Fatty Acid Metabolism

Fatty acid metabolism includes the processes of either breaking down fatty acids to generate energy (catabolic) or creating fatty acids for storage or use (anabolic). Besides being a source of energy, fatty acids can also be utilized for cellular membranes or signaling molecules. Synthesis and beta oxidation are almost the reverse of each other, and special reactions are required for variations (unsaturated fatty acids, very-long-chain fatty acids (VLCFAs)). Synthesis occurs in the cell cytoplasm, while oxidation occurs in mitochondria. Shuttling across membranes within a cell requires additional processes, such as the citrate and carnitine shuttles. In certain physiologic states, an increase in fatty acid oxidation can lead to the production of ketone bodies, which can also be utilized as an energy source, particularly in the brain and muscles.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Table of Contents

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Overview

Classification

Fatty acids (FAs) are classified based on their carbon chain saturation and length.

Saturation:

  • Saturated: no double bonds
  • Unsaturated: 
    • Monounsaturated: 1 carbon‒carbon double bond
    • Polyunsaturated: ≥ 2 carbon‒carbon double bonds
    • Most naturally occurring unsaturated FAs have cis double bonds (2 R groups are on the same side of the double bond).

Length:

  • Short chain (2–6 carbon atoms)
  • Medium chain (8–12 carbons)
  • Long chain (14–18 carbons)
  • Very long chain (20–26 carbons)

Numbering system

  • Delta numbering system:
    • Carbons are numbered from the carboxyl (COOH) group toward the methyl (CH3) group.
    • Generally from left → right
  • Omega numbering system:
    • Carbons are counted from the CH3 group toward the COOH group.
    • Generally from right → left
Delta and omega numbering systems for fatty acids

Comparison of the delta and omega numbering systems for fatty acids:
In the delta numbering system (green), carbons are numbered from the carboxyl (COOH) group (left) to the methyl (CH3) group (right). The opposite occurs in the omega numbering system (red).

Image by Lecturio.

Utility

FAs are utilized for:

  • Storage and alternative energy source (as triacylglycerides/triglycerides)
  • Cellular membranes
  • Lipid-signaling molecules (e.g., diacylglycerols, ceramides, eicosanoids Eicosanoids Eicosanoids are cell-signaling molecules produced from arachidonic acid. With the action of phospholipase A2, arachidonic acid is released from the plasma membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin (PGI2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes. Eicosanoids)

Fatty Acid Synthesis

Conversion of glucose

Glucose is needed to produce acetyl CoA, which is required for FA synthesis.

  • Glucose enters hepatocytes → undergoes glycolysis Glycolysis Glycolysis is a central metabolic pathway responsible for the breakdown of glucose and plays a vital role in generating free energy for the cell and metabolites for further oxidative degradation. Glucose primarily becomes available in the blood as a result of glycogen breakdown or from its synthesis from noncarbohydrate precursors (gluconeogenesis) and is imported into cells by specific transport proteins. Glycolysis → pyruvate
  • Pyruvate enters mitochondria → converted by: 
    • Pyruvate dehydrogenase to acetyl CoA
    • Pyruvate carboxylase to oxaloacetate
  • Both products can combine → citrate
  • Citrate can cross out into the cytosol (citrate shuttle) → converted back to acetyl CoA + oxaloacetate
    • Enzyme: citrate lyase
    • Requires adenosine triphosphate (ATP)
    • Induced by insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin
  • Oxaloacetate → malate
    • Enzyme: cytosolic malate dehydrogenase
    • Converts NADH → NAD+
  • Malate → pyruvate → can be reutilized in the mitochondria
    • Enzyme: nicotinamide adenine dinucleotide phosphate (NADP+)-dependent malate dehydrogenase)
    • Produces NADPH
    • Releases CO2

Synthesis of palmitic acid

The process of FA synthesis continues in the cytoplasm:

  • Acetyl CoA + CO2 → malonyl CoA (important regulatory step)
    • Enzyme: acetyl CoA carboxylase 
    • Requires:
      • Biotin
      • ATP
    • Activated/induced by: 
      • Insulin
      • Citrate
    • Inhibited by:
      • Glucagon
      • Palmitoyl-CoA (feedback inhibition)
  • Fatty acid synthase is needed for subsequent reactions.
  • CoA is replaced by acyl-carrier protein (ACP): acetyl-CoA and malonyl-CoA → malonyl-ACP and acetyl-ACP
  • Malonyl-ACP + acetyl-ACP → 4-carbon beta-ketoacyl chain
    • Enzyme: beta-ketoacyl ACP synthase
    • Releases:
      • ACP group
      • CO2
  • Reduction of the ketone on the beta carbon 
    • Enzyme: beta-ketoacyl ACP reductase
    • NADPH → NADP
  • Water molecule is removed by 3-hydroxyacyl ACP dehydrase → trans double bond
  • Double bond is reduced to a single bond → fatty acid molecule 
    • Enzyme: enoyl ACP reductase
    • NADPH → NADP
  • Resulting molecule has grown by 2 carbons → process repeats until a maximum of 16 carbons (palmitoyl-ACP)
  • Thioesterase hydrolyzes the fatty acid–ACP bond → palmitic acid
Saturated fatty acid synthesis

The process of fatty acid synthesis:
This series of reactions repeats, each cycle adding 2 carbons to the growing fatty acid chain, until the maximum of 16 carbons is reached (palmitic acid). Fatty acid synthase is the multienzyme complex responsible.
(a): Acetyltransferase
(b): Malonyltransferase
(c): Beta-ketoacyl ACP synthase
(d): Beta-ketoacyl ACP reductase
(e): 3-hydroxyacyl ACP dehydrase
(f): Enoyl ACP reductase
NADPH: reduced nicotinamide adenine dinucleotide phosphate
NADP+: oxidized nicotinamide adenine dinucleotide phosphate
ACP: acyl-carrier protein

Image: “Saturated Fatty Acid Synthesis” by Hbf878. License: CC0 1.0

Elongation and desaturation

  • Elongation:
    • Fatty acids longer than 16 carbons are synthesized in the ER and mitochondria.
    • The process is similar (malonyl-CoA provides 2 carbon units to the growing chain).
  • Desaturation:
    • Saturated fatty acids undergo desaturation in the ER.
    • Desaturases make double bonds up until the 9th carbon.
    • Note: Fatty acids with double bonds in the 12th and 15th carbons are known as essential because they must be included in the diet.
Structure of unsaturated fatty acid

Structure of an unsaturated fatty acid. It is not possible to make double bonds beyond position delta #9.

Image by Lecturio.

Oxidation

Overview

Beta oxidation is the process of fatty acid breakdown.

  • Occurs in mitochondria and peroxisomes
  • Proceeds 2 carbons at a time
  • Generates more ATP per carbon than sugar
  • Process is similar to the reverse of fatty acid synthesis
Diagram comparing fatty acid synthesis and oxidation

Diagram comparing fatty acid synthesis and oxidation.

Image by Lecturio.

Preparation for oxidation

Before oxidation happens, fatty acids need to be activated in the cytoplasm and transported to the mitochondrion.

  • Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) diffuse freely into mitochondria.
  • Long-chain fatty acids (LCFAs) are activated by acyl-CoA synthetase and require carnitine to enter the mitochondrial matrix (“carnitine shuttle”).
    • Fatty acid → fatty acyl-CoA
      • ATP → adenosine monophosphate (AMP) + pyrophosphate
      • Releases: H2O
    • Fatty acid acyl-CoA + carnitine → acyl-carnitine (enzyme: carnitine palmitoyltransferase I (CPT I))
    • Acyl-carnitine is now in the mitochondrion’s intermembrane space.
    • A carnitine acylcarnitine translocase (CACT) helps move acyl-carnitine across the inner membrane.
    • The reverse process happens inside the mitochondrion: acyl-carnitine → FA acyl-CoA + carnitine (enzyme: carnitine palmitoyltransferase II (CPT II))
Transport of fatty acyl-coa molecules across the mitochondrial membrane

Diagram showing the transport of fatty acyl-CoA molecules across the mitochondrial membrane via the carnitine shuttle.

Image by Lecturio.

Steps of beta oxidation

  • Oxidation of fatty acid acyl-CoA → trans-delta 2-enoyl-CoA (trans- intermediate)
    • Enzyme: acyl-CoA dehydrogenase (3 forms)
      • Long chain
      • Medium chain
      • Short chain
    • Flavin adenine dinucleotide (FAD) → FADH2 (used for the generation of ATP)
    • Rate-determining enzyme
  • Trans-delta 2-enoyl-CoA → L-3-hydroxyacyl-CoA 
    • Enzyme: enoyl-CoA hydratase
    • Adds H2O
  • Oxidation of L-3-hydroxyacyl-CoA → 3-ketoacyl-CoA 
    • Enzyme: hydroxyacyl-CoA dehydrogenase
    • NAD+ → NADH (used for the generation of ATP)
  • Cleavage of 3-ketoacyl-CoA → acyl-CoA + acetyl-CoA 
    • Enzyme: thiolase 
    • Products are taken to the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle or used to form ketone bodies.
  • Net: each palmitoyl CoA produces:
    • 2 ATP used for activation 
    • 7 FADH2 → 10.5 ATP (1.5 ATP per FADH2)
    • 7 NADH → 17.5 ATP (2.5 ATP per NADH)
    • 8 acetyl-CoA → 80 ATP (via citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle)
    • Total: 108 ATP (yield: 106 ATP)

Unsaturated FAs oxidation

  • Beta oxidation is carried out until a cis double bond is reached.
  • Enoyl-CoA isomerase changes the double bond to a trans configuration.
  • 2,4 dienoyl-CoA reductase combines trans and cis double bonds into a single trans double bond between carbons 3 and 4.
  • Enoyl-CoA isomerase moves the double bond to carbons 2 and 3.
  • Beta oxidation proceeds as normal.
Unsaturated fatty acid oxidation

Diagram showing the reactions needed for the beginning of unsaturated fatty acid oxidation.

Image by Lecturio.

Long-chain fatty acids

For fatty acids with > 20 carbons:

  • Oxidation starts in peroxisomes.
  • O2 is used to produce H2O2 in the 1st step.
  • FADH2 is not generated.
  • Once short enough, the fatty acid transfers to the mitochondria for beta oxidation.

Odd-chain fatty acids

Fatty acids with an odd number of carbons produce propionyl-CoA (3 carbons).

  • Propionyl-CoA carboxylase turns propionyl-CoA → methylmalonyl-CoA
  • Methylmalonyl-CoA mutase converts methylmalonyl-CoA → succinyl-CoA
  • Succinyl-CoA is an intermediate in the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle.
Synthesis of succinyl-coa from propionyl-coa

Diagram showing the reactions needed for the synthesis of succinyl-CoA from propionyl-CoA. Succinyl-CoA is an intermediate in the citric acid cycle Citric acid cycle The citric acid cycle, also known as the tricarboxylic acid (TCA) cycle or the Krebs cycle, is a cyclic set of reactions that occurs in the mitochondrial matrix. The TCA cycle is the continuation of any metabolic pathway that produces pyruvate, which is converted into its main substrate, acetyl-CoA. Citric Acid Cycle.

Image by Lecturio.

Ketones

Synthesis

Occurs:

  • In certain physiologic states, where oxaloacetate is diverted to gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis:
    • Starvation or fasting
    • ↓ Carbohydrate diet
    • Strenuous exercise
    • Insulin deficiency
  • In mitochondria of hepatocytes

Process:

  • Fatty acids undergo beta oxidation → NADH, ATP, acetyl CoA
  • Oxaloacetate is diverted to gluconeogenesis Gluconeogenesis Gluconeogenesis is the process of making glucose from noncarbohydrate precursors. This metabolic pathway is more than just a reversal of glycolysis. Gluconeogenesis provides the body with glucose not obtained from food, such as during a fasting period. The production of glucose is critical for organs and cells that cannot use fat for fuel. Gluconeogenesis → cannot combine with acetyl CoA
  • Thiolase combines 2 acetyl CoA → acetoacetyl CoA
  • HMG-CoA synthase combines acetoacetyl CoA + acetyl CoA → hydroxymethylglutaryl CoA (HMG-CoA)
  • HMG-CoA lyase cleaves HMG-CoA → acetyl CoA + acetoacetate
  • Acetoacetate can either be:
    • Reduced by 3-hydroxybutyrate dehydrogenase → beta-hydroxybutyrate
    • Spontaneously decarboxylated → acetone

Use

  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver is unable to utilize ketone bodies → releases them into the blood
  • Taken up by multiple tissues, including:
    • Muscles
    • Kidney
    • Brain (at high blood levels, such as in starvation states)
  • There, they can be oxidized for energy:
    • 3-hydroxybutyrate dehydrogenase oxidizes beta-hydroxybutyrate → acetoacetate + NADH (NADH can go on to produce ATP)
    • Acetoacetate + succinyl CoA → acetoacetyl CoA + succinate
    • Thiolase cleaves acetoacetyl CoA → 2 acetyl CoA (can enter tricarboxylic acid (TCA) cycle to produce 20 ATP)

Clinical Relevance

  • Eicosanoids: these signaling molecules are made by oxidation of arachidonic acid, which is derived from linoleic acid (an essential fatty acid). There are different families of eicosanoids Eicosanoids Eicosanoids are cell-signaling molecules produced from arachidonic acid. With the action of phospholipase A2, arachidonic acid is released from the plasma membrane. The different families of eicosanoids, which are prostaglandins (PGs), thromboxanes (TXA2s), prostacyclin (PGI2), lipoxins (LXs), and leukotrienes (LTs), emerge from a series of reactions catalyzed by different enzymes. Eicosanoids, including prostaglandins, thromboxanes, prostacyclin, lipoxins, and leukotrienes. The molecules play vital roles in the inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and coagulation cascades, as well platelet adhesion. 
  • Diabetic ketoacidosis Diabetic ketoacidosis Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises ( DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises): the absence of insulin Insulin Insulin is a peptide hormone that is produced by the beta cells of the pancreas. Insulin plays a role in metabolic functions such as glucose uptake, glycolysis, glycogenesis, lipogenesis, and protein synthesis. Exogenous insulin may be needed for individuals with diabetes mellitus, in whom there is a deficiency in endogenous insulin or increased insulin resistance. Insulin can increase the beta oxidation of fatty acids due to the influence of glucagon. An overabundance of acetyl-CoA will lead to the production of ketone bodies, resulting in a metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis. Individuals with DKA DKA Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are serious, acute complications of diabetes mellitus. Diabetic ketoacidosis is characterized by hyperglycemia and ketoacidosis due to an absolute insulin deficiency. Hyperglycemic Crises may have “fruity” breath, which is due to the accumulation of acetone, which is released during respiration.
  • Fatty acid metabolism disorders: a group of genetic conditions caused by disruptions in beta oxidation or the carnitine transport pathway. Due to the inability of the body to break down fatty acids, these fats accumulate in the liver and other internal organs. The clinical presentations of each disorder vary but commonly include hypoglycemia Hypoglycemia Hypoglycemia is an emergency condition defined as a serum glucose level ≤ 70 mg/dL (≤ 3.9 mmol/L) in diabetic patients. In nondiabetic patients, there is no specific or defined limit for normal serum glucose levels, and hypoglycemia is defined mainly by its clinical features. Hypoglycemia, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies, encephalopathy, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, myopathy, and liver dysfunction. Screening of newborns can detect these diseases, and DNA DNA The molecule DNA is the repository of heritable genetic information. In humans, DNA is contained in 23 chromosome pairs within the nucleus. The molecule provides the basic template for replication of genetic information, RNA transcription, and protein biosynthesis to promote cellular function and survival. DNA Types and Structure sequencing is usually performed to confirm the diagnosis. Management includes dietary changes or substrate supplementation.
  • Zellweger syndrome Zellweger syndrome Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Zellweger Syndrome: a rare congenital peroxisome disorder characterized by the reduction or absence of functional peroxisomes, which prevents the catabolism of very-long-chain fatty acids (VLCFAs), resulting in their accumulation in the membranes of neuronal cells and disruption of normal function. Symptoms are present from the time of birth and include hypotonia, poor feeding, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, and certain distinctive physical features, notably facial characteristics and skeletal malformations. There is no cure for Zellweger syndrome Zellweger syndrome Zellweger syndrome (ZWS), also called cerebrohepatorenal syndrome, is a rare congenital peroxisome biosynthesis disorder and is considered an inborn error of metabolism. Zellweger syndrome is the most severe form of a spectrum of conditions called Zellweger spectrum disorder (ZSD), and is characterized by the reduction or absence of functional peroxisomes. Zellweger Syndrome.

References

  1. Botham, KM, & Mayes, PA. (2018). Biosynthesis of fatty acids and eicosanoids. In Rodwell, VW, et al. (Eds.), Harper’s Illustrated Biochemistry, 31e. New York, NY: McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?aid=1163593486 
  2. Botham, KM., & Mayes, PA. (2018). Oxidation of fatty acids: Ketogenesis. In Rodwell, V. W., et al. (Eds.), Harper’s Illustrated Biochemistry, 31e. New York, NY: McGraw-Hill Education. https://accessmedicine.mhmedical.com/content.aspx?aid=1160192486 
  3. Lovera, C, et al. (2012). Sudden unexpected infant death (SUDI) in a newborn due to medium-chain acyl CoA dehydrogenase (MCAD) deficiency with an unusual severe genotype. Italian Journal of Pediatrics. 38, 59. https://pubmed.ncbi.nlm.nih.gov/23095120/ 
  4. Turner, N, et al. (2014). Fatty acid metabolism, energy expenditure, and insulin resistance in muscle. Journal of Endocrinology. 220(2), T61-T79. https://joe.bioscientifica.com/view/journals/joe/220/2/T61.xml
  5. DiTullio, D, & Dell’Angelica, EC. (Eds.). (2019). Lipid metabolism. In Fundamentals of Biochemistry: Medical Course & Step 1 Review. McGraw Hill. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2492&sectionid=204926092

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