BC10-2(part5)

D. Alternative Pathways for Fatty Acid Oxidation

1. w-Oxidation

- oxidation of the terminal methyl group to form w-hydroxy fatty acid → dicarboxylic acid

- minor pathway observed with liver microsomal preparations

D. Alternative Pathways for Fatty Acid Oxidation

2. a-Oxidation

- oxidation of long-chain fatty acids to 2-hydroxy fatty acids (constituents of brain lipids)

followed by oxidation to a fatty acid with 1 less carbon

D. Alternative Pathways for Fatty Acid Oxidation

2. a-Oxidation

a. Phytanic Acid

- not a substrate for acyl CoA dehydrogenase because of the methyl group on its third (B) carbon

→ hydroxylated at the a-carbon by fatty acid a-hydroxylase → product decarboxylated → activated to CoA derivative → B-oxidation

b. Normal Individuals

- a-oxidation of phytanic acid removes the terminal carbonyl before B-oxidation, allowing the latter pathway to operate, as the B-carbon is now available

c. Refsum’s Disease (Phytanic Acid Storage Disease)

- rare

- autosomal recessive

- fatty acid a-hydroxylase deficiency

- unable to oxidize fatty acids at the a-carbon → build-up of phytanic acid (derived from

animal fat and cow’s milk and probably originally from chlorophyll) in the

- plasma

- tissues

c. Refsum’s Disease (Phytanic Acid Storage Disease)

i. Phytanic Acid

- not a substrate for acyl CoA dehydrogenase

- cannot be oxidized by the B-oxidation system because the B position is blocked by a methyl group

- branched-chain fatty acid

ii. Symptoms

- retinitis pigmentosa

- failing night vision

- peripheral neuropathy

- cerebellar ataxia

iii. Treatment

- dietary restriction

CLINICAL ASPECTS

A. Carnitine Deficiency

- can occur in the newborn, especially in preterms, due to inadequate biosynthesis or renal leakage

- can also be caused by hemodialysis and defect in the transport system for carnitine in muscle

1. Signs and Symptoms

- episodic periods of hypoglycemia owing to decreased gluconeogenesis from impaired fatty acid oxidation in the presence of increased plasma free fatty acids → lipid accumulation with muscular weakness

2. Treatment

- supplementation with oral carnitine

B. Medium-Chain Acyl CoA Dehydrogenase (MCAD) Deficiency

- there are 4 fatty acyl CoA dehydrogenase species in the mitochondria with specificities for

— short- chain length fatty acids

-— medium- chain length fatty acids

-— long chain length fatty acids

—- very long-chain length fatty acids

- autosomal recessive

- one of the most common inborn errors of metabolism

- most common inborn errors of fatty acid oxidation

- found in 1/40,000 births (more prevalent than phenylketonuria) worldwide

- causes up to 10% of cases of sudden infant death syndrome (SIDS) or Reye’s syndrome

B. Medium-Chain Acyl CoA Dehydrogenase (MCAD) Deficiency

1. Hallmarks

- decrease in fatty acid oxidation

- profound fasting hypoglycemia

- low to absent ketones

- lethargy, coma, death if untreated

- C8-C10 acyl carnitines in blood

- episode may be provoked by overnight fast in an infant

- often provoked by illness (flu) that causes loss of appetite and vomiting in older child

2. Primary Treatment

- IV glucose

3. Prevention

- frequent feeding, high-carbohydrate, low-fat diet

C. Carnitine Palmitoyltransferase I Deficiency

- affects only the liver

1. Characteristics

- decreased fatty acid oxidation

- ketogenesis

- hypoglycemia

D. Carnitine Palmitoyltransferase II Deficiency (Myopathic Form)

- adolescent or adult onset

- affects primarily the skeletal muscles and liver in its most severe form

- muscle-specific CAT/CPT gene defect

- autosomal recessive

Carnitine Palmitoyltransferase II Deficiency (Myopathic Form)

1. Hallmarks

- muscle aches, mild to severe weakness

- rhabdomyolysis, myoglobinuria, “red urine”

- episode provoked by prolonged exercise especially after fasting, cold, or associated stress

- symptoms may be exacerbated by high-fat, low-carbohydrate diet

- muscle biopsy shows elevated muscle triglyceride detected as lipid droplets in cytoplasm

2. Primary Treatment

- cease muscle activity and give glucose

E. Oral Hypoglycemic Agent - Sulfunylurea (Glyburide, Tolbutamide)

- inhibits carnitine palmitoyltransferase → decreased fatty acid oxidation

F. Long-Chain 3-Hydroxyacyl CoA Dehydrogenase Deficiency

→ acute fatty liver of pregnancy

G. Jamaican Vomiting Sickness

1. Hypoglycin

- toxin from unripe fruit of akee tree

- inactivate short- and medium-chain acyl CoA dehydrogenase → inhibition of B-oxidation → hypoglycemia and excretion of medium- and short-chain mono- and dicarboxylic acids

H. Dicarboxylic Aciduria

1. Characterized by

- excretion of C6-C10 w-dicarboxylic acids

- non-ketotic hypoglycemia

2. Etiology

- deficiency of mitochondrial medium-chain acyl CoA dehydrogenase

I. Refsum’s Disease

J. Zellweger’s (Cerebrohepatorenal) Syndrome

- rare inherited absence of peroxisomes in all tissues

- accumulate C26-C38 polyenoic acids in brain tissues due to inability to oxidize long-chain fatty acids in

peroxisomes

SPECIALIZED FATTY ACIDS: PROSTAGLANDINS and RELATED COMPOUNDS

A. Prostaglandins and Related Compounds (Thromboxanes, Leukotrienes)

- eicosanoids

- extremely potent compounds

- elicit a wide range of physiologic responses

- extremely short half-life

- produced in very small amounts

- formed in almost all tissues

- generally act locally

- metabolized to inactive products at their site of synthesis

- not stored to any appreciable extent

KETONE BODIES: an ALTERNATE FUEL for CELLS

1. Liver Mitochondria

- capacity to divert any excess acetyl CoA derived from fatty acid or pyruvate oxidation into

ketone bodies

2. Ketone Bodies

- small

- water-soluble

- potential units of acetate

- transported in the blood to the peripheral tissues  reconverted to acetyl CoA  TCA cycle

a. Preferred Energy Substrates of the

- heart

- skeletal muscle

- kidney

- if blood levels of -hydroxybutyrate and acetoacetate increase sufficiently (after 20

days of starvation)  form valuable energy substrate for the brain (may

account for up to 75% of brain oxidation)

b. Important Sources of Energy for the Peripheral Tissues Because

- soluble in aqueous solution and do not need to be incorporated to lipoproteins or

carried by albumin

- produced in the liver during periods when the amount of acetyl CoA present exceeds

A. Synthesis of Ketone Bodies by the Liver

- synthesized in liver mitochondria  used as metabolic fuel by other tissues (liver cannot use ketone

bodies as metabolic fuel)

- synthesis is limited except under conditions of

- high rates of fatty acid oxidation

- limited carbohydrate intake

- ex: fasting

starvation

- flooding of liver with fatty acids  elevated hepatic acetyl CoA  pyruvate dehydrogenase

inhibition

pyruvate carboxylase activation

 oxaloacetate production  used by the liver for gluconeogenesis rather than for the TCA

cycle

acetyl CoA channelled into ketone body synthesis

1. 3-Hydroxy-3-Methylglutaryl CoA (HMG-CoA) Synthesis

a. Acetoacetyl CoA Formation

- 1st step

- can occur by 1 of 2 processes

- incomplete breakdown of fatty acid

- reversal of the thiolase reaction of fatty acid oxidation

b. Mitochondrial HMG-CoA Synthase

- catalyzes the rate-limiting step of ketone body synthesis

- present in significant quantities only in the liver

- combines a 3rd molecule of acetyl CoA with acetoacetyl CoA  produce 3-hydroxy-3-

methylglutaryl CoA (HMG-CoA)

c. HMG-CoA

- structural intermediate in the catabolism of leucine

- precursor of cholesterol

- cleaved to produce acetoacetate and acetyl CoA

2. Ketone Body Synthesis

a. HMG CoA Cleavage Yields

- acetoacetate

- acetyl CoA

b. Acetoacetate

- can be reduced to form 3-hydroxybutyrate (NADH as hydrogen donor)

- can be spontaneously decarboxylated  acetone formation

c. -Hydroxybutyrate

- formed from acetoacetate by -hydroxybutyrate dehydrogenase when the

NADH/NAD+

ratio is high (as it is in the liver during fasting)

d. Acetone

- volatile biologically nonmetabolizable side product

- formed spontaneously from a small fraction of circulating acetoacetate 

lost in the expired air from the lungs

i. Untreated DM

- odor of acetone is apparent on the patient’s fruity breath (in this condition,

ketone body production can be extremely high)

B. Utilization of Ketone Bodies by the Peripheral Tissues

- ketone bodies are constantly produced by the liver at low levels

- the liver cannot reconvert acetoacetate to acetoacetyl CoA  cannot use them as fuels

- production becomes more significant during starvation (when ketone bodies are much more needed to

provide energy to the peripheral tissues)

1. -Hydroxybutyrate Dehydrogenase

- oxidizes -hydroxybutyrate to acetoacetate

- produces NADH

2. Activation

- occurs by the formation of the CoA thioester of acetoacetate

- CoA provided by succinyl CoA

- catalyzed by succinyl CoA : acetoacetate CoA transferase (thiophorase)

- reversible reaction

3. Thiolase

- cleavage of acetoacetyl CoA to 2 acetyl CoAs  oxidation by the TCA cycle

C. Energy Yield from Oxidation of Ketone Bodies

- conversion of -hydroxybutyrate to acetoacetate  yields NADH  2.5 ATP molecules by electron

transport and oxidative phosphorylation

- each acetyl CoA  yields 10 ATP molecules via TCA cycle, electron transport, and oxidative

phosphorylation

- activation requires  1 mole ATP

- acetoacetate oxidation  2 acetyl CoAs  20 moles ATP

- -hydroxybutyrate oxidation  yield NADH  2.5 moles ATP

21.5 moles ATP

D. Ketoacidosis

- rate of ketone body formation > rate of use  increased blood levels (ketonemia)  increased urinary

levels (ketonuria)  ketosis

- high fatty acid degradation  excessive acetyl CoA  NAD+

depletion

increased NADH pool

 slowing of TCA cycle  acetyl CoAs forced to ketone body formation

1. Starvation

- ketone body production increases dramatically

- blood levels rise only slowly to a maximum of 7 mM after 20-30 days of starvation

- ketone bodies are the only source of fuel  consumed by the body  no excess to accumulate

 ketonuria and ketonemia are never high enough to

2. Diabetes Mellitus

a. Type 1 Insulin-Dependent Diabetes Mellitus (IDDM)

- adipose tissue lipolysis  fatty acid release  hepatic ketone body synthesis exceed

the ability of other tissues to metabolize them  profound, life-threatening

ketoacidosis may occur

- infection or trauma  increased cortisol, epinephrine  hormone-sensitive lipase

activation  may precipitate ketoacidosis

b. Type 2 Non-Insulin-Dependent Diabetes Mellitus (NIDDM)

- much less likely to show ketoacidosis (much slower, insidious onset)

- not complete insulin resistance in the peripheral tissues

- can develop ketoacidosis after an infection or trauma

c. Diabetic Patients with Ketosis

- urinary excretion of ketone bodies may be as high as 5000 mg/24 hours

- blood concentration may reach 90 mg/dL (< 3 mg/dL in normal individuals)

- elevated ketone body concentration in the blood  acidemia

- carboxyl group of a ketone body has a pKa of 4  losses proton (H+

) as it

circulates in the blood  lowers blood pH  acidosis (ketoacidosis)

- urinary excretion of glucose and ketone bodies (osmotic diuresis)  dehydration

3. Alcoholics

- can develop ketoacidosis

- chronic hypoglycemia (often present in chronic alcoholism)  fat release from adipose 

increased hepatic ketone body production

- slower than normal muscle ketone body utilization (hepatic alcohol conversion to

acetate  diffusion into blood  oxidation by muscle as alternative source of

acetyl-CoA)

4. Associated with Ketoacidosis

- polyuria, dehydration, and thirst (exacerbated by hyperglycemia and osmotic diuresis)

- CNS depression and coma

- potential depletion of K+

(loss may be masked by a mild hyperkalemia)

- decreased plasma bicarbonate

- breath with sweet or fruity odor (acetone)

E. Laboratory Measurement of Ketones

a. Normal Ketosis

- accompanies fasting

- does not produce acidosis

- acetoacetate and β-hydroxybutyrate formed in approximately equal quantities

b. Pathologic Conditions (Diabetes, Alcoholism)

- β-hydroxybutyrate production predominates

1. Urinary Nitroprusside Test

- detects only acetoacetate  can dramatically underestimate the extent of ketoacidosis and

its resolution during treatment

2. β-Hydroxybutyrate Measurement