LIPID METABOLISM

Lipid Metabolism

Lipid Metabolism

Lipid Metabolism

• Digestion - Hydrolysis Reaction

Emulsification of Dietary lipids in the small intestines

- emulsification inc. the surface area lipase activity

- detergent property of bile salt and peristalsis

> Pancreatic activity

Hormonal Control of Lipid Digestion

1. CCK/pancreozymin – (+)GB contraction and

release of bile; release of pancreatic enzymes; dec.

gastric motility

2. Secretin - (+) bicarbonate secretion

Digestive Lipid Metabolism

1. Triacyglycerol hydrolysis

- TAG are acted upon by pancreatic lipase and

removes FA at carbon 1 and 3

- products = 2-monoacylglycerol + FA

2. Cholesteryl ester degradation

- Cholesterol esterase

- Products: Cholesterol + FA

3. Phospholipids degradation

- phospholipase A2

- products: lysophospholipid + FA

Absorption of Lipids by intestinal mucosal cells

- FFA, free cholesterol, 2-monoacylglycerol and

lysophospholipid together with bile salts from mixed

micelles which is absorbed at the brush border membrane

of SI

- short and medium chain FA are directly absorbed

> Resynthesis of TAG, CE and PL

2-monoacylglycerol + fatty acyl-CoA = TAG

Cholesterol + FA = CE

Lysophospholipid + FA = Phospholipid

The two

processes

are in many ways

mirror images of

each other.

Steps in Fatty Acid Degradation and Synthesis

Biosintesis asam lemak

◘ Fatty acids are synthesized by an

extramitochondrial system (cytosolic)

◘ is present in many tissues :

Liver

Kidney

Brain

Lung

Mammary gland

Adipose tissue

Biosynthesis of Fatty Acids

Fatty Acid Synthase Multienzyme Complex

Schematic Representation of Animal Fatty Acid Synthase. Each of the identical chains in the dimer contains three domains. Domain 1 (blue) contains

acetyl transferase (AT), malonyl transferase (MT), and condensing enzyme (CE). Domain 2

(yellow) contains acyl carrier protein (ACP), b-ketoacyl reductase (KR), dehydratase (DH),

and enoyl reductase (ER). Domain 3 (red) contains thioesterase (TE). The flexible

phosphopantetheinyl group (green) carries the fatty acyl chain from one catalytic site on a

chain to another, as well as between chains in the dimer.

Transfer of Acetyl CoA to the Cytosol. Acetyl CoA is transferred from mitochondria to the cytosol, and the reducing

potential NADH is concomitantly converted into that of NADPH by this series

of reactions.

Production of Malonyl-CoA Is the Initial &

Controlling Step in Fatty Acid Synthesis

(acetyl-CoA carboxylase)

Control of Acetyl CoA Carboxylase

Regulation of acetyl-CoA carboxylase by

phosphorylation/dephosphorylation

Biosynthesis of

Long-Chain Fatty Acids

Reactions of Fatty Acid Synthase. Translocations of the elongating fatty acyl chain between the cysteine sulfhydryl

group of the condensing enzyme (CE, blue) and the phosphopantetheine

sulfhydryl group of the acyl carrier protein (ACP, yellow) lead to the growth of

the fatty acid chain.

PROSES DESATURASI

1. C ≥ 16

2. MULAI DARI C9

3. SELANJUTNYA SELISIH 3 C KEARAH -COOH

C-C-C-C-C-C-C=C-C-C=C-C-C=C-C-COOH

Δ 9 8 7 6 5 4 3 2 1

ASAM LEMAK ESENSIAL

- LINOLEAT 18 Δ 9, 12

- LINOLENAT 18 Δ 9, 12, 15

- ARACHIDONAT 18 Δ 5, 8, 11, 14

Ω

The Main Source

of NADPH

▪ PPP

▪ Malic enzyme

▪ Isocitrate

dehydrogenase

Acetyl CoA carboxylase is the key control site in fatty acid synthesis.

Regulation of Fatty Acid Synthesis

Mobilization of Triacylglycerols

Degradasi Asam lemak

(penggunaan asam lemak untuk

sumber energi)

Utilization of Fatty Acids as Fuel

GLYCEROL METABOLISM

Lipid Metabolism

Lipid Metabolism

carnitine acyltransferase (also called

carnitine palmitoyl transferase I)

Acyl Carnitine Translocase

Role of carnitine in the

transport of long-chain

fatty acids through the

inner mitochondrial

membrane.

Fatty Acid Oxidation

• Initial Step: Requires an ATP to synthesize

acetyl CoA with the fatty acid.

Beta Oxidation

Beta Oxidation

Beta Oxidation

Beta Oxidation

Beta Oxidation

Beta Oxidation

Beta Oxidation

Palmitic Acid Review

2 ATP

3 ATP

n X 12 ATP

(TCA cycle)

(n – 1) X 5 ATP

Palmitic Acid -ATP Synthesis

• Palmitic Acid is C-16

• Initiating Step - requires 1 ATP (text says 2)

• Step 1 - FAD into e.t.c. = 2 ATP

• Step 3 - NAD+ into e.t.c. = 3 ATP

• Total ATP per turn of spiral = 5 ATP

• Example with Palmitic Acid = 16 carbons = 8 acetyl

groups

• Number of turns of fatty acid spiral = 8-1 = 7 turns

• ATP from fatty acid spiral = 7 turns and 5 per turn =

35 ATP.

• NET ATP from Fatty Acid Spiral = 35 - 1 = 34 ATP

Palmitic Acid (C-16) -ATP Synthesis

• NET ATP - Fatty Acid Spiral = 35 - 1 = 34 ATP

• Review ATP - Citric Acid Cycle start with Acetyl

CoA

• Step ATP produced

• 7 visible ATP 1

• Step 4 (NAD+ to E.T.C.) 3

• Step 6 (NAD+ to E.T.C.) 3

• Step10 (NAD+ to E.T.C.) 3

• Step 8 (FAD to E.T.C.) 2

• NET 12 ATP per turn C.A.C.

• 8 Acetyl CoA = 8 turns C.A.C.

• 8 turns x 12 ATP/C.A.C. = 96 ATP

• GRAND TOTAL 130 ATP

Principal reactions in fatty acid oxidation

Odd-Chain Fatty Acids Yield Propionyl Coenzyme A

Propionyl CoA enters the citric acid cycle

after it has been converted into succinyl CoA.

succinyl CoA

(CYTRIC ACID CYCLE)

Control of Fatty Acid Degradation

Malonyl CoA inhibits fatty acid degradation by

inhibiting the formation of acyl carnitine.

Synthesis and Degradation of Triacylglycerols by Adipose Tissue.

Acetyl CoA

Lipogenesis

Major Metabolic Fates of Pyruvate and Acetyl CoA in Mammals

Compartmentation of the Major Pathways of Metabolism.

Formation of Ketone Bodies.

Acetoacetate spontaneously decarboxylates to form acetone

1) 3-ketothiolase

2) hydroxymethylglutaryl CoA synthase,

3) hydroxymethylglutaryl CoA cleavage enzyme

4) d-3-hydroxybutyrate dehydrogenase

(HMG CoA)

Formation, utilization, and excretion of ketone bodies.

(The main pathway is indicated by the solid arrows.)

Utilization of Acetoacetate as a Fuel

Transport of ketone bodies from the liver and pathways of utilization and

oxidation in extrahepatic tissues.

Ketone Bodies

Ketone Bodies

Blood Glucose and Glucosuria

Ketone Bodies

Asam arakhidonat sebagai precursor

hormon prostaglandin

Arachidonate Is the Major Precursor of Eicosanoid Hormones

Structures of Several Eicosanoids

trans- Fatty Acid

Pengaruhnya terhadap metabolisme

asam lemak

◘ Trans-unsaturated fatty acids are found in ruminant fat (eg, butter fat

has 2–7%), where they arise from the action of microorganisms in the rumen,

◘ Main source in the human diet is from partially hydrogenated vegetable

oils (eg, margarine).

◘ Trans fatty acids compete with essential fatty acids, exacerbate

essential fatty acid deficiency.

◘ Structurally similar to saturated fatty acids, have comparable effects

in the promotion of hypercholesterolemia and atherosclerosis.

Trans Fatty Acids Are Implicated in Various Disorders

KHOLESTEROL

biosintesis dan metabolismenya

CHOLESTEROL IS DERIVED ABOUT EQUALLY FROM THE DIET

& FROM BIOSYNTHESIS

Acetyl-CoA Is the Source of All Carbon Atoms in Cholesterol

Step 1—Biosynthesis of Mevalonate

Step 2—Formation of Isoprenoid Units

Step 3—Six Isoprenoid Units Form Squalene

Step 4—Formation of Lanosterol

Step 5—Formation of Cholesterol

Biosynthesis of

mevalonate.

6 X SQUALENE

LANOSTEROL

CHOLESTEROL

Transport of cholesterol between the tissues in humans.

Glycine

Taurine

CHOLESTEROL IS

EXCRETED FROM THE

BODY IN THE BILE AS

CHOLESTEROL OR

BILE ACIDS (SALTS)

Intestinal bacteria produce the

secondary bile acids.

Enterohepatic circulation 98-99%

Diet Can Play an Important Role in Reducing Serum Cholesterol

corn oil and sunflower seed oil : polyunsaturated and

monounsaturated fatty acids

olive oil : high concentration of monounsaturated fatty acids.

poly and monounsaturated

up-regulation of LDL receptors

catabolic rate of LDL (LDL = the main atherogenic lipoprotein).

cholesterol

Four Major Groups of Plasma Lipoproteins

Have Been Identified

1. Chylomicrons : TG (intestinal absorption)

2. VLDL or pre-β-lipoproteins : TG (from the liver)

3. LDL or β-lipoproteins : the catabolism of VLDL

4. HDL or α-lipoproteins : in VLDL / chylomicron

metabolism and cholesterol transport.

Triacylglycerol is the predominant lipid in chylomicrons and VLDL

Cholesterol and phospholipid are the predominant lipids in LDL and HDL

Generalized Structure of A Plasma Lipoprotein

Composition of the lipoproteins in plasma of humans

1Secreted with chylomicrons but transfers to HDL.

2Associated with HDL2 and HDL3 subfractions.

3Part of a minor fraction known as very high density lipoproteins (VHDL).

Secretion of (A) chylomicrons

by an intestinal cell

Secretion of (B) very low

density lipoproteins by a

hepatic cell.

SD, space of Disse

Metabolic fate of chylomicrons

Metabolic fate of very low density lipoproteins (VLDL) and production of

low-density lipoproteins (LDL)

Metabolism of high-density lipoprotein (HDL) in reverse

cholesterol transport

LCAT, lecithin:cholesterol acyltransferase; C, cholesterol; CE, cholesteryl ester; PL,

phospholipid; A-I, apolipoprotein A-I; SR-B1, scavenger receptor B1; ABC-1, ATP binding

cassette transporter 1.

Imbalance in

the Rate of

Triacylglycerol

Formation &

Export Causes

Fatty Liver

Primary disorders of plasma lipoproteins (dyslipoproteinemias)

Hypolipidemic Drugs Will Reduce Serum Cholesterol& Triacylglycerol

Cholestyramine resin : bile acids reabsorption ↓ (small intestine)

bile acid synthesis ↑(liver)

cholesterol excretion ↑

up-regulates LDL receptors

plasma cholesterol.

Sitosterol : absorption of cholesterol from the gastrointestinal tract ↓.

Statins : inhibit HMG-CoA reductase, thus up-regulating LDL receptors.

(atorvastatin, simvastatin, and pravastatin.)

Clofibrate and gemfibrozil : 1. VLDL secretion ↓, plasma triacylglycerols ↓.

2. stimulate hydrolysis of VLDL triacylglycerols by lipoprotein lipase.

Probucol : LDL catabolism ↑, accumulation of oxidized LDL ↓

Nicotinic acid : adipose tissue lipolysis ↓, FFA ↓, VLDL ↓

Metabolism of adipose tissue. Hormone-sensitive lipase is

activated by ACTH, TSH,

glucagon, epinephrine,

norepinephrine, and vasopressin

and inhibited by insulin,

prostaglandin E1, and

nicotinic acid.

Control of adipose tissue lipolysis.