Lipolysis, Fat Mobilization, Fatty Acid (beta, alpha, omega) Oxidation, Ketogenesis.pdf
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Lipolysis and the Oxidation of Fatty Acids
Introduction
Mobilization of Fat Stores
Cellular Uptake of Fatty Acids
Roles of Fatty Acid Binding Proteins, FABP
Mitochondrial (beta) -Oxidation ReactionsMinor Alternative Fatty Acid Oxidation Reactions
Peroxisomal (beta) -Oxidation Reactions
Microsomal (omega) -Oxidation Reactions
Phytanic Acid (alpha) -Oxidation Reactions
Regulation of Fatty Acid Metabolism
The Glucose-Fatty Acid Cycle
Clinical Aspects of Fatty Acid Metabolism
Ketogenesis
Diabetic Ketoacidosis
Regulation of Ketogenesis
Clinical Significance of Ketogenesis
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Introduction
Utilization of dietary lipids requires that they first be absorbed through the intestine. As
these molecules are oils they would be essentially insoluble in the aqueous intestinal
environment. Solubilization (emulsification) of dietary lipid is accomplished initially via the
agitation action as food passes through the stomach and then continues within the intestine via
bile saltsthat are synthesized in the liver and secreted from the gallbladder.
The emulsified fats can then be degraded by salivary, gastric and pancreatic lipases. The
lipases found in the gastrointestinal tract include lingual lipase (secreted by the serous glands
of the tongue), gastric lipase (secreted by chief cells of the stomach), pancreatic lipase, and
pancreatic lipase-related proteins 1 and 2. These enzymes generate free fatty acids and a
mixture of mono- and diacylglycerols from dietary triacylglycerols. Pancreatic lipase degrades
triacylglycerols at the 1 and 3 positions sequentially to generate 1,2-diacylglycerols and 2-
acylglycerols. Phospholipids are degraded at the 2 position by pancreatic phospholipase A2releasing a free fatty acid and the lysophospholipid.
Following absorption of the products of pancreatic lipase by the intestinal mucosal cells,
the resynthesis of triacylglycerides occurs. The triacylglycerides are then solubilized in
lipoprotein complexes(complexes of lipid and protein) called chylomicrons. A chylomicron
contains lipid droplets surrounded by the more polar lipids and finally a layer of proteins.
Triacylglycerides synthesized in the liver are packaged into VLDLs and released into the blood
directly. Chylomicrons from the intestine are then released into the blood via the lymph system
for delivery to the various tissues for storage or production of energy through oxidation.
The triacylglyceride components of VLDLs and chylomicrons are hydrolyzed to free fatty
acids and glycerol in the capillaries of tissues such as liver, adipose tissue and skeletal
muscle by the actions of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL). The
free fatty acids are then absorbed by the cells and the glycerol is returned via the blood to the
liver (principal site) and kidneys. The glycerol can then converted to the glycolytic intermediate
dihydroxyacetone phosphate DHAP or phosphorylated by glycerol kinase to glycerol-3-phosphate for reuse in triglyceride synthesis.
The classification of blood lipids is distinguished based upon the density of the different
lipoproteins. As lipid is less dense than protein, the lower the density of lipoprotein the less
protein there is.
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Biochemistry Clinical Medical Enzyme Deficiency Fatty Acids
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Additional proteins associated with lipid droplets (LD) in adipocytes participate in the CGI-58-mediated regulation
of ATGL. In resting adipocytes of both WAT and BAT, the LD protein perilipin-1 interacts with CGI-58, preventing its
binding to and, induction of ATGL. Following -adrenergic stimulation of WAT, PKA phosphorylates perilipin-1 at
multiple sites resulting in the release of CGI-58 which in turn, binds and stimulates ATGL. This demonstrates that -
adrenergic stimulation of PKA induces ATGL activity, not by direct phosphorylation of ATGL itself, but through
phosphorylation of perilipin-1. This model of ATGL regulation is evident from frameshift mutants that have been
identified in human perilipin-1. These mutations are identified as V398fs and L404fs indicating that the frame shift
occurs at valine 398 and leucine 404, respectively. Each of these mutant ATGL proteins fail to bind CGI-58, resulting in
unrestrained lipolysis, partial lipodystrophy, hypertriglyceridemia, and insulin resistance.
In non-adipose tissues with high rates of TG hydrolysis, such as skeletal muscle and liver, regulation of ATGL
activity occurs via a mechanism distinct from that in adipose tissues. In these tissues, perilipin-1 is replaced byperilipin-5. During fasting, perilipin-5 recruits both ATGL and CGI-58 to LDs by direct binding of the enzyme and its
coactivator. Data indicates that perilipin-5 is involved in the interaction of LDs with mitochondria and thereby inhibits
ATGL-mediated TG hydrolysis. Other perilipins exist in cells including perilipin-2, -3, and -4 but it is unclear if these
proteins are also involved in regulating the association of ATGL with LDs. In hepatocyte cell lines it has been shown
that overexpression of perilipin-2 inhibits ATGL activity by restricting its physical access to LDs.
Recently, a specific peptide inhibitor for ATGL was isolated from white blood cells, specifically mononuclear cells.
This peptide was originally identifed as being involved in the regulation of the G0to G1transition of the cell cycle. This
peptide was, therefore, called G0G1 switch protein 2 (G0S2). The protein is found in numerous tissues, with highest
concentrations in adipose tissue and liver. In adipose tissue G0S2 expression is very low during fasting but increases
after feeding. Conversely, fasting or PPAR-agonists increase hepatic G0S2 expression. The protein has been shown
to localize to LDs, cytoplasm, ER, and mitochondria. These different subcellular localizations likely relate to multiple
functions for G0S2 in regulating lipolysis, the cell cycle, and, possibly, apoptosis via its ability to interact with the
mitochondrial antiapoptotic factor Bcl-2. With respect to ATGL regulation, the binding of the enzyme to LDs andsubsequent is dependent on a physical interaction between the N-terminal region of G0S2 and the patatin domain of
ATGL.
The delivery of ATGL to LDs requires functional vesicular transport. When essential protein components of the
transport machinery are defective or missing, such as ADP-ribosylation factor 1 (ARF1), small GTP-binding protein 1
(SAR1), the guanine-nucleotide exchange factor Golgi-Brefeldin A resistance factor (GBF1), or the coatamer protein
coat-complex I (COPI) and COPII, ATGL translocation to LDs is blocked and the enzyme remains associated with the
ER.
Hormone-sensitive lipase: HSL
A landmark study published in 1964 demonstrated that a lipolytic activity present in adipose tissue was induced by
hormonal stimulation. This work described the isolation and characterization of both HSL and monoacylglyceride
lipase (MGL). This original study demonstrated that HSL had a higher level of activity as a DG hydrolase than as a TG
hydrolase. Nevertheless, it became dogma that HSL was rate-limiting for the catabolism of fat stores in adipose andmany non-adipose tissues. However, when HSL-deficient mice were produced and shown to efficiently hydrolyze TGs
the model began to emerge demonstrating ATGL, and not HSL, to be rate-limiting for adipose tissue TG hydrolysis.
HSL-deficient mice do not accumulate TGs in either adipose or non-adipose tissues, but they do accumulate large
amounts of DGs in many tissues. This indicated for the first time that HSL was more important as a DG hydrolase than
a TG hydrolase. It is now accepted that ATGL is responsible for the initial step of lipolysis in human adipocytes, and
that HSL is rate-limiting for the catabolism of DGs. HSL not only hydrolyzes DGs but is also active at hydrolyzing ester
bonds of many other lipids including TGs, MGs, cholesteryl esters, retinyl esters, and short-chain carbonic acid esters.
The HSL gene is located on chromosome 19q13.2. Alternative exon useage results in tissue-specific differences
in mRNA and protein size. In adipose tissue the HSL protein is composed of 775 amino acids, whereas the testicular
form is composed of 1,076 amino acids. The expression profile of HSL essentially mirrors that of ATGL. Highest
mRNA and protein concentrations are found in WAT and BAT with low levels of expression found in muscle, testis,
steroidogenic tissues, and pancreatic islets as well as several other tissues. Functional studies on the enzyme have
identified an N-terminal lipid-binding region, the / hydrolase fold domain including the catalytic triad, and theregulatory module containing all known phosphorylation sites important for regulation of enzyme activity.
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Model for the activation of adipose tissue hormone-sensitive lipase:Epinephrine binding to -adrenergic
receptors or glucagon binding its GPCR triggers activation of the associate Gs-type G-protein that in turn leads to
the activation of adenylate cyclase. The resultant increase in cAMP activates PKA which then phosphorylates and
activates hormone-sensitive lipase (HSL). Hormone-sensitive lipase hydrolyzes fatty acids from diacylglycerols that
result from the action of ATGL/desnutrin. The final fatty acid is released from monoglycerides through the action ofmonoglyceride lipase (MGL), an enzyme that is also active in the absence of hormonal stimulation.
HSL and ATGL share many regulatory similarities yet the mechanisms of the regulatory processes differ markedly
between the two enzymes. In adipose tissue, HSL enzyme activity is strongly induced by -adrenergic stimulation,
conversely insulin has a strong inhibitory effect. While -adrenergic stimulation regulates ATGL primarily via
recruitment of the coactivator CGI-58), HSL is a major target for PKA-mediated phosphorylation. Additional kinases,
including AMPK, extracellular signal-regulated kinase (ERK), glycogen synthase kinase-4 (GSK-4), and
Ca2+/calmodulin-dependent kinase 1 (CAMK1), also phosphorylate HSL to modulate the activity of the enzyme. HSL
has at least five potential phosphorylation sites, of which S660 and S663 appear to be particularly important for
hydrolytic activity. Enzyme phosphorylation affects enzyme activity only moderately resulting in an approximate 2-fold
increase in hydrolytic activity. For full activation, HSL must gain access to LDs, which, in adipose tissue, is mediated
by perilipin-1. In addition to phosphorylating HSL, PKA also phosphorylates perilipin-1 on six consensus serine
residues. The result of these phosphorylations is the binding of HSL to the N-terminal region of perilipin-1. This protein-
protein interaction is the means by which HSL gains access to LDs. The net effect, of HSL-phosphorylation andenzyme translocation to LDs, coupled with ATGL activation by CGI-58, leads to a more than 100-fold increase in TG
hydrolysis in adipocytes.
Additional factors modulate the activation of HSL and ATGL. One such factor is receptor-interacting protein 140
(RIP-140) which induces lipolysis by binding to perilipin-1, increasing HSL translocation to LDs, and activating ATGL
via CGI-58 dissociation from perilipin-1. In non-adipose tissues, such as skeletal muscle, HSL is activated by
phosphorylation in response to epinephrine (-adrenergic receptor-mediated activation of PKA) and muscle
contraction (calcium release from sarcoplasmic reticulum). Since skeletal muscles lack perilipin-1 it has not yet been
determined which alternative mechanisms regulate HSL access to LDs.
Insulin-mediated deactivation of lipolysis is associated with transcriptional downregulation of ATGL and HSL
expression. Additionally, insulin signaling results in phosphorylation and activation of various phosphodiesterase
(PDE) isoforms by PKB/Akt leading to PDE-catalyzed hydrolysis of cAMP which in turn results in reduced activation of
PKA. These actions turn off lipolysis by preventing phosphorylation of both HSL and perilipin-1, activation and
translocation of HSL, and activation of ATGL by CGI-58. In addition to its peripheral action, insulin also functions within
the sympathetic nervous system to inhibit lipolysis in WAT. Increased insulin levels in the brain inhibit HSL and perilipin
phosphorylation which results in reduced HSL and ATGL activities.
Monoacylglyceride lipase: MGL
MGL is considered to be the rate-limiting enzyme for the breakdown of MGs that are the result of both extracellular
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Medical Transport A Fatty Liver Fat Metabolism Liver Enzyme
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FATP6 levels in the heart; protein only detected in heart and testis; exhibits a preference for the transport of
palmitic acid and linoleic acid, does not transport fatty acids less than 10 carbons long; located on
chromosome 5q23.3 spanning 67 kb and composed of 11 exons encoding a 619 amino acidprotein
The result of the interaction of fatty acids with plasma membrane receptors/binding proteins is a transmembrane
concentration gradient. At the plasma membrane the apparent pKa of the fatty acid shifts from about 4.5 in aqueous
solutions to about 7.6. This pKa change is independent of fatty acid type. As a consequence, about half of the fatty
acids are present in the un-ionized form. This local environment effect promotes a transfer (flip-flop) of uncharged fatty
acids from the outer leaflet across the phospholipid bilayer. At the cytosolic surface of the plasma membrane, fatty
acids can associate with the cytosolic fatty acid binding protein (FABPc) or with caveolin-1. Caveolin-1 is a constituent
of caveolae (Latin for little caves) which are specialized "lipid rafts" present in flask-shaped indentations in the plasma
membranes of many cells types that perform a number of signaling functions by serving as lipid delivery vehicles for
subcellular organelles. In order that the fatty acids that are thus taken up to be directed to the various metabolic
pathways (e.g. oxidation or triglyceride synthesis) they must be activated to acyl-CoA. Members of the atty acid
transport protein (FATP) family have been shown to possess acyl-CoA synthetase (ACS) activity. Activation of fatty
acids by FATPs occurs at the highly conserved cytosolic AMP-binding site of these proteins. The overall process of
cellular fatty acid uptake and subsequent intracellular utilization represents a continuum of dissociation from albumin by
interaction with the membrane-associated transport proteins, binding to FABPc and caveolin-1 at the cytosolic plasma
membrane, activation to acyl-CoA (in many cases via FATP action) followed by intracellular trafficking via FABPcand/or caveolae to si tes of metabolic disposition.
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Roles of Intracellular Fatty Acid Binding Proteins, FABPFatty acid binding proteins (FABPs) represent a family of intracellular lipid-binding proteins whose functions are to
reversibly bind intracellular hydrophobic ligands and transport the bound ligand throughout the various cellular
compartments, including the peroxisomes, mitochondria, endoplasmic reticulum and nucleus. FABPs have broad
binding characteristics which includes the ability to bind long-chain (C16C20) fatty acids (LCFAs), eicosanoids, bile
salts and peroxisome proliferators. There are currently nine well characterized FABP genes in the human genome.
Each of these FABPs was originally named for the tissue in which it was first isolated and characterized or in which it
predominates. However, many of these FABPs are expressed in numerous tissues.
Expression of a particular FABP gene directly reflects the lipid metabolic capacity of that tissue. In high lipid
metabolizing tissues, such as the liver, adipose tissue, and the heart, the expressed FABPs can account for 1%5%
per cent of total soluble cytosolic proteins. The expression of FABPs in the cell is essential for the binding of
hydrophobic ligands, particularly free fatty acids, in order to reduce the detergent-like properties of high concentrations
of fatty acids, thereby keeping them soluble. FABPs are critical to the process of lipid trafficking within cells to thevarious cellular compartments where they will be stored, oxidized, utilized for membrane synthesis, and for their roles in
the activation of nuclear receptors. With respect to the latter function, it has been shown that FABPs are involved in the
targeting of fatty acids to transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. In
addition to their importance in intracellular lipid trafficking, many FABPs interact with phospholipid-rich membranes
and bind eicosanoid intermediates protecting these substrates against peroxidation strongly implicating these proteins
in antioxidant-type behaviour.
FABP Alternate NamesTissue
LocationFunctions / Comments
FABP1
(L-FABP)
Z protein, hepatic
FABP, heme-binding
protein
liver, intestine,
pancreas, kidney,
lung, stomach
represents up to 5% of hepatocyte cytosolic protein;
unique ability to bind multiple ligands at once; in
addition to various free fatty acids FABP1 binds bindsfatty acyl-carnitines, intermediates in glyceride
synthesis, lysophospholipids, cholesterol, bile acids,
prostaglandins, lipoxygenase products, retinoids,
heme and bilirubin; FABP1 also binds numerous
xenobiotic drugs such as NSAIDs, fibrates, beta
blockers, and benzodiazepines
FABP2
(I-FABP) gut FABP, gFABP intestine, livermediates dietary fat absorption of free long-chain fatty
acids (LCFAs)
FABP3
(H-FABP)
O-FABP, mammary-
derived growth
inhibitor, MDGI
skeletal and heart
muscle, brain,
kidney, lung,stomach, testes,
placenta, ovary,
brown adipose
tissue (BAT),
adrenal glands,
mammary glands
makes up 4%8% of cytosolic protein in the heart;
major function is to traffic fatty acids to the
mitochondria for oxidaiton; also binds non-prostanoidoxygenated fatty aicds; measurement of protein in the
blood is considered an early marker for myocardial
infarct; may also be a marker for CreutzfeldtJakob
disease (CJD) by measurement of levels in the
cerebrospinal fluid
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FABP4
(A-FABP)
adipocyte protein 2,
aP2
adipocytes and
macrophages of
adipose tissue,
dendritic cells
specific binding capacity for LCFAs; is a marker for
adipocyte maturation; modulates the activity of HSL
through direct interaction; macrophage FABP4
modulates inflammatory responses; recently
demonstrated to be a secreted adipokine involved in
regulating hepatic glucose production
FABP5
(E-FABP)
psoriasis-associated
FABP (PA-FABP);
keratinocyte-type
FABP (KFABP)
skin, brain,
stomach,
intestines,kidney, liver, lung,
heart, skeletal
muscle, tongue,
adipocytes,
macrophages,
dendritic cells,
testes, retina,
placenta, spleen
physiological ligands not completely determined; in
vitrothe protein binds stearic acid with high affinity
while having reduced affinity for unsaturated fatty
acids; interacts with HSL like FABP3
FABP6
(Il-FABP)
ileal lipid-binding
protein (ILBP);
gastrotropin;
intestinal bile acid-
binding protein (I-BABP)
ileum, stomach,
adrenal glands,
ovary
involved in enterohepatic circulation of bile acids;
binds bile acids with highest affinity then fatty acids;
interacts with the ileal bile acid transporter protein
FABP7
(B-FABP)
brain lipid-binding
protein (BLBP)
brain, glial cells,
mammary
glands, retina
grey matter neurons do not express FABP7; highest
affinity for long-chain omega-3 polyunsaturated fatty
acids (PUFAs) particularly EPA and DHA; also binds
oleic acid and arachidonic acid but does not bind
palmitic acid or retinoic acid
FABP8
(M-FABP)
peripheral myelin
protein 2 (PMP2)
Schwann cells,
peripheral
nervous system
binds LCFAs; thought to be involved in stabilizing
myelin membranes
FABP9(T-FABP)
testes lipid-bindingprotein (TLBP);
testes, mammaryglands, salivary
glands
precise functions not clearly defined; thought to beinvolved in protection of fatty acids in sperm from
oxidation
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Mitochondrial (beta) -Oxidation Reactions
Oxidation of fatty acids occurs in the mitochondria and the peroxisomes (see below). Fatty acids of between 48
and between 612 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: 1016 carbons long) are
oxidized in both the mitochondria and the peroxisomes with the peroxisomes exhibiting preference for 14-carbon andlonger LCFAs. Very-long-chain fatty acids (VLCFAs: C17C26) are preferentially oxidized in the peroxisomes.
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.
Fatty acid + ATP + CoA > Acyl-CoA + PPi+ AMP
The transport of fatty acyl-CoA into the mitochondria is accomplished via an acyl-carnitine intermediate, which
itself is generated by the action of carnitine palmitoyltransferase 1 (CPT-1 or CPT-I) an enzyme that resides in the
outer mitochondrial membrane. There are three CPT-1 genes in humans identified as CPT-1A, CPT-1B, and CPT-1C.
Expression of CPT-1A predominates in the liver and is thus, referred to as the liver isoform. CPT-1B expression
predominates in skeletal muscle and is thus, referred to as the muscle isoform. CPT-1C expression is exclusive to the
brain and testes. The CPT-1A gene (symbol = CPT1A) is located on chromosome 11q13.3 and consists of 20 exons
spanning 60 kb encoding a 773 amino acid protein. The CPT-1B gene (symbol = CPT1B) is located on chromosome
22q13.33 and consists of 21 exons spanning 10 kb. The CPT-1C gene (symbol = CPT1C) is located on chromosome
19q13.3 and consists of 20 exons spanning 23 kb. The activity of CPT-1C is distinct from those of CPT-1A and CPT-
1B in that it does not act on the same types of fatty acyl-CoAs that are substrates for the latter two enzymes. However,
CPT-1C does exhibit high-affinity malonyl-CoA binding.
Following carnitine acyl-carnitine-mediated transfer of the CPT-1-generated fatty acyl-carnitines across the inner
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mitochondrial membrane, the fatty acyl-carnitine molecules are acted on by the inner mitochondria membrane carnitine
palmitoyltransferase 2 (CPT-2 or CPT-II) regenerating the fatty acyl-CoA molecules. The CPT-2 gene (symbol = CPT2)
is located on chromosome 1p32.3 and consists of 5 exons that span 20 kb.
Transport of fatty acids from the cytoplasm to the inner mitochondrial space for oxidation. Following activation to
a fatty-CoA, the CoA is exchanged for carnitine by CPT-1. The fatty-carnitine is then transported to the inside of the
mitochondrion where a reversal exchange takes place through the action of CPT-2. Once inside the mitochondrion
the fatty-CoA is a substrate for the -oxidation machinery.
The process of mitochondrial fatty acid oxidation is termed -oxidation since it occurs through the sequential
removal of 2-carbon units by oxidation at the -carbon position of the fatty acyl-CoA molecule. The oxidation of fattyacids and lipids in the peroxisomes (see below) also occurs via a process of -oxidation. Each round of -oxidation
involves four steps that, in order, are oxidation, hydration, oxidation, and cleavage.
The first oxidation step in mitochondrial -oxidation involves a family of FAD-dependent acyl-CoA
dehydrogenases. Each of these dehydrogenases has a range of substrate specificity determined by the length of the
fatty acid. Short-chain acyl-CoA dehydrogenase (SCAD, also called butyryl-CoA dehydrogenase) prefers fats of 46
carbons in length; medium-chain acyl-CoA dehydrogenase (MCAD) prefers fats of 416 carbons in length with
maximal activity for C10 acyl-CoAs; long-chain acyl-CoA dehydrogenase (LCAD) prefers fats of 616 carbons in
length with maximal activity for C12 acyl-CoAs.
The next three steps in mitochondrial -oxidation involve a hydration step, another oxidation step, and finally a
hydrolytic reaction that requires CoA and releases acetyl-CoA and an acy-CoA two carbon atoms shorter than the
initial substrate. The water addition is catalyzed by an enoyl-CoA hydratase activity, the second oxidation step is
catalyzed by an NAD-dependent long-chain hydroxacyl-CoA dehydrogenase activity (3-hydroxyacyl-CoA
dehydrogenase activity), and finally the cleavage into an acyl-CoA and an acetyl-CoA is catalyzed by a thiolase activity.These three activities are encoded in a multifunctional enzyme called the mitochondrial trifunctional protein, MTP. MTP
is composed of eight protein subunits, four -subunits encoded by the HADHA gene and four -subunits encoded by
the HADHB gene. The -subunits contain the enoyl-CoA hydratase and long-chain hydroxyacyl-CoA dehydrogenase
activities, while the -subunits possess the 3-ketoacyl-CoA thiolase (-ketothiolase or just thiolase) activity. The
mammalian genome actually encodes five distinct enzymes with thiolase activity.
Mammalian Thiolase Genes
Thiolase
Gene
Symbol
Comments
ACAA1 acetyl-CoA acyltransferase 1; also called peroxisomal 3-oxoacyl-CoA thiolase; involved in peroxisomalfatty acid -oxidation; located on chromosome 3p22.2 spanning 11 kb composed of 12 exons encoding
a 424 amino acid protein
ACAA2
acetyl-CoA acyltransferase 2; also called mitochondrial 3-oxoacyl-CoA thiolase; catalyzes the terminal
reaction of mitochnodrial fatty acid -oxidation in addition to that catalyzed by HADHB of the MTP;
located on chromosome 18q21.1 encoding a 397 amino acid protein
ACAT1
acetyl-CoA acetyltransferase 1; also called mitochondrial acetoacetyl-CoA thiolase; involved in ketone
body synthesis (see below) in the liver; located on chromosome 11q22.3 spanning 27 kb composed of
12 exons encoding a 427 amino acid protein
ACAT2acetyl-CoA acetyltransferase 2; also called cytosolic acetoacetyl-CoA thiolase; involved in cholesterol
biosynthesisand in the utilization of ketone bodies by the brain; located on chromosome 6q25.3
HADHB
hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, beta subunit; 3-
ketoacyl-CoA thiolase; -ketothiolase; HADHB encodes the -subunit of mitochondrial trifunctional
protein (MTP); located on chromosome 2p23.3 composed of 16 exons
Each round of -oxidation produces one mole of FADH2, one mole of NADH, and one mole of acetyl-CoA. The
acetyl-CoA, the end product of each round of -oxidation, then enters the TCA cycle, where it is further oxidized to CO2with the concomitant generation of three moles of NADH, one mole of FADH2and one mole of ATP. The NADH and
FADH2generated during the fat oxidation and acetyl-CoA oxidation in the TCA cycle then can enter the respiratory
pathway for the production of ATP via oxidative phosphorylation.
Pathway of mitochondrial -oxidation
The oxidation of fatty acids yields significantly more energy per carbon atom than does the oxidation of
carbohydrates. The net result of the oxidation of one mole of oleic acid (an 18-carbon fatty acid) will be 146 moles of
ATP (2 mole equivalents are used during the activation of the fatty acid), as compared with 114 moles from an
equivalent number of glucose carbon atoms.
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Fat Removal Medical Medical Glucose Reduce Body Fat
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DBP is the primary, if not exclusive enzyme involved in the oxidation of VLCFAs, pristanic acid, and di- and
trihydroxycholestanoic acids. The precise role of LBP in human peroxisomal lipid oxidation is unclear. Human
peroxisomes contain the thiolase acetyl-CoA C-acyltransferase 1 (ACAA1) that catalyzes the terminal step in the
peroxisoaml -oxidation pathway.
The clinical significance of the activity of the acyl-CoA oxidases of peroxisomal -oxidation is related to tissue
specific oxidation processes. In the pancreatic -cell there is little, if any, catalase expressed so that peroxisomal
oxidation of VLCFAs results in an increased release of ROS that can damage the -cell contributing to the progressive
insulin deficiency seen in obesity.
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Microsomal (omega) -Oxidation Reactions
The microsomal (endoplasmic reticulum, ER) pathway of fatty acid -oxidation represents a minor pathway of
overall fatty acid oxidation. However, in certain pathophysiological states, such as diabetes, chronic alcohol
consumption, and starvation, the -oxidation pathway may provide an effective means for the elimination of toxic levels
of free fatty acids. The pathway refers to the fact that fatty acids first undergo a hydroxylation step at the terminal
(omega, ) carbon. Human -hydroxylases are all members of the cytochrome P450 family (CYP) of enzymes. These
enzymes are abundant in the liver and kidneys. Specifically, it is members of the CYP4A and CYP4F families that
preferentially hydroxylate the terminal methyl group of C10C26 length fatty acids. CYP4A11 is the human homolog of
the rat liver CYP4A1 gene whose encoded enzyme was the first -hydroxylase characterized. CYP4A11 utilizes
NADPH and O2to introduce an alcohol to -CH3 of several fatty acids including lauric (12:0), myristic (14:0), palmitic
(16:0), oleic (18:1) and arachidonic acid (20:4). Following addition of the -hydroxyl the fatty acid is a substrate for
alcohol dehydrogenase (ADH) which generates an oxo-fatty acid, followed by generation of the correspondingdicarboxylic acid via the action of aldehyde dehydrogenases (ALDH). Further metabolism then takes place via the -
oxidation pathway in peroxisomes.
Pathway of microsomal (omega) -oxidation as initiated by CYP4A11.
Another human CYP4A subfamily member has been identified and designated CYP4A22. This protein is highly
homologous with CYP4A11 and has been shown to exhibit lauric acid -hydroxylase activity. Expression of CYP4A22
is low in all tissue in which it is found. The CYP4A subfamily is not the only CYP4 family of proteins that have been
found to possess -hydroxylase activity. The CYP4F family enzyme CYP4F3A, which is expressed in leukocytes, isnecessary for the -hydroxylation and subsequent degradation of leukotriene B4(LTB4). LTB4plays an important role
in the modulation of inflammatory processes. The CYP4F3 gene is subject to alternative promoter usage and tissue-
specific gene splicing, which results in two different proteins being produced. These two enzymes are designated
CYP4F3A and CYP4F3B, with the latter enzyme being expressed in the liver. CYP4F3B has higher affinity for
arachidonic acid.
Another CYP4F family member, identified as CYP4F2, has been identified that also has LTB4-hydroxylating
activity. This CYP4F2 protein has a high degree of homology to the CYP4F3B protein and is expressed in the liver and
kidneys. CYP4F2 has been shown to be the major arachidonic acid -hydroxylase in human liver and kidney. Indeed,
the substrate specificity of CYP4F2 for arachidonic acid is much higher than that of CYP4A11 which was originally
described as a signficant arachidonic acid -hydroxylase. The formation of -hydroxylated arachidonic acid (20-
hydroxyeicosatetraenoic acid, 20-HETE) by CYP4A11 plays an important role in the regulation of the cardiovascular
system because 20-HETE is a known vasoconstrictor. Polymorphisms in the CYP4A11 gene are associated with
hypertension in certain population, particular Asian populations. In addition to -hydroxylation of arachidonic acid and
LTB4, CYP4F2 has been shown to be responsible for the -hydroxylation of the phytyl tail of the tocopherols and
tocotrienols (collectively known as vitamin E). Metabolism of vitamin E requires an initial -hydroxylation step followed
by subsequent -oxidation.
Additional members of the CYP4F subfamily have been identified in humans. These genes are designated
CYP4F8, CYP4F11, and CYP4F12. CYP4F8 is present in epithelial linings and catalyzes the (-1)-hydroxylation of
prostaglandin H2(PGH2). CYP4F11 is primarily expressed in liver, but also found in kidney, heart, brain and skeletal
muscle. The primary endogenous substrates for CYP4F11 are long-chain 3-hydroxydicarboxylic acids (3-OHDCAs)
and the enzyme is also very active at hydroxylating various xenobiotics. CYP4F12 is expressed liver, heart,
gastrointestinal and urogenital epithelia and its primary substrates are eicosanoids and xenobiotics.
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Phytanic Acid -Oxidation Reactions
Phytanic acid is a fatty acid present in the tissues of ruminants and in dairy products and is, therefore, an important
dietary component of fatty acid intake. Because phytanic acid is methylated, it cannot act as a substrate for the first
enzyme of the mitochondrial -oxidation pathway (acyl-CoA dehydrogenase). Phytanic acid is first converted to its
CoA-ester and then phytanoyl-CoA serves as a substrate in an -oxidation process. The -oxidation reaction (as well
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as the remainder of the reactions of phytanic acid oxidation) occurs within the peroxisomes and requires a specific -
hydroxylase (specifically phytanoyl-CoA hydroxylase, PhyH), which adds a hydroxyl group to the -carbon of phytanic
acid generating the 19-carbon homologue, pristanic acid. Pristanic acid then serves as a substrate for the remainder
of the normal process of -oxidation. Because the first step in phytanic acid oxidation involves an -oxidation step, the
process is termed -oxidation. For more details on peroxisome function see the Refsum disease page.
Phytanic oxidation pathway
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Regulation of Fatty Acid Metabolism
In order to understand how the synthesis and degradation of fats needs to be exquisitely regulated, one must
consider the energy requirements of the organism as a whole. The blood is the carrier of triglycerides in the form of
VLDLs and chylomicrons, fatty acids bound to albumin, amino acids, lactate, ketone bodies and glucose. The
pancreas is the primary organ involved in sensing the organism's dietary and energetic states by monitoring glucose
concentrations in the blood. Low blood glucose stimulates the secretion of glucagon, whereas, elevated blood glucose
calls for the secretion of insulin.
The metabolism of fat is regulated by two distinct mechanisms. One is short-term regulation, which can come
about through events such as substrate availability, allosteric effectors and/or enzyme modification. The other
mechanism, long-term regulation, is achieved by alteration of the rate of enzyme synthesis and turn-over.
ACC is the rate-limiting (committed) step in fatty acid synthesis. There are two major isoforms of ACC inmammalian tissues. These are identified as ACC1 and ACC2. ACC1 is strictly cytosolic and is enriched in liver,
adipose tissue and lactating mammary tissue. ACC2 was originally discovered in rat heart but is also expressed in
liver and skeletal muscle. ACC2 has an N-terminal extension that contains a mitochondrial targeting motif and is found
associated with CPT-1 allowing for rapid regulation of CPT-1 by the malonyl-CoA produced by ACC. Both isoforms of
ACC are allosterically activated by citrate and inhibited by palmitoyl-CoA and other short- and long-chain fatty acyl-
CoAs. Citrate triggers the polymerization of ACC1 which leads to significant increases in its activity. Although ACC2
does not undergo significant polymerization (presumably due to its mitochondrial association) it is allosterically
activated by citrate. Glutamate and other dicarboxylic acids can also allosterically activate both ACC isoforms.
ACC activity can also be affected by phosphorylation. Both ACC1 and ACC2 contain at least eight sites that
undergo phosphorylation. The sites of phosphorylation in ACC2 have not been as extensively studied as those in
ACC1. Phosphorylation of ACC1 at three serine residues (S79, S1200, and S1215) byAMPKleads to inhibition of
the enzyme. Glucagon-stimulated increases in cAMP and subsequently to increased PKA activity also lead to
phosphorylation of ACC. ACC2 is a better substrate for PKA than is ACC1. The activating effects of insulin on ACCare complex and not completely resolved. It is known that insulin leads to the dephosphorylation of the serines in ACC1
that are AMPK targets in the heart enzyme. This insulin-mediated effect has not been observed in hepatocytes or
adipose tissues cells. At least a portion of the activating effects of insulin are related to changes in cAMP levels. Early
evidence has shown that phosphorylation and activation of ACC occurs via the action of an insulin-activated kinase.
However, contradicting evidence indicates that although there is insulin-mediated phosphorylation of ACC this does
not result in activation of the enzyme. Activation of -adrenergic receptors in liver and skeletal muscle cells inhibits
ACC activity as a result of phosphorylation by an as yet undetermined kinase.
Insulin, a product of the well-fed state, stimulates ACC and FAS synthesis, whereas starvation leads to a decrease
in the synthesis of these enzymes. Adipose tissue levels of lipoprotein lipase also are increased by insulin and
decreased by starvation. However, the effects of insulin and starvation on lipoprotein lipase in the heart are just the
inverse of those in adipose tissue. This sensitivity allows the heart to absorb any available fatty acids in the blood in
order to oxidize them for energy production. Starvation also leads to increases in the levels of cardiac enzymes of fatty
acid oxidation, and to decreases in FAS and related enzymes of synthesis.Adipose tissue contains hormone-sensitive lipase (HSL), which is activated by PKA-dependent phosphorylation;
this activation increases the release of fatty acids into the blood. This in turn leads to the increased oxidation of fatty
acids in other tissues such as muscle and liver. In the liver, the net result (due to increased acetyl-CoA levels) is the
production of ketone bodies (see below). This would occur under conditions in which the carbohydrate stores and
gluconeogenic precursors available in the liver are not sufficient to allow increased glucose production. The increased
levels of fatty acid that become available in response to glucagon or epinephrine are assured of being completely
oxidized, because PKA also phosphorylates ACC; the synthesis of fatty acid is thereby inhibited.
The activity of HSL is also affected via phosphorylation by AMPK. In this case the phosphorylation inhibits the
enzyme. Inhibition of HSL by AMPK may seem paradoxical since the release of fatty acids stored in triglycerides would
seem necessary to promote the production of ATP via fatty acid oxidation and the major function of AMPK is to shift
cells to ATP production from ATP consumption. This paradigm can be explained if one considers that if the fatty acids
that are released from triglycerides are not consumed they will be recycled back into triglycerides at the expense of
ATP consumption. Thus, it has been proposed that inhibition of HSL by AMPK mediated-phosphorylation is amechanism to ensure that the rate of fatty acid release does not exceed the rate at which they are utilized either by
export or oxidation.
Insulin has the opposite effect to glucagon and epinephrine: it increases the synthesis of triacylglycerols (and
glycogen). One of the many effects of insulin is to lower cAMP levels, which leads to increased dephosphorylation
through the enhanced activity of protein phosphatases such as PP-1. With respect to fatty acid metabolism, this yields
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dephosphorylated and inactive hormone-sensitive lipase. Insulin also stimulates certain phosphorylation events. This
occurs through activation of several cAMP-independent kinases.
Fat metabolism can also be regulated by malonyl-CoA-mediated inhibition of CPT I. Such regulation serves to
prevent de novosynthesized fatty acids from entering the mitochondria and being oxidized.
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The Glucose-Fatty Acid Cycle
The glucose-fatty acid cycle describes interrelationships of glucose and fatty acid oxidation as defined by fuel flux
and fuel selection by various organs. This cycle is not a metabolic cycle such as can be defined by the TCA cycleas anexample, but defines the dynamic interactions between these two major energy substrate pools. The glucose-fatty acid
cycle was first proposed by Philip Randle and co-workers in 1963 and is, therefore, sometimes referred to as the
Randle cycle or Randle hypothesis. The cycle describes how nutrients in the diet can fine-tune metabolic processes on
top of the more coarse control exerted by various peptide and steroid hormones. The underlying theme of the glucose-
fatty acid cycle is that the utilization of one nutrient (e.g. glucose) directly inhibits the use of the other (in this case fatty
acids) without hormonal mediation. The general interrelationships between glucose and fatty acid utilization in skeletal
muscle and adipose tissue that constitutes the glucose-fatty acid cycle are diagrammed in the Figure below.
The glucose-fatty acid cycle represents the interactions between glucose uptake and metabolism and the
consequent inhibition of fatty acid oxidation and the effects of fatty acid oxidation on the inhibition of glucose
utilization. The reciprocal regulation is most prevalent in skeletal muscle and adipose tissue. When glucose levels
are high it is taken into cells via the GLUT4 transporter and phosphorylated by hexokinase. The reactions of
glycolysis drive the carbon atoms to pyruvate where they are oxidized to acetyl-CoA. The fate of the acetyl-CoA iscomplete oxidation in the TCA cycleor return to the cytosol via citrate for conversion back to acetyl-CoA via ATP-
citrate lyase (ACLY) and then into into malonyl-CoA and subsequent long-chain fatty acid (LCFA) synthesis. The
synthesis of malonyl-CoA is catalyzed by acetyl-CoA carboxylase (ACC) and once produced will inhibit the import of
long-chain fatty acyl-CoAs (LCFacyl-CoA) into the mitochondria via inhibition of carnitine palmitoyltransferase 1
(CPT-1). This effectively blocks the oxidation of fatty acids leading to increased triacylglyceride synthesis (TAG). The
equilibrium between malonyl-CoA synthesis and breakdown back to acetyl-CoA is determined by the regulation of
ACC and malonyl-CoA decarboxylase (MCD). As long as there is sufficient capacity to divert glucose carbons to
TCA cycle oxidation and fatty acid synthesis there will be limited acetyl-CoA mediated inhibition of the pyruvate
dehydrogenase complex (PDHc). On the other hand, when fatty acid levels are high they enter the cell via one of
several fatty acid transporter complexes [fatty acid translocase (FAT)/CD36 is shown since this transporter has a
preference for LCFAs], and are then transported into the mitochondria to be oxidized. The large increase in fatty acid
oxidation subsequently inhibits the utilization of glucose. This is the result of increased cytosolic citrate production
from acetyl-CoA and the inhibition of phosphofructokinase-1 (PFK1). The increased acetyl-CoA derived from fat
oxidation will in turn further inhibit glucose utilization via activation of PDH kinases (PDKs) that will phosphorylate and
inhibit the PDHc. Although not shown, PDKs are also activated by increased mitochondrial NADH/NAD + ratios in
response to increased fatty acid -oxidation. Under conditions where fat oxidation is favored ACC will be inhibited
and MCD will be activated ensuring that LCFA that enter the cell will be able to be transported into the mitochondria.
PS is pyruvate symporter responsible for mitochondrial uptake of pyruvate. TCAT is tricarboxylic acid transporter.
How do the dynamics of the glucose-fatty acid cycle play out under various physiological conditions and changing
fuel substrate pools? In the fasted state it is imperative that glucose be spared so that the brain can have adequate
access to this vital fuel. Under these conditions, hormonal signals from the pancreas, in the form of glucagon, stimulate
adipose tissue lipolysis releasing free fatty acids (FFAs) to the blood for use as a fuel by other peripheral tissues.
When the released FFAs enter the liver they oxidized and also serve as substrates for ketogenesis. The oxidation of
fatty acids inhibits glucose oxidation as outlined in the above figure. In addition to sparing glucose for the brain, fatty
acid oxidation also preserves pyruvate and lactate which are important gluconeogenesis substrates. The effects of
fatty acids on glucose utilization can also be observed in the well fed state after a high fat meal and during periods ofexercise.
As outlined in the above Figure, the inhibition of glucose utilization by fatty acid oxidation is mediated by short-
term effects on several steps of overall glycolysis that include glucose uptake, glucose phosphorylation and pyruvate
oxidation. During fatty acid oxidation the resultant acetyl-CoA allosterically activates PDKs that phosphorylate and
inhibit the PDHc. PDKs are also activated by increasing levels of NADH that will be the result of increased fatty acid
oxidation. Thus, two products of fat oxidation result in inhibition of the PDHc. In addition, excess acetyl-CoA is
transported to the cytosol either as citrate (as diagrammed) or as acetyl-carnitine. Mitochondrial acetyl-carnitine is
formed through the action of carnitine acetyltransferase (CAT). Acetyl-carnitine is transported out of the the
mitochondria via the action of carnitine-acylcarnitine translocase (CACT). Once in the cytosol acetyl-carnitine is
converted to acetyl-CoA via the action of cytosolic CAT. In the cytosol, citrate serves as an allosteric inhibitor of PFK1
thus limiting entry of glucose into glycolysis. The increase in glucose-6-phosphate that results from inhibition of PFK1
leads to feed-back inhibition of hexokinase which in turn limits glucose uptake via GLUT4. Additional mechanisms of
fatty acid metabolism that lead to interference in glucose uptake and utilization are the result of impaired insulinreceptor signaling. These latter processes are discussed in detail in the Insulin Functionpage.
Mechanisms by which glucose utilization inhibits fatty acid oxidation are tissue specific due primarily to the
differences in Km of hepatic glucokinase and skeletal muscle and adipose tissue hexokinase. In addition, hepatic
CPT-1 is approximately 100-fold less sensitive to inhibition by malonyl-CoA than are the skeletal muscle and cardiac
isoforms. When glucose is oxidized in glycolysis the resultant pyruvate enters the mitochondria via the pyruvate
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symporter. Increasing mitochondrial pyruvate inhibits the PDKs allowing for rapid decarboxylation of pyruvate by the
PDHc ensuring continued entry of glucose into the glycolytic stream. Some of the acetyl-CoA derived from pyruvate
oxidation will be diverted from the TCA cycle as citrate and transported to the cytosol by the tricarboxylic acid
transporter (TCAT). The citrate is converted to acetyl-CoA and oxaloacetate by ATP-citrate lyase (ACLY) and can now
serve as a substrate for ACC. The resultant malonyl-CoA will inhibit CPT-1 thus, restricting mitochondrial uptake and
oxidation of fatty acyl-CoAs. The inhibition of fatty acid oxidation in the liver re-routes LCFAs into triglycerides (TAGs).
Long term effects of excess glucose are reflected in hepatic steatosis resulting from the diversion of fats into TAGs
instead of being oxidized.
In addition to being regulated by intermediates of glucose and fat oxidation, several enzymes in these two
pathways are regulated at the level of post-translational modification and/or gene expression. Most of these regulatory
schemes have been covered in the above sections.
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Clinical Significance of Fatty Acids
The majority of clinical problems related to fatty acid metabolism are associated with processes of oxidation.
These disorders fall into four main groups:
1. Deficiencies in Carnitine: Deficiencies in carnitine lead to an inability to transport fatty acids into the
mitochondria for oxidation. This can occur in newborns and particularly in pre-term infants. Carnitine deficiencies also
are found in patients undergoing hemodialysis or exhibiting organic aciduria. Carnitine deficiencies may manifest
systemic symptomology or may be limited to only muscles. Symptoms can range from mild occasional muscle
cramping to severe weakness or even death. Treatment is by oral carnitine administration.
2. Carnitine palmitoyltransferase deficiencies:Deficiencies in CPT-1 are relatively rare and affect primarily
the liver and lead to reduced fatty acid oxidation and ketogenesis. The most common symptom associated with CPT-1
deficiency is hypoketotic hypoglycemia. There is also an elevation in blood levels of carnitine. The liver involvement
results in hepatomegaly and in muscles results in weakness. CPT-2 deficiencies can be classified into three main
forms. The adult form affects primarily the skeletal muscles and is called the adult myopathic form. This form of the
disease causes muscle pain and fatigue and myoglobinuria following exercise. The severe infantile multisystem form
manifest in the first 624 months of life with most afflicted infants demonstrating significant involvement before 1 year.
The primary symptom of this form of CPT-2 deficiency is hypoketotic hypoglycemia. Symptoms will progress to severe
hepatomegaly and cardiomyopathy. Often times death from CPT-2 deficiency may be mis-diagnosed as sudden infant
death syndrome, SIDS. The rarest form of CPT-2 deficiency is referred to as the neonatal lethal form. Symptoms of this
form appear within hours to 4 days after birth and include respiratory failure, hepatomegaly, seizures, hypoglycemia,
and cardiomegaly. The cardiomegaly will lead to fatal arrhythmias. Carnitine acyltransferases may also be inhibited by
sulfonylurea drugs such as tolbutamide and glyburide.
3. Deficiencies in Acyl-CoA Dehydrogenases: A group of inherited diseases that impair -oxidation result
from deficiencies in acyl-CoA dehydrogenases. The enzymes affected may belong to one of three categories:
long-chain acyl-CoA dehydrogenase (LCAD)
medium-chain acyl-CoA dehydrogenase (MCAD)
short-chain acyl-CoA dehydrogenase (SCAD)
MCAD deficiencyis the most common form of acyl-CoA dehydrogenase deficiency. In the first years of life this
deficiency will become apparent following a prolonged fasting period. Symptoms include vomiting, lethargy and
frequently coma. Excessive urinary excretion of medium-chain dicarboxylic acids as well as their glycine and carnitine
esters is diagnostic of this condition. In the case of this enzyme deficiency taking care to avoid prolonged fasting is
sufficient to prevent clinical problems.
4. Refsum Disease: Refsum disease is a rare inherited disorder in which patients harbor a defect in theperoxisomal -oxidizing enzyme, phytanoyl-CoA hydroxylase (PhyH). Although mutations in PhyH are the primary
cause of Refsum disease, the syndrome can also result from defects in the peroxisomal protein (PEX7) responsible
for the import of PhyH into the peroxisome. Patients accumulate large quantities of phytanic acid in their tissues and
serum. This leads to severe symptoms, including cerebellar ataxia, retinitis pigmentosa, nerve deafness and
peripheral neuropathy. As expected, the restriction of dairy products and ruminant meat from the diet can ameliorate
the symptoms of this disease. It should be noted that accumulation of phytanic acid is not solely the result of defects in
PhyH. Phytanic acid accumulation is also seen when there are inherited defects in peroxisome function leading to
Zellweger syndrome, neonatal adrenoleukodystrophy and infantile Refsum disease. In addition, rhizomelic
chondrodysplasia punctata, type 1(RCDP1) results in phytanic acid accumulation. Refsum disease due to deficiency
in PhyH is properly referred to as classical Refsum diseaseto distinguish it from infantile Refsum due to peroxisome
dysfunction.
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Ketogenesis
During high rates of fatty acid oxidation, primarily in the liver, large amounts of acetyl-CoA are generated. These
exceed the capacity of the TCA cycle, and one result is the synthesis of ketone bodies. The synthesis of the ketone
bodies (ketogenesis) occurs in the mitochondria allowing this process to be intimately coupled to rate of hepatic fatty
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acid oxidation. Conversely, the utilization of the ketones (ketolysis) occurs in the cytosol. The ketone bodies are
acetoacetate, -hydroxybutyrate, and acetone.
The formation of acetoacetyl-CoA occurs by condensation of two moles of acetyl-CoA. This reaction is essentially
a reversal of the thiolase (HADHB or ACAA2) catalyzed reaction of -oxidation but is in fact catalyzed by the
mitochondrial enzyme acetoacetyl-CoA thiolase (encoded by the ACAT1 gene). Acetoacetyl-CoA and an additional
acetyl-CoA are converted to -hydroxy--methylglutaryl-CoA (HMG-CoA) by mitochondrial HMG-CoA synthase
(encoded by the HMGCS2 gene), an enzyme found in large amounts only in the liver. HMG-CoA in the mitochondria is
converted to acetoacetate by the action of HMG-CoA lyase. Acetoacetate can undergo spontaneous decarboxylation
to acetone, or be enzymatically converted to -hydroxybutyrate through the action of -hydroxybutyrate dehydrogenase.
The ketone bodies freely diffuse out of the mitochondria and hepatocytes and enter the circulation where they can be
taken up by non-hepatic tissues such as the brain, heart, and skeletal muscle.
Synthesis of the ketones
When the level of glycogen in the liver is high the production of -hydroxybutyrate increases. When carbohydrate
utilization is low or deficient, the level of oxaloacetate will also be low, resulting in a reduced flux through the TCA cycle.
This in turn leads to increased release of ketone bodies from the liver for use as fuel by other tissues. In early stages of
starvation, when the last remnants of fat are oxidized, heart and skeletal muscle will consume primarily ketone bodies
to preserve glucose for use by the brain. Acetoacetate and -hydroxybutyrate, in particular, also serve as major
substrates for the biosynthesis of neonatal cerebral lipids.
Ketone bodies are utilized by extrahepatic tissues via a series of cytosolic reactions that are essentially a reversal
of ketone body synthesis. The initial steps involve the conversion of -hydroxybutyrate to acetoacetate and of
acetoacetate to acetoacetyl-CoA. The first step involves the reversal of the -hydroxybutyrate dehydrogenase reaction.
It is important to appreciate that under conditions where tissues are utilizing ketones for energy production their
NAD+/NADH ratios are going to be relatively high, thus driving the -hydroxybutyrate dehydrogenase catalyzed
reaction in the direction of acetoacetate synthesis. The second reaction of ketolysis involves the action (shown below)
of succinyl-CoA:3-oxoacid-CoA transferase (SCOT), also called 3-oxoacid-CoA transferase 1 (OXCT1). The latter
enzyme is present at high levels in most tissues except the liver. Importantly, very low level of SCOT expression in the
liver allows the liver to produce ketone bodies but not to utilize them. This ensures that extrahepatic tissues have
access to ketone bodies as a fuel source during prolonged fasting and starvation.
Utilization of the ketones
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Regulation of KetogenesisThe fate of the products of fatty acid metabolism is determined by an individual's dietary and physiological status.
The overall rate of hepatic ketogenesis may by affected by several factors:
1.Control in the release of free fatty acids from adipose tissue directly affects the level of ketogenesis in the
liver. This is, of course, substrate-level regulation. Fatty acid release from adipose tissue is controlled via the
activity of hormone-sensitive lipase (HSL). When glucose levels fall, pancreatic glucagon secretion increases
resulting in phosphorylation of adipose tissue HSL, thus resulting in increased hepatic ketogenesis due to
increased substrate (free fatty acids) delivery from adipose tissue. Conversely, insulin, released in the well-fed
state, inhibits ketogenesis via the triggering of dephosphorylation and inactivation of adipose tissue HSL.
2.Once fats enter the liver, they have two distinct fates. They may be activated to acyl-CoAs and oxidized, or
esterified to glycerol in the production of triacylglycerols. If the liver has sufficient supplies of glycerol-3-
phosphate, most of the fats will be turned to the production of triacylglycerols.
3.The acetyl-CoA generated by the oxidation of fats can be completely oxidized in the TCA cycle or it can be
diverted into lipid biosynthesis. If the hepatic demand for ATP is high the fate of acetyl-CoA is likely to be further
oxidation to CO2. This is especially true under conditions of hepatic stimulation by glucagon which results in
increased gluconeogenesis and the energy for this process is derived primarily from the oxidation of fatty acids
supplied from adipose tissue.
4. In addition, glucagon results in phosphorylation and inhibition of acetyl-CoA carboxylase (ACC), the rate
limiting enzyme of de novofatty acid synthesis. Conversely, under conditions of insulin release, hepatic ACC is
activated and the excess acetyl-CoA will be converted into malonyl-CoA and then free fatty acids. The increased
malonyl-CoA results in inhibition of fatty acid transport into the mitochondria resulting in reduced fat oxidation
and reduced production of excess acetyl-CoA.
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Clinical Significance of Ketogenesis
The production of ketone bodies occurs at a relatively low rate during normal feeding and under conditions of
normal physiological status. Normal physiological responses to carbohydrate shortages cause the liver to increase the
production of ketone bodies from the acetyl-CoA generated from fatty acid oxidation. This allows the heart and skeletal
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muscles primarily to use ketone bodies for energy, thereby preserving the limited glucose for use by the brain.
The most significant disruption in the level of ketosis, leading to profound clinical manifestations, occurs in
untreated insulin-dependent diabetes mellitus. This physiological state, diabetic ketoacidosis(DKA) results from a
reduced supply of glucose (due to a significant decline in circulating insulin) and a concomitant increase in fatty acid
oxidation (due to a concomitant increase in circulating glucagon). The increased production of acetyl-CoA leads to
ketone body production that exceeds the ability of peripheral tissues to oxidize them. Ketone bodies are relatively
strong acids (pKa around 3.5), and their increase lowers the pH of the blood. This acidification of the blood is
dangerous chiefly because it impairs the ability of hemoglobin to bind oxygen.
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Michael W King, PhD | 19962013 themedicalbiochemistrypage.org, LLC | info @ themedicalbiochemistrypage.org
Last modified: September 25, 2013
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