Fatty Acid Metabolism

Overview

Classification

Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (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 CIS Multiple Sclerosis 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

Utility

FAs are utilized for:

• Storage and alternative energy source (as triacylglycerides Triacylglycerides Digestion and Absorption/ triglycerides Triglycerides Fatty Acids and Lipids)
• 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 A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance

Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance is needed to produce acetyl CoA, which is required for FA FA Inhaled Anesthetics synthesis Synthesis Polymerase Chain Reaction (PCR).

• Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance enters hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy → 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 Derivatives of pyruvic acid, including its salts and esters. Glycolysis
• Pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis enters mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles → converted by:
  • Pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis dehydrogenase to acetyl CoA
  • Pyruvate carboxylase Pyruvate carboxylase A biotin-dependent enzyme belonging to the ligase family that catalyzes the addition of carbon dioxide to pyruvate. It is occurs in both plants and animals. Gluconeogenesis to oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle
• Both products can combine → citrate
• Citrate can cross out into the cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton (citrate shuttle) → converted back to acetyl CoA + oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle
  • Enzyme: citrate lyase
  • Requires adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs 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 Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle → malate
  • Enzyme: cytosolic malate dehydrogenase
  • Converts NADH → NAD NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway+
• Malate → pyruvate Pyruvate Derivatives of pyruvic acid, including its salts and esters. Glycolysis → can be reutilized in the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles
  • Enzyme: nicotinamide adenine dinucleotide Nicotinamide adenine dinucleotide A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (NADP+)-dependent malate dehydrogenase)
  • Produces NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway
  • Releases CO₂

Synthesis Synthesis Polymerase Chain Reaction (PCR) of palmitic acid Palmitic acid A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids. Fatty Acids and Lipids

The process of FA FA Inhaled Anesthetics synthesis Synthesis Polymerase Chain Reaction (PCR) continues in the cytoplasm:

• Acetyl CoA + CO₂ → malonyl CoA (important regulatory step)
  • Enzyme: acetyl CoA carboxylase 
  • Requires:
    • Biotin
    • ATP
  • Activated/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
    • Citrate
  • Inhibited by:
    • Glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions
    • Palmitoyl-CoA (feedback inhibition)
• Fatty acid synthase is needed for subsequent reactions.
• CoA is replaced by acyl-carrier protein (ACP): acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle 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 NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway → NADP
• Water molecule is removed by 3-hydroxyacyl ACP dehydratase → trans double bond
• Double bond is reduced to a single bond → fatty acid molecule
  • Enzyme: enoyl ACP reductase
  • NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5′-phosphate (nmn) coupled by pyrophosphate linkage to the 5′-phosphate adenosine 2. Pentose Phosphate Pathway → 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 Palmitic acid A common saturated fatty acid found in fats and waxes including olive oil, palm oil, and body lipids. Fatty Acids and Lipids

Elongation Elongation Polymerase Chain Reaction (PCR) and desaturation

• Elongation Elongation Polymerase Chain Reaction (PCR):
  • Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance longer than 16 carbons are synthesized in the ER and mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles.
  • The process is similar (malonyl-CoA provides 2 carbon units to the growing chain).
• Desaturation:
  • Saturated fatty acids Saturated fatty acids Fatty Acids and Lipids undergo desaturation in the ER.
  • Desaturases make double bonds up until the 9th carbon.
  • Note: Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance with double bonds in the 12th and 15th carbons are known as essential because they must be included in the diet.

Oxidation

Overview

Beta oxidation is the process of fatty acid breakdown.

• Occurs in mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles and peroxisomes Peroxisomes Microbodies which occur in animal and plant cells and in certain fungi and protozoa. They contain peroxidase, catalase, and allied enzymes. The Cell: Organelles
• Proceeds 2 carbons at a time
• Generates more ATP per carbon than sugar
• Process is similar to the reverse of fatty acid synthesis Synthesis Polymerase Chain Reaction (PCR)

Preparation for oxidation

Before oxidation happens, fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance need to be activated in the cytoplasm and transported to the mitochondrion.

• Short-chain fatty acids Short-chain fatty acids Digestion and Absorption ( SCFAs SCFAs Digestion and Absorption) and medium-chain fatty acids Medium-chain fatty acids Digestion and Absorption ( MCFAs MCFAs Digestion and Absorption) diffuse freely into mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles.
• Long-chain fatty acids Long-chain fatty acids Digestion and Absorption ( LCFAs LCFAs Digestion and Absorption) are activated by acyl-CoA synthetase and require carnitine to enter the mitochondrial matrix (“carnitine shuttle”).
  • Fatty acid → fatty acyl-CoA
    • ATP → adenosine Adenosine A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA and RNA. Adenosine itself is a neurotransmitter. Class 5 Antiarrhythmic Drugs 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 FA Inhaled Anesthetics acyl-CoA + carnitine (enzyme: carnitine palmitoyltransferase II (CPT II))

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 Adenine A purine base and a fundamental unit of adenine nucleotides. Nucleic Acids 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 NAD+ A coenzyme composed of ribosylnicotinamide 5′-diphosphate coupled to adenosine 5′-phosphate by pyrophosphate linkage. It is found widely in nature and is involved in numerous enzymatic reactions in which it serves as an electron carrier by being alternately oxidized (NAD+) and reduced (NADH). Pentose Phosphate Pathway+ → NADH (used for the generation of ATP)
• Cleavage of 3-ketoacyl-CoA → acyl-CoA + acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle
  • 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 Ketone bodies The metabolic substances acetone; 3-hydroxybutyric acid; and acetoacetic acid (acetoacetates). They are produced in the liver and kidney during fatty acids oxidation and used as a source of energy by the heart, muscle and brain. Ketone Body Metabolism.
• 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 Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle → 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 CIS Multiple Sclerosis double bond is reached.
• Enoyl-CoA isomerase changes the double bond to a trans configuration.
• 2,4 dienoyl-CoA reductase combines trans and cis CIS Multiple Sclerosis 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.

Long-chain fatty acids Long-chain fatty acids Digestion and Absorption

For fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance with > 20 carbons:

• Oxidation starts in peroxisomes Peroxisomes Microbodies which occur in animal and plant cells and in certain fungi and protozoa. They contain peroxidase, catalase, and allied enzymes. The Cell: Organelles.
• O₂ is used to produce H₂O₂ in the 1st step.
• FADH2 is not generated.
• Once short enough, the fatty acid transfers to the mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles for beta oxidation.

Odd-chain fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance

Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance 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 Citric Acid Cycle
• Succinyl-CoA Succinyl-CoA Citric Acid Cycle 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.

Ketones

Synthesis Synthesis Polymerase Chain Reaction (PCR)

Occurs:

• In certain physiologic states, where oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle 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 Strenuous exercise Physical activity which is usually regular and done with the intention of improving or maintaining physical fitness or health. Contrast with physical exertion which is concerned largely with the physiologic and metabolic response to energy expenditure. Cardiovascular Response to Exercise
  • 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 deficiency
• In mitochondria Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive ribosomes, transfer RNAs; amino Acyl tRNA synthetases; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs. Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. The Cell: Organelles of hepatocytes Hepatocytes The main structural component of the liver. They are specialized epithelial cells that are organized into interconnected plates called lobules. Liver: Anatomy

Process:

• Fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance undergo beta oxidation → NADH, ATP, acetyl CoA
• Oxaloacetate Oxaloacetate Derivatives of oxaloacetic acid. Included under this heading are a broad variety of acid forms, salts, esters, and amides that include a 2-keto-1, 4-carboxy aliphatic structure. Citric Acid Cycle 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 HMG-CoA synthase An enzyme that catalyzes the synthesis of hydroxymethylglutaryl-CoA from acetyl-CoA and acetoacetyl-CoA. This is a key enzyme in steroid biosynthesis. Ketone Body Metabolism combines acetoacetyl CoA + acetyl CoA → hydroxymethylglutaryl CoA (HMG-CoA)
• HMG-CoA lyase HMG-CoA lyase Ketone Body Metabolism cleaves HMG-CoA → acetyl CoA + acetoacetate Acetoacetate Salts and derivatives of acetoacetic acid. Ketone Body Metabolism
• Acetoacetate Acetoacetate Salts and derivatives of acetoacetic acid. Ketone Body Metabolism can either be:
  • Reduced by 3-hydroxybutyrate dehydrogenase → beta-hydroxybutyrate Beta-hydroxybutyrate Butyric acid substituted in the beta or 3 position. It is one of the ketone bodies produced in the liver. Ketone Body Metabolism
  • Spontaneously decarboxylated → acetone Acetone A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. Ketone Body Metabolism

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: Anatomy is unable to utilize ketone bodies Ketone bodies The metabolic substances acetone; 3-hydroxybutyric acid; and acetoacetic acid (acetoacetates). They are produced in the liver and kidney during fatty acids oxidation and used as a source of energy by the heart, muscle and brain. Ketone Body Metabolism → releases them into the blood
• Taken up by multiple tissues, including:
  • Muscles
  • Kidney
  • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification (at high blood levels, such as in starvation states)
• There, they can be oxidized for energy:
  • 3-hydroxybutyrate dehydrogenase oxidizes beta-hydroxybutyrate Beta-hydroxybutyrate Butyric acid substituted in the beta or 3 position. It is one of the ketone bodies produced in the liver. Ketone Body Metabolism → acetoacetate Acetoacetate Salts and derivatives of acetoacetic acid. Ketone Body Metabolism + NADH (NADH can go on to produce ATP)
  • Acetoacetate Acetoacetate Salts and derivatives of acetoacetic acid. Ketone Body Metabolism + 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 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: these signaling molecules Signaling molecules Second Messengers are made by oxidation of arachidonic acid Arachidonic Acid An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. Nonsteroidal Antiinflammatory Drugs (NSAIDs), which is derived from linoleic acid Linoleic acid A doubly unsaturated fatty acid, occurring widely in plant glycosides. It is an essential fatty acid in mammalian nutrition and is used in the biosynthesis of prostaglandins and cell membranes. Fatty Acids and Lipids (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 Prostaglandins A group of compounds derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway. They are extremely potent mediators of a diverse group of physiological processes. Eicosanoids, thromboxanes Thromboxanes Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. Eicosanoids, prostacyclin Prostacyclin A prostaglandin that is a powerful vasodilator and inhibits platelet aggregation. It is biosynthesized enzymatically from prostaglandin endoperoxides in human vascular tissue. The sodium salt has been also used to treat primary pulmonary hypertension. Eicosanoids, lipoxins Lipoxins Trihydroxy derivatives of eicosanoic acids. They are primarily derived from arachidonic acid, however eicosapentaenoic acid derivatives also exist. Many of them are naturally occurring mediators of immune regulation. Eicosanoids, and leukotrienes Leukotrienes A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. Eicosanoids. 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 Adhesion The process whereby platelets adhere to something other than platelets, e.g., collagen; basement membrane; microfibrils; or other ‘foreign’ surfaces. Coagulation Studies. 
• Diabetic ketoacidosis Ketoacidosis A life-threatening complication of diabetes mellitus, primarily of type 1 diabetes mellitus with severe insulin deficiency and extreme hyperglycemia. It is characterized by ketosis; dehydration; and depressed consciousness leading to coma. Metabolic Acidosis ( 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 Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance due to the influence of glucagon Glucagon A 29-amino acid pancreatic peptide derived from proglucagon which is also the precursor of intestinal glucagon-like peptides. Glucagon is secreted by pancreatic alpha cells and plays an important role in regulation of blood glucose concentration, ketone metabolism, and several other biochemical and physiological processes. Gastrointestinal Secretions. An overabundance of acetyl-CoA Acetyl-CoA Acetyl CoA participates in the biosynthesis of fatty acids and sterols, in the oxidation of fatty acids and in the metabolism of many amino acids. It also acts as a biological acetylating agent. Citric Acid Cycle will lead to the production of ketone bodies Ketone bodies The metabolic substances acetone; 3-hydroxybutyric acid; and acetoacetic acid (acetoacetates). They are produced in the liver and kidney during fatty acids oxidation and used as a source of energy by the heart, muscle and brain. Ketone Body Metabolism, resulting in a metabolic acidosis Acidosis A pathologic condition of acid accumulation or depletion of base in the body. The two main types are respiratory acidosis and metabolic acidosis, due to metabolic acid build up. Respiratory 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 Acetone A colorless liquid used as a solvent and an antiseptic. It is one of the ketone bodies produced during ketoacidosis. Ketone Body Metabolism, which is released during respiration Respiration The act of breathing with the lungs, consisting of inhalation, or the taking into the lungs of the ambient air, and of exhalation, or the expelling of the modified air which contains more carbon dioxide than the air taken in. Nose Anatomy (External & Internal).
• 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 Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance, these fats Fats The glyceryl esters of a fatty acid, or of a mixture of fatty acids. They are generally odorless, colorless, and tasteless if pure, but they may be flavored according to origin. Fats are insoluble in water, soluble in most organic solvents. They occur in animal and vegetable tissue and are generally obtained by boiling or by extraction under pressure. They are important in the diet (dietary fats) as a source of energy. Energy Homeostasis accumulate in the 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: Anatomy 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). Cardiomyopathy: Overview and Types, encephalopathy Encephalopathy Hyper-IgM Syndrome, 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 Myopathy Dermatomyositis, and 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: Anatomy dysfunction. Screening Screening Preoperative Care of newborns can detect these diseases, and DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure sequencing is usually performed to confirm the diagnosis. Management includes dietary changes or substrate Substrate A substance upon which the enzyme acts. Basics of Enzymes 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 Congenital Chorioretinitis peroxisome disorder characterized by the reduction or absence of functional peroxisomes Peroxisomes Microbodies which occur in animal and plant cells and in certain fungi and protozoa. They contain peroxidase, catalase, and allied enzymes. The Cell: Organelles, which prevents the catabolism of very-long-chain fatty acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance (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 Hypotonia Duchenne Muscular Dystrophy, 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.