Download FATTY ACID OXIDATION Fatty acids are oxidized in several tissues

LIPID MOBILIZATION
In the postabsorptive state, fatty acids can be released from adipose tissue to be
used for energy production. Although human adipose tissue does not respond
directly to glucagon,
the fall
in insulin activates a hormone-sensitive
triacylglycerol lipase (HSL) that hydrolyzes triglycerides yielding fatty acids and
glycerol. Epinephrine and cortisol also activate HSL. Glycerol may be picked up
by
liver
and
converted
to
dihydroxyacetone
phosphate
(DHAP)
for
gluconeogenesis,and the fatty acids are distributed to tissues that can use them.
Free fatty acids are transported through the blood in association with albumin.
Lipolysis of Triglyceride in Response to Hypoglycemia and Stress
FATTY ACID OXIDATION
Fatty acids are oxidized in several tissues, including liver, muscle, and adipose
tissue, by the pathway of β-oxidation.Neither erythrocytes nor brain can use fatty
acids, and so continue to rely on glucose during normal periods of fasting.
Erythrocytes lack mitochondria, and fatty acids do not cross the blood-brain
barrier efficiently.
After uptake by the cell, fatty acids are activated by conversion into their CoA
derivatives—acyl CoA is formed. For channeling into the mitochondria, the acyl
residues are first transferred to carnitine and then transported across the inner
membrane as acyl carnitine. The degradation of the fatty acids occurs in the
mitochondrial matrix through an oxidative cycle in which C2 units are
successively cleaved off as acetyl CoA (activated acetic acid). Before the release
of the acetyl groups, each CH2 group at C-3 of the acyl residue (the β-C atom)
is oxidized to the keto group— hence the term β-oxidation for this metabolic
pathway. Both spatially and functionally, it is closely linked to the tricarboxylic
acid cycle and to the respiratory chain.
[1] The first step is dehydrogenation of acyl CoA at C-2 and C-3. This yields an
unsaturated 2-enoyl-CoA derivative with a trans-configured double bond. The
two hydrogen atoms are initially transferred from FAD-containing acyl CoA
dehydrogenase
to
the
electron-transferring
flavoprotein
(ETF).
ETF
dehydrogenase
passes them on from ETF to ubiquinone (coenzyme Q), a
component of the respiratory chain
[2] The next step in fatty acid degradation is the addition of a water molecule to
the double bond of the enoyl CoA (hydration), with formation of β-hydroxyacyl
CoA.
[3] In the next reaction, the OH group at C- 3 is oxidized to a carbonyl group
(dehydrogenation). This gives rise to β-ketoacyl CoA, and the reduction
equivalents are transferred to NAD+, which also passes them on to the
respiratory chain
[4] β-Ketoacyl-CoA is now broken down by an acyl transferase into acetyl CoA
and an acyl CoA shortened by 2 C atoms (“thioclastic cleavage”). Several cycles
are required for complete degradation of long-chain fatty acids—eight cycles in
the case of stearyl-CoA (C18:0), for example. The acetyl CoA formed can then
undergo further metabolism in the tricarboxylic acid cycle , or can be used for
biosynthesis. When there is an excess of acetyl CoA, the liver can also form
ketone bodies.
When oxidative degradation is complete, one molecule of palmitic acid supplies
around 130 molecules of ATP, corresponding to an energy of 3300 kJ mol–1.
This high energy yield makes fats an ideal form of storage for metabolic energy.
Hibernating animals such as polar bears can meet their own energy requirements
for up to 6 months solely by fat degradation, while at the same time producing
the vital water they need via the respiratory chain (“respiratory water”).
Fatty acid transport :
The inner mitochondrial membrane has a group-specific transport system for
fatty acids. In the cytoplasm, the acyl groups of activated fatty acids are
transferred to carnitine by carnitine acyltransferase [1]. They are then channeled
into the matrix by an acyl carnitine/ carnitine exchange. In the matrix, the
mitochondrial enzyme carnitine acyltransferase catalyzes the return transfer of
the acyl residue to CoA. The carnitine shuttle is the rate-determining step in
mitochondrial fatty acid degradation. Malonyl CoA, a precursor of fatty acid
biosynthesis, inhibits carnitine acyltransferase ,and therefore also inhibits uptake
of fatty acids into the mitochondrial matrix. The most important regulator of βoxidation is the NAD+/NADH+H+ ratio. If the respiratory chain is not using any
NADH+H+, then not only the tricarboxylic acid cycle but also β-oxidation come
to a standstill due to the lack of NAD+.
Cytoplasm
mitochondria
Genetic Deficiencies of Fatty Acid Oxidation
Two of the most common genetic deficiencies affecting fatty acid oxidation are:
.□ Medium chain acyl CoA dehydrogenase (MCAD) deficiency,primary etiology
hepatic
.□ Myopathic carnitine acyltransferase (CAT/CPT) deficiency, primary etiology
myopathic
Medium Chain Acyl CoA Dehydrogenase (MCAD) Deficiency:
Non-ketotic
hypoglycemia should be strongly associated with a block in hepatic β-oxidation.
During fasting, hypoglycemia can become profound due to lack of ATP to
support glyconeogenesis. Decreased acetyl-CoA
lowers pyruvate carboxylase
activity and also limits ketogenesis. Hallmarks of MCAD deficiency include:
 . Profound fasting hypoglycemia
 . Low to absent ketones
 . Lethargy, coma, death if untreated
 . Dicarboxylic acidemia and Dicarboxylic aciduria

. Episode may be provoked by overnight fast in an infant
 . In older child, often provoked by illness (flu) that causes loss of
appetite and vomiting
 . Primary treatment: IV glucose
 . Prevention: frequent feeding, high-carbohydrate, low-fat diet
Carnitine Acyltransferase (CAT/CPT) Deficiency (Myopathic Form): Although all
tissues with mitochondria contain carnitine acyltransferase, the most common
form of this genetic deficiency is myopathic and due to a defect in the musclespecific CAT/CPT gene. Hallmarks of this disease include:
 . 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
 . Primary treatment: cease muscle activity; give glucose
Minor pathways of fatty acid degradation
Most fatty acids are saturated and even-numbered. They are broken down via βoxidation .In addition, there are special pathways involving degradation of
unsaturated fatty acids ,degradation of fatty acids with an odd number of C
atoms .
A. Degradation of unsaturated fatty acids
Unsaturated fatty acids usually contain a cis double bond at position 9 or 12 e.
g., linoleic acid (18:2; 9,12). As with saturated fatty acids, degradation in this
case occurs via β-oxidation until the C-9-cis double bond is reached. Since
enoyl-CoA hydratase only accepts substrates with trans
double bonds, the
corresponding enoyl-CoA is converted by an isomerase from the cis-∆3, cis- ∆6
isomer into thetrans-∆3,cis-∆6 isomer [1]. Degradation by β-oxidation can now
continue until a shortened trans-∆2, cis-∆4 derivative occurs in the next cycle.
This cannot be isomerized in the same way as before, and instead is reduced in
an NADPH-dependent way to the trans-∆3 compound[2]. After rearrangement
by enoyl-CoA isomerase [1], degradation can finally be completed via normal
β-oxidation.
B. Degradation of odd numbered fatty acids
Fatty acids with an odd number of C atoms are treated in the same way as
“normal” fatty acids—i. e., they are taken up by the cell with ATP dependent
activation to acyl CoA and are transported into the mitochondria with the help of
the carnitine shuttle and broken down there by β−oxidation . In the last step,
propionyl CoA arises instead of acetyl CoA. This is first carboxylated by
propionylCoA carboxylase into methylmalonylCoA, which
is isomerized by
mutase into succinyl CoA . Various coenzymes are involved in these reactions.
The carboxylase requires biotin, and the mutase is dependent on coenzyme B12.
Odd-numbered fatty acids from propionyl-CoA can therefore be used to
synthesize glucose. This pathway is also important for ruminant animals, which
are dependent on symbiotic microorganisms to break down their food. The
microorganisms produce large amounts of propionic acid as a degradation
product, which the host can channel into the metabolism in the way described.
Degradation of Phosphoglycerols
Although phospholipids are actively degraded, each portion of the molecule turns
over at a different rate . Phospholipase A2 catalyzes the hydrolysis of
glycerophospholipids to form a free fatty acid and lysophospholipid, which in turn
may be reacylated by acyl-CoA in the presence of an acyltransferase.
Alternatively,
lysophospholipid
(eg,
lysolecithin
)
is
attacked
by
lysophospholipase, forming the corresponding glyceryl phosphoryl base, which in
turn may be split by a hydrolase liberating glycerol 3-phosphate plus base.
Phospholipases A1, A2, C, and D attack lipid bonds . Phospholipase A2 is found
in pancreatic fluid and snake venom as well as in many types of cells;
phospholipase C is one of the major toxins secreted by bacteria; and
phospholipase D is known to be involved in mammalian signal transduction.
Long-chain saturated fatty acids are found predominantly in the 1 position of
phospholipids, whereas the polyunsaturated acids (eg, the precursors of
prostaglandins) are incorporated more into the 2 position.
Sphingolipids are Degraded in Lysosomes
Most cells continually degrade and replace their membrane lipids. For each
hydrolyzable bond in a phospholipid, there is a specific hydrolytic enzyme
in the lysosome .
Gangliosides are degraded by a set of lysosomal enzymes that catalyze the
stepwise removal of sugar units, finally yielding a ceramide. A genetic defect in
any of these hydrolytic enzymes leads to the accumulation of gangliosides in the
cell, with severe medical consequences .
CHOLESTEROL IS DERIVED ABOUT EQUALLY FROM THE
DIET& FROM BIOSYNTHESIS
A little more than half the cholesterol of the body arises by synthesis (about 700
mg/d), and the remainder is provided by the average diet. The liver and intestine
account for approximately 10% each of total synthesis in humans. Virtually all
tissues containing nucleated cells are capable of cholesterol synthesis, which
occurs in the endoplasmic reticulum and the cytosol.
CHOLESTEROL IS EXCRETED FROM THE BODY IN THE BILE
AS CHOLESTEROL OR BILE ACIDS
About 1 g of cholesterol is eliminated from the body per day. Approximately half
is excreted in the feces after conversion to bile acids. The remainder is excreted
as cholesterol. Coprostanol is the principal sterol in the feces; it is formed from
cholesterol by the bacteria in the lower intestine.
Bile Acids Are Formed From Cholesterol
The primary bile acids are synthesized in the liver from cholesterol. These are
cholic acid (found in the largest amount) and chenodeoxycholic acid . Primary
bile acids are those synthesized by the liver. Secondary bile acids result from
bacterial actions in the colon. A portion of the primary bile acids in the intestine
is subjected to further changes by the activity of the intestinal bacteria.
MANY HORMONES ARE MADE FROM CHOLESTEROL
 Adrenal Steroidogenesis
All mammalian steroid hormones are formed from cholesterol via pregnenolone
through a series of reactions that occur in either the mitochondria or
endoplasmic reticulum of the adrenal cell. Hydroxylases that require molecular
oxygen and NADPH are essential, and dehydrogenases, an isomerase, and a
lyase reaction are also necessary for certain steps. There is cellular specificity in
adrenal steroidogenesis. For instance, 18- hydroxylase and 19-hydroxysteroid
dehydrogenase, which are required for aldosterone synthesis, are found only in
the zona glomerulosa cells (the outer region of the adrenal cortex), so that the
biosynthesis of this mineralocorticoid is confined to this region.
 Testicular Steroidogenesis
 Ovarian Steroidogenesis
 1,25(OH)2-D3 (Calcitriol) Is Synthesized From a Cholesterol
Derivative
Lipid metabolic scheme
1- Electrolytes




Sodium
Potassium
Chloride
Bicarbonate
2- Renal (Kidney) Function Tests


Creatinine
Blood urea nitrogen
3- Liver Function Tests






Total protein (serum)
 Albumin
 Globulins
 A/G ratio (albumin-globulin)
 Protein electrophoresis
 Urine protein
Bilirubin; direct; indirect; total
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase (ALP)
4- Cardiac Markers





H-FABP (Heart-type Fatty Acid Binding Protein)
Troponin
Myoglobin
CK-MB
B-type natriuretic peptide (BNP)
5- Minerals




Calcium
Magnesium
Phosphate
Potassium
6- Blood Disorders






Iron
Transferrin
TIBC
Vitamin B12
Vitamin D
Folic acid
7-Diabetes mellitus
8-Miscellaneous



C-reactive protein
Glycated hemoglobin (HbA1c)
Uric acid
9-Cancer
10-Digestion and absorption
1- Electrolytes




Sodium
Potassium
Chloride
Bicarbonate
2- Renal (Kidney) Function Tests


6- Blood Disorders






Iron
Transferrin
TIBC
Vitamin B12
Vitamin D
Folic acid
7-Diabetes mellitus
Creatinine
Blood urea nitrogen
3- Liver Function Tests
8-Miscellaneous




Total protein (serum)
 Albumin
 Globulins
 A/G ratio (albumin-globulin)
 Protein electrophoresis
 Urine protein
 Bilirubin; direct; indirect; total
 Aspartate transaminase (AST)
 Alanine transaminase (ALT)
 Gamma-glutamyl transpeptidase (GGT)
Alkaline phosphatase (ALP
4- Cardiac Markers





9-Cancer
H-FABP (Heart-type Fatty Acid Binding Protein)
Troponin
Myoglobin
CK-MB
B-type natriuretic peptide (BNP)
5- Minerals




C-reactive protein
Glycated hemoglobin (HbA1c)
Uric acid
Calcium
Magnesium
Phosphate
Potassium
10-Digestion and absorption