Ketogenesis

High rate of fatty acid oxidation in the liver.

Enzymes responsible for ketone body
formation are assosiated mainly with the
mitochondria
Amount increase in DM and starvation.
Acetoacetate and hydroxybutirate are
interconverted (D-3- hyroxybutyrate
dehydrogenase), controlled by mitochondria
ratio of [NAD+] to [NADH].
 Utization in extra hepatic tissue for
activation acetoacetate acetoacetyl
CoA Acetyl CoA Citric acid
cycle.
Ketonemia :due to increased production of
KB by the liver and deficiency their
utilization by extrahepatic tissue.
Acetoacetate and hydroxybutirate are
readily oxidized by ex.hepatic tissue
,acetone is difficult to oxidized in vivo and
to large extent is volatilized in the lung .
Acetoacetate : 33 mol ATP
Hydroxybutyrate : 21 mol ATP
 Ketogenesis is regulated at three crucial
steps :
1.Mobilization of FFA from adiposa tissue.
FFA precursor of ketone bodies in the
liver.
2.Activity of carnitine palmitoyltransferase I
in liver, which determines the proportion of
the fatty acid flux that is oxidized rather
than esterified.
3.Acetyl CoA Citric acid cycle or ketogenesis
 Ketoacidosis
Result prolong ketosis.
Ketonemia ketonuria ketosis.
Uncontrolled diabetes melitus.
Starvation
Pregnancy toxemia
Ketones in Diabetes Mellitus
Ketogenic
Amino Acids Fatty
Glycolysis Acids
Glucose Oxaloacetate
Gluconeogenesis Acetyl CoA

TCA Ketone
Glucogenic Cycle Bodies
Amino Acids
Citrate

Glucose in cells Gluconeogenesis Oxaloacetate

Fatty Acid breakdown Acetoacetyl CoA Ketone Bodies

LIPID BIOSYNTHESIS
LIPID OXIDATION AND LIPID
SYNTHESIS
 Lipogenesis
Location : cytoplasm.
Cofactor requirements include NADPH,ATP,
Mn2+, biotin, HCO3, acetyl CoA.
Acetyl CoA is the immediate substrate.
Free palmitate is the end product.
Initial reaction : carboxylation of acetyl CoA
to malonyl CoA by ATP and acetyl CoA
carboxylase .
Acetyl CoA carboxylase has a requirement for
the vitamin biotin
 Fatty Acid Biosynthesis:
Formation of Malonyl CoA

Acetyl CoA
Carboxylase Malonyl CoA
CH3COSCoA + ATP + HCO3- -O CCH COSCoA
2 2

+ ADP + Pi + H+
Committed step in fatty acid synthesis
Reaction is irreversible
Regulation of acetyl CoA carboxylase activity:
by palmitoyl CoA
by citrate
Malonyl CoA inhibits carnitine acyl transferase I
Blocks beta oxidation
 Production of malonyl CoA is the initial
and controlling step in fatty acid
synthesis.
The reaction take place in two steps :
1. carboxylation of biotin
2. transfer of the carboxyl to acetyl CoA
malonyl CoA.
The fatty acid synthase complex is
polypeptide containing seven enzym
activities
Acyl carrier protein (pantothenic acid)
NADPH as reductant PMP shunt
Carboxylation acetyl CoA
 Acetyl CoA + HCO3+ ATP malonyl CoA +
ADP + Pi + H.
Acetyl CoA + ACP Acetyl ACP + CoA
Malonyl CoA + ACP Malonyl ACP + CoA
Acetyl ACP + Malonyl ACP acetoacetyl-
ACP + ACP + CO2.
Acetoacetyl ACP + NADPH + H D-3-
hidroxybutyryl- ACP + NADP.
D-3-hidroxybutyryl-ACP crotonyl ACP +
H2O.
Crotonyl ACP + NADPH + H butyryl ACP
Intermediates in fatty acid synthesis are linked
to an
acyl carrier protein
 Reaction in lipid synthesis

Condensation reaction

Acyl-malonyl ACP
condensing enzyme
 REDUCTION REACTION
-Ketoacyl ACP reductase
Dehydration Reaction

3-Hydroxyacyl ACP
dehydratase
 Reduction Reaction

Enoyl ACP reductase

Schematic representation of animal
fatty acid synthase
LIPID BIOSYNTHESIS
Long-Chain Saturated Fatty Acids Are
Synthesized from Palmitate
 Desaturation of Fatty Acids Requires a
Mixed-Function Oxidase
Palmitate and stearate precursors of the two most
common monounsaturated fatty acids of animal tissues:
palmitoleate, 16:1(9), and oleate, 18:1(9);
fatty acids have a single cis double bond between C-9
and C-10 .
The double bond is introduced into the fatty acid chain by
an oxidative reaction catalyzed by fatty acylCoA
desaturase mixed-function oxidase.
Two d ifferent substrates, the fatty acid and
NADH or NADPH, simultaneously undergo two-electron
oxidations.
 The path of electron flow includes a cytochrome
(cytochrome b5) and a flavoprotein (cytochrome b5
reductase), both of which, like fatty acylCoA
desaturase, are in the smooth ER.
Bacteria have two cytochrome b5 reductases, one
NADH-dependent and the other NADPH-dependent;
which of these is the main electron donor in vivo is
unclear. In plants, oleate is produced by a stearoyl-
ACP desaturase in the chloroplas stroma that uses
reduced ferredoxin as the electron donor.
Storage of fatty acids as components
of triacylglycerols
 Essential fatty acids
linoleic and - linolenic acid cannot be
synthesized must be supplied from diet
(polyunsaturated fatty acid) it is called
as nutritionally essential fatty acids.
The essential fatty acids are found in
high concentrations in various vegetable
oils.
Arachidonic acid essential fatty acid
can be formed from linoleic acid in
most mammals
 Function of Essensial fatty acid
To form eicosanoic (C20)
prostaglandin, thromboxane,
leukotriene, and lipoxine formation.
Vital body structures
Perform important roles in immune
system function and vision.
To form cell membranes
 Arachidonic acid present in membrane
and 5 15 % of the fatty acids in
phospholipids.
DHA (docosahexosa) :synthesized from
-linolenic acid retina, cerebral
cortex, testis, and sperm.
DHA development of the brain, retina
 Prostaglandin and tromboxan : Local hormon.
PG : mediator inflamasi, blood koaguation,
reproduction.
Thromboxane :synthesized in platelets
vasoconstriction and platelets aggregation
(inhibited by aspirin).
Thromboxane and prostacyclin : antagonist.
Leucotriene : Respon immunologic and
nonimunologic.
Leucotriene is formed in leucocytes,
mastocytoma cells, plateletes and
macrophage.
Abnormal metabolism Essensial Fatty
Acids
Connected with dietary insufficiency.
Cystic fibrosis, acrodermatitis
enteropathica,hepatorenal syndrome,
SjorgenLarson syndrome, multisystem
neuronal degeneration, chron s disease,
cirrhosis and Reys syndrome
 Cholesterol metabolism
Sources : diet and de novo synthesis
Biosynthesis : stimulating when the diet
is low in cholesterol.
Function :
component membrane cell
synthesis important metabolite
synthesis bile acid
synthesis vitamin D
Cholesterol metabolism
SYNTHESIS OF CHOLESTEROL
SYNTHESIS OF CHOLESTEROL
important metabolite FROM
CHOLESTEROL
Regulation of cholesterol synthesis
HMG CoA reductase, major control point for
cholesterol biosynthesis.
1. Expression ofthe gene for HMG CoA reductase
controlled by the transcriptionfactor SREBP-
2 (sterol regulatory elementbinding protein-2)
binds DNA at the cis-acting sterol regulatory
element (SRE) of the reductase gene
. SREBP integral protein of the ER membrane,
associates with a second ER membrane
protein,SCAP (SREBP cleavageactivating
protein).
 2. Sterol-accelerated
enzyme degradation:
The reductase itself is a
sterol-sensing integral
protein of the ER
membrane.
When sterol levels in
the cell are high, the
reductase binds to insig
proteins.
 Binding leads to
ubiquitination and
proteasomal
degradation of
thereductase
 3.Sterol-independent
phosphorylation/dephosphorylation: HMG
CoA reductase activity is controlled covalently
through the actions of adenosine
monophosphate (AMP)activated protein kinase
(AMPK) and a phosphoprotein phosphatase .
The phosphorylated form of the enzyme is
inactive, whereas the dephosphorylated form is
active.
4.Hormonal regulation:
The mount and activity ofHMG CoA reductase
controlled hormonally.
An increase in insulin and thyroxine favors up-
regulation of the expression of the gene for
HMG CoA reductase.
Glucagon and the glucocorticoids have the
opposite effect.
Regulation of HMG CoA reductase
 Regulation of LDL receptor
Supression of cholesterol biosynthesis
by LDL- bound cholesterol involves
specific LDL receptors that project
from the plasma membrane.
regulatory mechanism involves binding
of lipoprotein LDL to these LDL
receptor, thereby extrating the LDL
particles from the plasma.
 DEGRADATION OF CHOLESTEROL
The ring structure of cholesterol cannot be
metabolized to CO2 and H2O.
eliminated from the body by conversion to
bile acids and bile salts are excreted in the
feces, and by secretion of cholesterol into the
bile, which transports it to the intestine for
elimination.
 Degradation of cholesterol
Bile acids are the end products of
cholesterol metabolism.
cholic acids and chenodeoxycholic .
Because of the ring structure of
cholesterol can not be metabolized to
CO2 and H2O so cholesterol is
eliminated from the body by conversion
to bile acids which are excreted in the
feces
 Synthesis bile acid
multistep pathway in which hydroxyl
groups are inserted at specific position
on the steroid structure, the double
bond of cholesterol B ring is reduced
and the hydrocarbon chain is shortened
by three carbons, introducing a carboxyl
group at the end of the chain.
 The rate limiting step in bile acid
synthesis is the introducing of a
hydroxyl group at carbon 7 of the
steroid ring by 7-- hydroxylase
 Before the bile acids leave the liver , they
are conjugated to a molecule of either
glycine or taurine by an amide bond between
the carboxyl group of the bile acid and amino
group on the added compound .
These new structures are called bile salts
and include glycocholic and
glycochenodeoxycolic acids and taurocholic
and taurochenodeoxycholic acids .
Bile salts secreted into the intestinal are
efficiently reabsorbed and reused.
 The liver converts both primary and
secondary bile acids into bile salts by
conjugation with glycine or taurine and
they are then ready to be secreted in
the bile .
In the gut the glycine and taurine
residues are removed and the bile acids
are either excreted (only a small
percentage) or reabsorbed by the gut
and returned to the liver. This process
is termed the enterohepatic circulation
Excretion of cholesterol
 clinical aspect
Bile salt deficiency: cholelithiasis
The movement of cholesterol from the liver into
the bile must be accompanied by the
simultaneous secretion of phospholipid and bile
salts.
Excess cholesterol enters the bile than can be
solubilized by the bile salts and phosphatidyl
choline present, precipitate in the gallbladder,
leading to cholesterol gallstone disease
cholelithiasis.
 Decrease of bile acids in the bile result
1) gross malabsorption of bile acids from the
intestine (ileal disease)
2) obstruction of the biliary tract, interrupting
the enterohepatic circulation
3) severe hepatic dysfunction, leading to
decreased synthesis of bile salts, or other
abnormalities in bile production
4) excessive feedback suppression of bile acid
synthesis as a result of an accelerated rate of
recycling of bile acids.