of odd-chain fatty acids results in the formation of acetyl CoA and one molecule of what?

Propionyl CoA Signup and view all the answers

Propionyl CoA is converted to which molecule by carboxylase?

Methylmalonyl CoA Signup and view all the answers

What vitamin is a coenzyme for the mutase that converts methylmalonyl CoA during odd-chain fatty acid oxidation?

Vitamin B12 Signup and view all the answers

Alpha oxidation results in the removal of how many carbons from a fatty acid molecule at a time?

One carbon Signup and view all the answers

What is the name for the C24 alpha-hydroxy fatty acid found in brain lipids?

Cerebronic acid Signup and view all the answers

What is the primary function of carnitine in fatty acid metabolism?

To transport long-chain fatty acids into the mitochondria for beta-oxidation. Signup and view all the answers

Which enzyme is responsible for the dehydration step in beta-oxidation?

Enoyl CoA hydratase Signup and view all the answers

What is a common symptom of genetic CAT-I deficiency?

Hypoglycemia due to impaired liver glucose synthesis. Signup and view all the answers

What coenzyme is used in the first dehydrogenation step of beta oxidation?

FAD Signup and view all the answers

Why can short and medium-chain fatty acids enter the mitochondria without carnitine?

They are activated to their CoA form inside the mitochondrial matrix. Signup and view all the answers

Which vitamin is required for carnitine synthesis?

Ascorbic acid Signup and view all the answers

During beta-oxidation, what molecule is produced in a 4-step round?

Acetyl CoA Signup and view all the answers

What is the main factor in secondary carnitine deficiencies?

Malnutrition or strict vegetarian diets. Signup and view all the answers

Under conditions where tissues utilize ketone bodies for energy, what is the relative state of their NAD+/NADH ratios?

Relatively high, favoring oxidation. Signup and view all the answers

What is the primary role of Coenzyme A in the utilization of acetoacetate?

It adds to acetoacetate, forming a high-energy bond. Signup and view all the answers

Which molecule donates the CoA needed for acetoacetate activation, via transesterification?

Succinyl CoA Signup and view all the answers

How does glucagon influence hepatic ketogenesis?

It stimulates ketogenesis by increasing free fatty acid delivery. Signup and view all the answers

What is the effect of insulin on hormone-sensitive lipase (HSL) in adipose tissue?

It inactivates HSL by dephosphorylation. Signup and view all the answers

What is the primary role of carnitine acyltransferase-I (CAT-I) in regulating ketogenesis?

It facilitates fatty acid transport into the mitochondrial matrix. Signup and view all the answers

How does malonyl-CoA affect the activity of carnitine acyltransferase-I (CAT-I)?

It inhibits CAT-I, reducing fatty acid entry into the mitochondria. Signup and view all the answers

What is the state of CAT-1 activity during starvation?

High, increasing fatty acid oxidation. Signup and view all the answers

Besides hyperglycemia, which of the following is a necessary diagnostic criterion for diabetic ketoacidosis?

Presence of ketones in urine Signup and view all the answers

In the context of diabetic ketoacidosis (DKA), what is a common reason for recurrent episodes in young patients?

Insufficient insulin use due to fear of weight gain Signup and view all the answers

What is a predisposing factor to alcoholic ketoacidosis (AKA) that is directly linked to alcohol metabolism?

Elevated ratio of NADH to NAD+ Signup and view all the answers

During the metabolism of alcohol, what product is formed by the action of alcohol dehydrogenase?

Acetaldehyde Signup and view all the answers

What is the primary implication of a decreased NAD+/NADH ratio in alcoholic ketoacidosis?

Impaired gluconeogenesis Signup and view all the answers

In contrast to diabetic ketoacidosis, what is the predominant ketone body found in alcoholic ketoacidosis (AKA)?

β-hydroxybutyrate Signup and view all the answers

What is a common consequence of using insufficient insulin in type 1 diabetes?

Diabetic ketoacidosis Signup and view all the answers

Why might routine clinical assays underestimate the level of ketonemia in alcoholic ketoacidosis (AKA)?

They do not measure β-hydroxybutyrate Signup and view all the answers

What molecule attacks the methylene group of malonyl residue during the condensation step of fatty acid synthesis?

Acetyl group Signup and view all the answers

Which enzyme catalyzes the reduction of acetoacetyl-ACP to β-hydroxybutyryl-ACP?

β-ketoacyl-ACP reductase Signup and view all the answers

What type of bond is formed during the dehydration step of fatty acid synthesis?

Double bond Signup and view all the answers

Which of the following is NOT a required cofactor for the fatty acid synthesis cycle?

FAD Signup and view all the answers

What is the role of the enzyme thioesterase in fatty acid synthesis?

It liberates the fatty acid from the enzyme complex Signup and view all the answers

How many carbon atoms are present in the saturated acyl radical at the end of the fatty acid synthesis cycle?

16 Signup and view all the answers

What type of reaction is catalyzed by β-hydroxybutyryl-ACP dehydratase?

Dehydration Signup and view all the answers

What product is formed after the first four steps of fatty acid synthesis?

Butyryl-ACP Signup and view all the answers

Which apolipoprotein is essential for the formation of VLDL?

Apo B-100 Signup and view all the answers

Apart from the mammary gland, what are the primary tissues from which particulate lipid is secreted?

Intestine and liver Signup and view all the answers

The hydrolysis of triacylglycerol within VLDL is facilitated by lipoprotein lipase and requires which cofactors?

Phospholipids and apo C-II Signup and view all the answers

What is the primary function of apolipoproteins in lipoprotein metabolism?

To act as recognition sites for cell-surface receptors and enzyme cofactors Signup and view all the answers

Which lipoproteins are characterized as pre-beta lipoproteins via electrophoresis?

VLDL Signup and view all the answers

How do the newly secreted VLDL particles acquire their full complement of apolipoproteins C and E?

From HDL in the circulation Signup and view all the answers

What is the end-product of triacylglycerol hydrolysis by lipoprotein lipase?

Free fatty acids and glycerol Signup and view all the answers

Which of the following factors can influence cholesterol levels in the blood?

Heredity and dietary fats Signup and view all the answers

Signup and view all the answers

Study Notes

Lipid Metabolism

Lipids are a diverse group of molecules that are essential for various bodily functions, including energy storage, hormone production, and cell membrane structure.
The digestion and absorption of lipids are complex processes that involve several enzymes and hormones.
Lipid metabolism comprises multiple stages, including digestion, absorption, transport, and utilization.

Digestion and Absorption of Lipids

Lingual lipase in the mouth initiates lipid digestion, primarily targeting short and medium-chain fatty acids in milk fat. Its activity is highest in newborns and declines with age.
Gastric lipase in the stomach continues lipid digestion, requiring emulsification by substances like polysaccharides, phospholipids, and digested proteins.
Bile salts aid emulsification of lipids in the small intestine, increasing the surface area for enzyme action.
Pancreatic lipase, activated by calcium and colipase, further degrades dietary triacylglycerols (TAGs) into fatty acids and 2-monoacylglycerol.
Cholesteryl esterase breaks down cholesterol esters into cholesterol and free fatty acids, whose activity is enhanced by bile salts.
Phospholipases, such as A₂ and A₁, break down phospholipids, releasing fatty acids.

Absorption of Lipids

In the small intestine, free fatty acids, 2-monoacylglycerol, and other components form micelles, aiding their absorption across the intestinal mucosal cells.
Micelles facilitate the absorption of nonpolar fatty acids, cholesterol, and fat-soluble vitamins.
Inside the enterocytes, fatty acids and monoglycerides are re-esterified to form triacylglycerol (TAG).
Chylomicrons, lipoprotein particles, are formed in the epithelial cells of the small intestine, packaging TAG, cholesterol, and fat-soluble vitamins for transport into the lymphatic system and into the bloodstream.

Lipid Metabolism and Hormonal Regulation

Hormones like cholecystokinin (CCK), secretin, and gastric inhibitory peptide (GIP) regulate various stages of lipid digestion and absorption in response to food intake.
The presence of fat in the stomach stimulates the release of hormones like CCK to regulate secretions from the pancreas and gallbladder. This facilitates the digestion process.
Other hormones play a part in the mobilization and utilization of lipids.

Lipid Malabsorption

Steatorrhea, characterized by the presence of excessive fat in stool, indicates malabsorption of lipids.
This can result from defects in lipid digestion or absorption, potentially due to issues with pancreatic enzyme production, bile secretion, or intestinal absorption.

Metabolism of Chylomicrons and VLDL

Nascent chylomicrons are synthesized in the intestines, acquiring apolipoproteins C and E from HDL.
Lipoprotein lipase degrades the triacylglycerols in chylomicrons, releasing fatty acids and glycerol into tissues.
VLDL, synthesized in the liver, transports endogenous triacylglycerols and cholesterol to tissues.
Chylomicrons and remnants are taken up by the liver through apolipoprotein E.
Catabolism of remnant chylomicrons and VLDL follows similar mechanisms.

Metabolism of LDL

LDL carries cholesterol to peripheral tissues.
The liver and many extrahepatic tissues express LDL (apo B-100, E) receptors, which are essential for LDL uptake.
The LDL receptor is subject to regulation and is crucial for cholesterol homeostasis.
Degradation of LDL plays a crucial role in overall cholesterol balance.

Metabolism of HDL

HDL is synthesized and secreted from both liver and intestine, with apolipoproteins C and E being transferred to HDL when it enters the plasma.
HDL functions as a repository for apolipoproteins.
LCAT and the LCAT activator apo A-I bind to the nascent HDL, converting free cholesterol to cholesteryl esters for uptake by peripheral tissues or the liver.

Fate of Dietary Lipids by Tissues

Fatty acids are oxidized by various tissues for energy production.
Glycerol is used by the liver to form glycerol 3-phosphate, which enters glycolysis or gluconeogenesis.
The oxidation of fatty acids involves three primary stages, with acetyl-CoA, FADH2, and NADH being produced.

Oxidation of Fatty Acids

Fatty acid oxidation provides energy for cellular metabolic work.
The process occurs via β-oxidation and is highly active in tissues with high metabolic activity, such as skeletal and heart muscles.
Oxidation of fatty acids occurs in various physiological conditions, including fasting, heavy exercise, and diets with reduced carbohydrate intake.
Specific physiological conditions contribute to fatty acid oxidation.
Fatty acid oxidation is also a source of heat, especially with the help of thermogenin function in brown fat tissue.
Fatty acids also yield metabolic intermediates that can be used in synthetic processes, including phospholipids and eicosanoids (like prostaglandins).
The transport of long-chain fatty acids inside the mitochondria involves the carnitine shuttle.
Specific enzymes are involved in the process inside mitochondria, which are regulated.
The products from β-oxidation, acetyl-CoA and NADH, are crucial for generating ATP.

Oxidation of Unsaturated Fatty Acids

Unsaturated fatty acids undergo similar β-oxidation but involve additional enzymes.
The number of double bonds impacts the oxidation process.
The presence of a double bond affects the rate of β-oxidation.
Several enzymes act to modify the form of unsaturated fatty acids, aiding β-oxidation processing; such as isomerases or reductases.
There are also specific oxidation processes associated with these fatty acids (such as α-oxidation and ω-oxidation).
There are three main types of fatty acyl-CoA dehydrogenase, which differ based on the chain length involved in the process.

β-Oxidation in Peroxisomes

Very-long-chain fatty acids (VLCFAs) are initially oxidized in peroxisomes, generating H2O2.
H2O2 produced during oxidation is a toxic product, metabolized by catalase.
The process of β-oxidation inside peroxisomes generates acetyl-CoA which ultimately provides energy for the cells.
Peroxisomes utilize specific enzymes during β-oxidation.

Degradation of Odd-Chain Fatty Acids

Odd-chain fatty acids yield propionyl-CoA as a product of β-oxidation, which undergoes further conversion.
A biotin-dependent enzyme, propionyl-CoA carboxylase, converts propionyl-CoA into methylmalonyl-CoA.
This molecule is further converted to succinyl-CoA through a vitamin B12-dependent process, a crucial step in energy production and metabolic pathways.
Defects in these enzymes can cause metabolic disorders (e.g., propionic acidemia, methylmalonic acidemia).

Degradation of α-hydroxy fatty acids

α-oxidation processes lead to the removal of individual carbon atoms (one at a time) from the carboxyl end of the fatty acid chain.
The process of α-oxidation produces hydroxy fatty acids, to finally obtain 2-keto acid products for further processing.
Special enzymes are involved in all steps of this reaction.
A major example of a substrate of this reaction is phytanic acid, a very-long-chain fatty acid.
The absence of enzymes in these processes causes metabolic disturbances.

Omega-Oxidation of Fatty Acids

Omega-oxidation occurs in the endoplasmic reticulum and involves oxidizing the terminal (ω-) carbon.
Through a similar process, fatty acids may undergo omega-oxidation, where oxidation takes place at the terminal carbon atom of the fatty acid chain.
Dicarboxylic acids serve as products of this oxidation.
They are important as they enter further catabolic pathways and are easily excreted.

Regulation of β-oxidation

Fatty acid oxidation primarily depends on fatty acid availability and the presence of sufficient CoA and NAD+.
Malonyl-CoA, a product of fatty acid synthesis, acts as an inhibitor of transport of the fatty acids to the mitochondria for degradation, hence, effectively inhibiting β-oxidation.

Regulation of Ketogenesis

Ketogenesis is a metabolic pathway that contributes to energy production, particularly during periods of low carbohydrate availability.
Lipolysis or fat breakdown is crucial for ketogenesis, which takes place in the liver.
The main regulation points are in the stages associated with lipolysis and conversion of fatty acids to ketone bodies, as well as the subsequent utilization of these ketone bodies by tissues.
Insulin and glucagon play key roles in regulating ketogenesis via their effect on enzymes associated with the metabolic process.

Regulation of Acetyl-CoA Carboxylase

Acetyl-CoA carboxylase is the primary regulatory point in fatty acid synthesis, the rate-controlling step.
Allosteric mechanisms and covalent modifcation regulate its activity.
Citrate activates, while palmitoyl-CoA inhibits the enzyme to maintain metabolic balance.
Hormonal regulation plays a part in regulating the activity of the acetyl-CoA carboxylase.

Regulation of Cholesterol Synthesis

HMG-CoA reductase enzyme activity is the primary regulator for cholesterol synthesis.
The balance between synthesis and uptake of cholesterol is important for regulating homeostasis.
Hormonal regulation and the feedback effects of different molecules influence cholesterol synthesis and availability.

Lipid Synthesis and Storage in Liver and Adipocytes

In the liver, newly synthesized TAGs and other lipids are packaged into lipoproteins (like VLDL) for transport to other tissues.
Adipocytes primarily store TAGs, which can be mobilized during fasting or energy demands.

Synthesis of Phospholipids

Different phospholipids are synthesized through a series of enzymatic reactions involving CDP-diacylglycerols, inositol, and other components.
The synthesis of specific phospholipids occurs in the endoplasmic reticulum and Golgi complex.
Various cells, except mature red blood cells, produce various types of phospholipids.

Degradation of Sphingolipids

Specific lysosomal enzymes are involved in the degradation of sphingolipids
Individual enzymes degrade different sphingolipids, removing components like the phospho-choline group(e.g. sphingomyelin).
The degradation of sphingolipids serves as a crucial part of cellular homeostasis for different processes, as well as lipid homeostasis.

Sphingolipidoses

Sphingolipidoses comprise a group of inherited metabolic disorders resulting from the accumulation of sphingolipids in lysosomes due to defects in specific enzyme activities required for degradation of sphingolipids.
Different types of sphingolipidoses are categorized by affected enzymes and the sphingolipids that accumulate as a result of these defects.
Accumulation of specific sphingolipids leads to progressive involvement of the nervous system, and other organs.

Physiological Actions of Eicosanoids

Eicosanoids exert various biological effects at extremely low concentrations by stimulating specific receptors. Their short half-lives and local actions define their effects.
They regulate pain and fever, blood pressure, and blood clotting, and also play a role in inflammation, labor, and other bodily processes.

Mechanisms of Action of Eicosanoids

Eicosanoids, like hormones, use G protein-coupled receptors and other signal transduction pathways for mediating their diverse biological effects.
Different Eicosanoid types use slightly different mechanisms of action.

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Description

Test your knowledge on fatty acid metabolism, focusing on peroxisomal beta-oxidation and related metabolic disorders. This quiz covers key enzymes, products of oxidation, and the implications of conditions like Zellweger syndrome. Challenge yourself to understand the biochemical pathways involved in fatty acid metabolism.