LIPID METABOLISM

16/6/52 นศพ.
 Metabolism (Catabolism and
Anabolism), Regulation and
Importance of fatty acids (FÂ)
and lipids
FÂ -Saturated FÂ
-Unsaturated FÂ
-Monounsaturated FÂ
-Polyunsaturated FÂ
-Eicosanoids
Lipids
Storage lipids ; Fat, oils
Membrane lipids
Phospholipids
Glycolipids
Cholesterol

Precursor & derived lipids

Sterols
Polyprenoid compounds
 FA FA
FA FA FA
FA
GLYCEROL MG DG TG

R – COOH carboxylic acid CHOLESTEROL – FA = CH. ESTER

O
R–C- acyl = FA -
FA FA FA
FA FA
P P-X P-X
PA PL LYSO-PL
PA = phosphatidic acid
PL = phospholipid
= phosphatidyl - x
( x = choline ; lecithin )
LYSO - PL = lysophosphatidyl - x
MG = monoacylglycerol
CTP = cytidine triphosphate
CDP = cytidine diphosphate
gastrin stomach
Hormones action
gastric -
motility
cholecystokinin
(in blood)
small
intestine
+

gut
endocrine duodenum
dietary lipids
cells
and proteins
(enlarged)

+
bicarbonate
+ secretin
(in blood)

pancreatic
enz.

bile
pancreas
+
Intestinal motility
gall
bladder
 pan.lipase
MG MG apoprotein

LCTG FA FA TG
G G
FCH
CH CH
CH.E CH.E
FA FA

LPL LPL
PL PL
FA FA
chylomicron
MCTG MCTG
Int. lipase

FFA G
DIGESTION + alb
AND portal vein lymphatic
ABSORPTION TG , CHE , PL ,
OF LIPIDS target tissue PROT.
CHYLOMICRON
steatorrhea small intestine
liver
dietary lipids

gall
bile bladder

pancreas
pancreatic
large intestine juice

bile pigment defective

cells Intestinal
mucosal
stercobilin cells
( สี feces )
Excess lipid in feces
(steatorrhea)
Ca++ + FA Ca SOAP

Possible causes of steatorrhea :

Feces : bacteria ¼ - ½ total
Orlistat (xenecal, tetrahydrolipstatin)
- Inhibit gastric and pancreatic lipases
- Obesity, non-alcoholic steatohepatitis (NASH)
treatment
ENZYMES DIGEST LIPIDS : LIPASE

FA
FA FA + 2FA ; + 3FA
FA
TG MG GLYCEROL
1 2
1 PANCREATIC (CO-LIPASE) : LC-FA
2 2.1 gastric : SC - FA
2.2 lipoprotein (extrahepatic tiss.)
TG in chylomicron , VLDL activated by heparin , apo –C-II

2.3 hormone sensitive lipase in adipocyte :

stim. : Gg , Epi , T4 , etc.
inh. : Pgs , Is
2.4 Int. lipase
MCTG
 FATTY ACIDS :
1. CHAIN : RCOOH

short chain (SC) medium chain (MC) long chain (LC) very long chain (VLC)
(<4) (6 – 12) ( 12 - 20 ) (>20)

2. ODD CHAIN : WAX ( C25 – C35 ) , EVEN

3. SAT. VS. UNSAT. :

SAT. : palmitic acid ( C16 : 0)

stearic acid ( C18 : 0)

ω γ β α
CH3 CH2 CH2 CH2 CH2 CH2 CH2 COOH

: 1▲
UNSAT. : oleic acid ( C18 9)

: 1▲
palmitoleic acid ( C16 9)

LINOLEIC LINOLENIC ARACHIDONIC

18 : 2▲ 18 : 3▲ 20 : 4▲
9,12 9,12,15 5,8,11,14
 FATTY ACID OXIDATION :

supply energy : 40 % normal ; 90 + % - fast

3 ways : β- (major) ; α - & ω - (minor)

STEPS :
activation : 2ATP (cyto -)
GTP (FAs in mito -)

transfer ( cyto mito ) - carnitine

β- oxidation ( mito )
1. DHase : FAD+ 2. hydratase : + H2O
3. DHase : NAD+ 4. thiolase : 2C
end products : Ac. CoA ; propionyl CoA
Krebs succinyl CoA
palmitic ac. (C16 ) C16H32O2 + 23 O2 16 CO2 + 16 H2O + E
 FATTY ACID ACTIVATION AND TRANSPORT
O
RCOOH + CoA + ATP RCSCoA + AMP +PPi
Acyl CoA synthetase (thiokinase)
Acyl CoA ligase

translocase

SC-FA and MCFA can cross the inner membrane of

mitochondria without the aid of carnitine or CAT system
 ACTIVATION TRANSLOCATION
mito-memb.
cytosol matrix
outer inner

O carnitine GDP + Pi
PPi
RCSCoA RCSCoA
+
AMP I II
GTP
ATP CoASH CoASH
RCOOH RCO-C RCOOH

Acyl CoA-synthetase or thiokinase

CAT I : carnitine acyl transferase I is inhibited by malonyl CoA

CAT II : carnitine acyl transferase II

Synthesized from lysine and methionine in liver and
kidney but not in skeletal and heart muscles (MCFAs
are plentiful in human milk)

Deficiency cause cardiomyopathy and muscle weakness

- liver disease
- strictly vegetarian diets
BETA – OXIDATION (not found in nerve and red cells)
(β-) O
FA R – CH2 – CH2 – CH2 – C - OH
CoA , ATP GTP , CoA
THIOKINASE 1
AMP , PPi GDP , Pi

R – CH2 – CH2 – CH2 – CO ~S CoA

Acyl CoA FAD
- DHase FADH2
2

R – CH2 – CH = CH – CO ~S CoA
▲2- TRANS -
ENOYL CoA H2O
3
- hydratase
R – CH2 – CH - CH – CO ~S CoA
L – 3 – OH – acyl CoA
OH H
4
-DHase NADH + H+

R – CH2 – C - CH2 – CO ~S CoA

3 – KETO – acyl CoA
O CoA SH
THIOLASE 5

2 R – CH2CO ~S CoA + CH3 CO ~S CoA

 END PRODUCTS OF β - OXIDATION OF FA
EVEN – CARBON FA :
3 2 β 1 O
CH3 – CH2 – CH2 – CH2 – CH2 - CH2 – CH2 – C ~S CoA

n ครัง้ ; CH3 CO.SCoA = n + 1

ODD – CARBON FA :
2 1 O
CH3 – CH2 – CH2 – CH2 – CH2 - CH2– C ~S CoA
1. PROPIONYL CoA + n ACETYL CoA

GLUC.
“TCA”
OAA
SUCCINYL CoA
CO2 + H2O + E
“KREBS”
FATE OF PROPIONYL CoA :
CO2 COOH
ATP ADP , Pi
CH2 CH3 HC CH3
C ~ S CoA C ~ S CoA
CARBOXYLASE
O ( B7 ) O
( BIOTIN ) D – Mt – MALONYL CoA
PROPIONYL CoA

RACEMASE

COOH
MUTASE
COOH
CH2
H3C CH
CH2 ( B12 ) C ~ S CoA
CO ~ S CoA
O
SUCCINYL CoA L – Mt – MALONYL CoA

B12 DEF : PROPIONIC ; Mt – MALONIC ACID

ACIDEMIA & ACIDURIA
( PERNICIOUS ANEMIA )
Acyl CoA dehydrogenase
1. short-chain acyl CoA dehydrogenase
- oxidised 4 and 6 carbon
2. medium-chain acyl CoA dehydrogenase
- oxidised 4- 14 carbon
3. long-chain acyl CoA dehydrogenase
- oxidised 12-18 carbon

Medium-chain acyl CoA dehydrogenase deficiency

- deficiency of ketone bodies but high in
dicarboxylic acid
- fasting hypoglycemia
sudden infant death syndrome
- avoid excessive fasting
hyhoglycin from unripened akee fruit inhibits acyl CoA DH

hypoglycemia

Vomiting, convulsion, coma, death

(Jamaican vomiting sickness)
SAT. BETA - OXIDATION

C16 S CoA
7 6 5 4 3 2 β 1
O

PALMITIC ACID Ac. CoA ( n+1 ); n = BETA - OXIDATION

UNSAT. double bond at an odd-numbered carbon

OLEIC ACID : C18 : 1▲9 CIS-

CIS
S CoA
18 9 3 2 1 O

S CoA + 3 Ac. CoA

12 3
O ISOMERASE
▲3 - CIS -
O

12 2 S CoA 6Ac. CoA

▲2 - TRANS -
UNSAT. double bond at an even-numbered carbon

CoA
POLYUNSAT.

Acyl CoA DH
cis
β-oxidation of very long chain fatty acid
- Peroxisome

- Membrane transport is unknown

- Peroxisomal oxidation differs from β-oxidation in

the initial dehydrogenase reaction

- FADH2 of acyl dehydrogenase in peroxisome

transfers electron to O2 to yield H2O2

- Catalase is needed to convert H2O2 into H2O and O2

- Subsequent steps are identical with β-oxidation

 catalase
H2O + 1/2O2
Acyl-CoA DH

hydratase

DH

β-ketothiolase
Zellweger syndrome (cerebrohepatorenal syndrome)

- in the family of leukodystrophies

- result from the defect in the import of enzymes into

peroxisome

- characterized by liver, kidney, brain and muscle

abnormalities

- Death by age six to twelve

Symptoms
-Enlarged liver

- Lack of muscle tone, an inability to move, suck

and/or swallow

- Glaucoma (ตอหิน)

- Mental retardation, seizure

- albuminuria
 พลังงานจากการสลายกรดไขมัน
กรดไขมันแตละชนิด ใหพลังงานไมเทากัน ขึ้นอยูกับจํานวนคารบอน และ unsaturation
ตัวอยาง
1. การสลายกรด palmitic ; ( กรดไขมันอิ่มตัวมีคารบอน 16 ตัว ) ได 106 ATP

C 16 : 0
Activation
AMP - 2 ATP
palmitoyl CoA
CH3 – CH2 – CH2 – CH2 – CH2 - CH2 – CH2 – C ~S CoA

β - oxidation x 7
(FADH2 + NADH) x 7 = 4 ATP x 7 28 ATP

8 acetyl CoA

TCA cycle x 8 (3NADH + FADH2) x 8 = 10 ATP x 8 80 ATP

+ GTP
16 CO2 Net = 106 ATP
 2. การสลายกรด stearic ; ( กรดไขมันอิ่มตัวมีคารบอน 18 ตัว ) ได 120
ATP
C 18 : 0
Activation
AMP - 2 ATP
β - oxidation x 8
4 ATP x 8 32 ATP
TCA cycle x 9
10 ATP x 9 90 ATP
Net = 120 ATP
18 CO2

3. กรดไขมันไมอม่ิ ตัว จะเปนไปตามปกติจนกวาจะถึงพันธะคู

ของกรดไขมัน ซึ่งเปนแบบ cis จะตองมีเอนไซมอื่นชวยเปลี่ยนใหเปนแบบ
trans เพื่อใหเอนไซมตัวที่ 2 ของ β - oxidation ทํางานได เนือ่ งจากมี
พันธะคูแลว จึงไมได FADH2 (1.5 ATP) ทําใหไดพลังงานนอยลง 1.5 ATP ตอ 1
พันธะคู
 α - OXIDATION OF FATTY ACIDS :

- MICROSOME, PEROXISOME, MITO. (HEART , LIVER , OTHERS)

- BRANCHED , α-OH – FA ( CEREBROSIDE in brain)

CH3 CH2 CH2 COOH CH3 CH2 COOH + CO2

PHYTOL ( CHLOROPHYLL IN GREEN VEGETABLE )

^
O
COOH ( PHYTANIC ACID )
O2 α REFSUM’S DISEASE
Hydroxylase , Vc (phytanic acid storage
H2O (monooxygenase) , 4H-biopterin disease)
α-OH – FA COOH -hydroxylase deficiency
H2
-slowly progressive
OH peripheral neuropathy
COOH with weakness and
Oxidase
muscle wasting,
H2 O combined with blindness
Pristanic acid OH + CO2
-avoid green vegetables
Isobutyryl CoA 3 Acetyl CoA 3 Propionyl CoA
O
ω - OXIDATION OF FATTY ACID :
- LIVER MICROSOME

- MEDIUM , LONG CHAIN FA.

- OXYGENASE SYSTEM :

ANIMAL : CYT. P 450 , NADPH2

BACT : RUBRIDOXIN : HC , DETERGENT

α
ω
H3C O2 COOH

H2C COOH
OH

HC COOH
O

HOC COOH β-
O
FA OXIDATION : β- α- ω-

1. SITE mito microsome

2. ORGAN general general, brain L , other

3. P’ way major minor

4. FA even , odd Br , OH - MC , LC
sat , unsat

5. ENZYME multi oxygenase

( hydroxylase )

6. PRODUCTS : Ac. CoA FA ( - 1C ) ω-

Propionyl CoA + CO2 DI - COOH

7. NEXT ^
O : TCA β- β-
( KREBS )
LIPOLYSIS
 KETOGENESIS

-liver
-mitochondrial matrix
-significant amount of
HMG-CoA synthase
-HMG CoA synthase is a
rate-limiting enzyme
-stimulated by fasting,
dietary fat, insulin
deficiency
 KETOLYSIS

EXTRAHEPATIC TISSUES
-brain, heart, kidney,
skeletal tissue
-mitochondrial matrix
-significant amount of β-
ketoacyl-CoA transferase
(thiophorase)
KETOGENESIS AND KETOLYSIS
 Myocardial ischaemia

reduced O2

anaerobic glycolysis β−oxidation

lactate increase acetyl CoA increase

cell acidosis ketone bodies increase

cell acidosis
trimetazidine inhibits β-ketothiolase in β-oxidation

inhibits fatty acid oxidation

increases carbohydrate oxidation

reduces lactate production

higher cell pH

reduces angina pectoris (chest pain)

 FA SYNTHESIS : cyto , ACP palmitic acid

-liver, lactating mammary gland

-cytosol

Acetyl CoA + 7 malonyl CoA + 14 NADPH2

Palmitic Acid (C16) + 8 CoA + 14 NADP+ + 7 CO2 + 6 H2O

A. Production of cytosolic acetyl CoA
B. Carboxylation of acetyl CoA to form malonyl CoA
CONTROL OF FATTY ACID SYNTHESIS

NADH, Citrate activates acetyl CoA

carboxylase
Long chain fatty acyl CoA inhibits acetyl
CoA carboxylase
C. Major sources of NADPH required for fatty acid synthesis

1. Pentose phosphate pathway (major)

2. NAD(P)+ - dependent malate dehydrogenase

(malic enzyme) (minor)
 D. Fatty acid synthesis

Palmitoyl thioesterase (TE) Liberation of palmitate product

TE

TE
 FATTY ACID SYNTHESIS

synthase
transacetylase

transferase
FATTY ACID SYNTHESIS

TE
FA ELONGATION :

1. MITO : SAT. ; Ac. CoA

2. MICROSOME : SAT. , UNSAT. ; Mal. CoA

R CH2 COSCoA + 2 NADPH2 + ACETYL CoA ( MITO )

R (CH2)3 COSCoA + 2 NADP+ + CoA

FA DESATURATION : SAT. FA UNSAT. FA

- MICROSOME ; ER of liver , adipose tissue

- MONOXYGENASE SYSTEM : NADPH2 , O2

CH3 – (CH2)7 – CH2 – CH2 – (CH2)7 –COOH + NADPH2 , O2

CH3 – (CH2)7 – CH = CH – (CH2)7 –COOH + NADP+ + 2H2O

DESATURATION OF FATTY ACID

non-heme iron
 FATTY ACID SYNTHESIS IN PLANT AND ANIMAL

essential fatty acid deficiency

- dermatitis
- poor wound healing

(in mammals)

EPA and DHA

support neural
and visual
development
Linoleic, C 18:2 9, 12 α - Linolenic, C 18:3 9, 12, 15

(C 18:2n-6) (C 18:3n-3)
-2H
6 - desaturase
γ- Linolenic, C 18:3 6, 9, 12 C 18:4 6, 9, 12, 15

(C 18:3n-6) C2 (C 18:4n-3)
elongase

Dinorno - y - linolenic, C 20:3 8, 11, 14 C 20:4 8, 11, 14, 17

(C 20:3n-6) -2H (C 20:4n-3)

5 - desaturase

Arachidonic, C 20:4 5, 8, 11, 14 Eicosapentaenoic, C 20:5 5, 8, 11, 14, 17

(C 20:4n-6) C2 (C 22:5n-3) EPA

elongase

C 22:4 7, 10, 13, 16 C 22:5 7, 10, 13, 16, 19

(C 22:4n-6) -2H (C 20:5n-3)

4
FISH OIL
-desaturase

C 22:5 4, 7 10, 13, 16 C 22:6 4, 7, 10, 13, 16, 19

Docosahexaenoic DHA
(C 22:5n-6) (C 22:6n-3)
SUMMARY OF FA SYNTHESIS + ELONGATION
(Ac.CoA) C2 ATP + CO2 C2 - C (MALONYL CoA)
1
2NADPH2
CO2 2NADPH2 3
C2 - C2
CO2 2

C2 - C2 - C2
2CO2
C2+2C3 CH3- CH2 - CH2 - CH2 - CH2 COOH C6 : 0
6 5 4 3 2 1

C6 : 1 3 CH3 CH2 - CH = CH - CH2 COOH + C2

3 2 1
C8 : 1 5
CH3 CH2 - CH = CH - CH2 CH2 CH2 COOH
5 4 3 2 1
DESATURATION : -H2 , NADPH2
STEARIC ; CH3 : -(CH2)7 - CH2 - CH2 - (CH2) 7 COOH (C18 : 0)

OLEIC ; CH3 : -(CH2)7 - CH = CH - (CH2)7 COOH (C18 : 1 9)

PLANT -2H 9 ANIMAL, คน
LINOLEIC
(ω-6) C18 : 2 9, 12 C18:2 6,9 (ω-9)
(ω-3) -2H
C18 : 3 3, 6, 9
LINOLENIC C18 : 3 9, 12, 15
 Triacylglycerol synthesis

Glycerol phosphate production

1. Liver and adipose tissue

synthesized from dihydroxyacetone
phosphate (DHAP) by glycerol phosphate
dehydrogenase

2. Liver
synthesized from glycerol by glycerol kinase
 SYNTHESIS OF GLYCEROL 3 - PO4

INSULIN

LIVER AND ADIPOCYTE LIVER ONLY

3. Conversion of free fatty acid to its activated form

- Attached to CoA by fatty acyl CoA synthetase

before participating in TG synthesis

4. Fate of TG

- TG is stored in adipose tissue and serves as

depot fat
- TG in liver is exported in the form of lipoprotein
particles called VLDL and secreted into the blood to the
peripheral tissue
adipocyte (visceral fat)

adipocytokines (adipokines)
- plasminogen activator inhibitor-1 (PAI-1)
- tumor necrosis factor-α (TNF- α)
: thrombosis and insulin resistance
- adiponectin
: insulin-sensitizing, anti-atherogenic effect
- interleukin-6 (IL-6)
- monocyte chemotactic protein-1(MCP-1)
: inflammation
: กระตุน NADPH oxidase

reactive oxygen species (ROS)

T2DM, CAD, cancer

• NEFA ยับยั้ง glycosis ในกลามเนื้อ และกระตุน
gluconeogenesis ที่ตับ ทําใหเกิด hyperglycemia

Insulin resistance

T2DM
Fatty liver
ก. steatosis โดยเฉพาะในตับ ทําใหเกิด insulin
resistance ยังไมมีอาการของตับ
risk factor
1. DM
2. protein mulnutrition
3. hypertension
4. obesity
5. anoxia
6. alcohol
7. cell toxin
Alcohol and FA synthesis
Ethanol + NAD+
Alcohol DH

Acetaldehyde + NADH
Aldehyde DH

Acetyl CoA+ NADH

ข. non-alcoholic steatohepatitis (NASH)

มีอาการตับอักเสบเรื้อรังเกิดจาก TNF-α ทีไ่ มไดเกิดจาก
hepatitis B, C, alcohol หรือรับประทานยา
Cholesterol synthesis
- cholesterol is the least soluble membrane lipid

- only important membrane steroid in animals

- most of it are in the form of “free” (unesterified)

cholesterol in cellular membrane

- brain contains large amounts of cholesterol

- brain is considered as unhealthy kind of food

- also used for synthesized steroid hormones and

bile salts
Steroid hormones

– Progestins (Progesterone)

– Glucocorticoids (Cortisol)

– Mineralocorticoids ( Aldosterone)

– Androgens (Testosterone)

– Estrogens (Estradiol)
 CHOLESTEROL SYNTHESIS
- occur in liver and intestine
- cytosol, ER
 CHOLESTEROL
SYNTHESIS

Regulation of cholesterol synthesis

- HMG CoA reductase is allosteric enzyme
- feedback-inhibited by free cholesterol
- insulin stimulates HMG CoA reductase
HMG CoA REDUCTASE INHIBITORS
- liver
- intestine
 EXOGENOUS ENDOGENOUS
DIET
SYNTHESIS PERIPHERAL
SAT. FA LIVER C2 TISSUE
CHOLESTEROL INTESTINE
สมอง ไขมันสัตว
ไขแดง RESIN กะทิ LDL-

ตับ RECEPTOR
HMG CoA REDUCTASE
INHIBITORS
เนย
หอยนางรม
CHOLESTEROL

HORMONES: CATABOLISM EXCRETION

STEROID
SEX
BILE ACIDS COPROSTEROL
CELL MEMB.

FECES
CHOLESTEROL METABOLISM
Plant sterols

-inhibit cholesterol absorption

-found in cereal and vegetables (most)

fruit (less)
CBH MET. IN LIVER
LIPID MET. IN LIVER
 DIABETES MELLITUS

1.IDDM: INSULIN DEPENDENT

2.NIDDM: INSULIN INDEPENDENT
 LIPID
METABOLISM
IN DIABETES
MELLITUS

CHOLESTEROL

KETOLYSIS
( Is dependent,indirect )