Metabolism (Catabolism and Anabolism), Regulation and Importance of fatty acids (FÂ) and lipidsFÂ -Saturated FÂ
-Unsaturated FÂ-Monounsaturated FÂ -Polyunsaturated FÂ-Eicosanoids
Lipids Storage lipids ; Fat, oilsMembrane lipids
PhospholipidsGlycolipidsCholesterol
Precursor & derived lipidsSterolsPolyprenoid compounds
FA
FA
FATG
FA
MGGLYCEROL
FA
DG
CHOLESTEROL – FA = CH. ESTERR – COOH carboxylic acid
R – C - acyl = FA -O
FA
FA
PPA
FA
FA
P-XPL
FA
P-XLYSO-PL
PA = phosphatidic acid
PL = phospholipid
= phosphatidyl - x
( x = choline ; lecithin )
LYSO - PL = lysophosphatidyl - x
MG = monoacylglycerol
CTP = cytidine triphosphate
CDP = cytidine diphosphate
FA
small intestine
dietary lipids and proteins
gall bladder
pancreas
secretin (in blood)
gut endocrine
cells (enlarged)
cholecystokinin (in blood)
stomach
gastric motility
bicarbonate
pancreatic enz.
bile
+
+
+
+
-
duodenum
Hormones actiongastrin
Intestinal motility
LCTG
MG
FA
G
CH.ECH
FA
PLLPL
FA
MG
FA
G
CH
FA
LPL
FA
TG
CH.E
PL
apoprotein
chylomicron
MCTG MCTG
FFA G
Int. lipase
portal vein
target tissue
lymphatic
TG , CHE , PL , PROT.
FCH
+ albDIGESTION AND
ABSORPTION OF LIPIDS
pan.lipase
dietary lipids
gall bladder
pancreaspancreatic
juice
bile
defective cells
liversmall intestine
Intestinal mucosal
cells
Excess lipid in feces (steatorrhea)
Ca++ + FA Ca SOAP
Possible causes of steatorrhea :
Feces : bacteria ¼ - ½ total
large intestine
bile pigment
stercobilin
( สี feces )
steatorrhea
Orlistat (xenecal, tetrahydrolipstatin)
- Inhibit gastric and pancreatic lipases- Obesity, non-alcoholic steatohepatitis (NASH)
treatment
ENZYMES DIGEST LIPIDS : LIPASE
FA
FA
FATG
FA + 2FA
MG
+ 3FA
GLYCEROL
;
1 2
PANCREATIC (CO-LIPASE) : LC-FA
2.1 gastric : SC - FA2.2 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
1
2
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 )
CH3 CH2 CH2 CH2 CH2 CH2 CH2 COOH
ω αβγ
UNSAT. : oleic acid ( C18 : 1▲9 )
palmitoleic acid ( C16 : 1▲9 )
LINOLEIC LINOLENIC ARACHIDONIC
18 : 2▲9,1218 : 3▲9,12,15
20 : 4▲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 ) + 23 O2 16 CO2 + 16 H2O + EC16H32O2
FATTY ACID ACTIVATION AND TRANSPORT
RCOOH + CoA + ATP RCSCoA + AMP +PPiO
Acyl CoA synthetase (thiokinase)
SC-FA and MCFA can cross the inner membrane of mitochondria without the aid of carnitine or CAT system
translocase
Acyl CoA ligase
cytosolouter inner
mito-memb. matrix
PPi+
AMP
ATP
RCOOH
RCSCoA
CoASH
carnitine
RCO-C
RCSCoA
CoASH
RCOOH
GDP + Pi
GTP
O
I II
Acyl CoA-synthetase or thiokinase
CAT I : carnitine acyl transferase I is inhibited by malonyl CoA
CAT II : carnitine acyl transferase II
ACTIVATION TRANSLOCATION
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)
FA R – CH2 – CH2 – CH2 – C - OHO
R – CH2 – CH2 – CH2 – CO ~S CoA
R – CH2 – CH = CH – CO ~S CoA
R – CH2 – CH - CH – CO ~S CoA
OH H
R – CH2 – C - CH2 – CO ~S CoA
O
R – CH2CO ~S CoA + CH3 CO ~S CoA
GTP , CoA
GDP , PiAMP , PPi
CoA , ATP
FADH2
FAD
-hydrataseH2O
NADH + H+
CoA SH
THIOKINASE
Acyl CoA- DHase
▲2- TRANS -ENOYL CoA
L – 3 – OH – acyl CoA
-DHase
3 – KETO – acyl CoATHIOLASE
(β-)
1
2
3
4
5
2
END PRODUCTS OF β - OXIDATION OF FA
EVEN – CARBON FA :
CH3 – CH2 – CH2 – CH2 – CH2 - CH2 – CH2 – C ~S CoA
Oβ 123
n คร้ัง ; CH3 CO.SCoA = n + 1
ODD – CARBON FA :
CH3 – CH2 – CH2 – CH2 – CH2 - CH2– C ~S CoA
O12
1. PROPIONYL CoA + n ACETYL CoA
SUCCINYL CoA
“KREBS”
“TCA”OAA
GLUC.
CO2 + H2O + E
FATE OF PROPIONYL CoA :
CH2 CH3
C ~ S CoA
O
HC CH3
O
C ~ S CoA
COOH
CARBOXYLASE( B7 )
( BIOTIN )
CO2 ATP ADP , Pi
PROPIONYL CoA D – Mt – MALONYL CoA
CHH3C
O
C ~ S CoA
COOH
L – Mt – MALONYL CoA
MUTASE
( B12 )CH2
CH2
CO ~ S CoA
COOH
SUCCINYL CoA
B12 DEF : PROPIONIC ; Mt – MALONIC ACIDACIDEMIA & ACIDURIA
( PERNICIOUS ANEMIA )
RACEMASE
Acyl CoA dehydrogenase1. short-chain acyl CoA dehydrogenase
- oxidised 4 and 6 carbon2. medium-chain acyl CoA dehydrogenase
- oxidised 4- 14 carbon3. 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)
BETA - OXIDATION
C16S CoA
1234567 β O
PALMITIC ACID Ac. CoA ( n+1 ); n = BETA - OXIDATION
OLEIC ACID : C18 : 1▲9 CIS-
O
S CoA
123918CIS
S CoA + 3 Ac. CoA
312▲3 - CIS -
OO
S CoA212▲2 - TRANS -
6Ac. CoA
ISOMERASE
SAT.
UNSAT. double bond at an odd-numbered carbon
β-oxidation of very long chain fatty acid - Peroxisome
- Membrane transport is unknown
- Peroxisomal oxidation differs from β-oxidation inthe 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
Zellweger syndrome (cerebrohepatorenal syndrome)
- in the family of leukodystrophies
- result from the defect in the import of enzymes intoperoxisome
- 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 (ตอหิน)
- Mental retardation, seizure
- albuminuria
พลังงานจากการสลายกรดไขมัน
กรดไขมันแตละชนดิ ใหพลังงานไมเทากัน ขึ้นอยูกับจํานวนคารบอน และ unsaturation
ตัวอยาง
1. การสลายกรด palmitic ; ( กรดไขมันอิ่มตัวมีคารบอน 16 ตัว ) ได 106 ATP
C 16 : 0
palmitoyl CoACH3 – CH2 – CH2 – CH2 – CH2 - CH2 – CH2 – C ~S CoA
8 acetyl CoA
16 CO2
Activation
β - oxidation x 7
TCA cycle x 8
AMP
(FADH2 + NADH) x 7 = 4 ATP x 7
(3NADH + FADH2) x 8 = 10 ATP x 8
+ GTP
- 2 ATP
28 ATP
80 ATP
Net = 106 ATP
2. การสลายกรด stearic ; ( กรดไขมันอ่ิมตัวมีคารบอน 18 ตัว ) ได 120 ATP C 18 : 0
Activation
β - oxidation x 8TCA cycle x 9
18 CO2
AMP - 2 ATP
4 ATP x 8 32 ATP10 ATP x 9 90 ATP
Net = 120 ATP
3. กรดไขมันไมอ่ิมตวั จะเปนไปตามปกติจนกวาจะถึงพันธะคู
ของกรดไขมัน ซ่ึงเปนแบบ cis จะตองมีเอนไซมอ่ืนชวยเปล่ียนใหเปนแบบ
trans เพื่อใหเอนไซมตัวท่ี 2 ของ β - oxidation ทํางานได เน่ืองจากมี
พันธะคูแลว จึงไมได FADH2 (1.5 ATP) ทําใหไดพลังงานนอยลง 1.5 ATP ตอ 1พนัธะคู
^
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
COOH ( PHYTANIC ACID )
PHYTOL ( CHLOROPHYLL IN GREEN VEGETABLE )
O
COOH
OHCOOH
OOH + CO2
O
αHydroxylase , Vc(monooxygenase) , 4H-biopterin
O2
H2O
H2
H2
REFSUM’S DISEASE (phytanic acid storage disease)-hydroxylase deficiency -slowly progressive peripheral neuropathy with weakness and muscle wasting, combined with blindness-avoid green vegetables
OxidasePristanic acid
Isobutyryl CoA 3 Acetyl CoA 3 Propionyl CoA
α-OH – FA
ω - OXIDATION OF FATTY ACID :
- LIVER MICROSOME
- MEDIUM , LONG CHAIN FA.
- OXYGENASE SYSTEM :
ANIMAL : CYT. P 450 , NADPH2
BACT : RUBRIDOXIN : HC , DETERGENT
COOHH3Cω
α
H2C
OH
HCO
HOCO
COOH
COOH
COOH
O2
β -
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 , LCsat , 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 )
-liver
-mitochondrial matrix
-significant amount of HMG-CoA synthase
-HMG CoA synthase is a rate-limiting enzyme
-stimulated by fasting, dietary fat, insulin deficiency
KETOGENESIS
KETOLYSIS
EXTRAHEPATIC TISSUES
-brain, heart, kidney, skeletal tissue
-mitochondrial matrix
-significant amount of β-ketoacyl-CoA transferase
(thiophorase)
Myocardial ischaemia
reduced O2
anaerobic glycolysis
lactate increase
cell acidosis
β−oxidation
acetyl CoA increase
ketone bodies increase
cell acidosis
trimetazidine inhibits β-ketothiolase in β-oxidation
inhibits fatty acid oxidationincreases carbohydrate oxidation
reduces lactate production
higher cell pH
reduces angina pectoris (chest pain)
FA SYNTHESIS : cyto , ACP palmitic acid
Acetyl CoA + 7 malonyl CoA + 14 NADPH2
Palmitic Acid (C16) + 8 CoA + 14 NADP+ + 7 CO2 + 6 H2O
-liver, lactating mammary gland-cytosol
CONTROL OF FATTY ACID SYNTHESIS
NADH, Citrate activates acetyl CoA carboxylase
Long chain fatty acyl CoA inhibits acetylCoA 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)
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 ELONGATION :
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
FATTY ACID SYNTHESIS IN PLANT AND ANIMAL
(in mammals)
essential fatty acid deficiency- dermatitis- poor wound healing
EPA and DHAsupport neuraland visual development
Linoleic, C 18:2 9, 12 α - Linolenic, C 18:3 9, 12, 15
(C 18:2n-6) (C 18:3n-3)
γ- Linolenic, C 18:3 6, 9, 12 C 18:4 6, 9, 12, 15
6 - desaturase
(C 18:3n-6) (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) (C 20:4n-3)
Arachidonic, C 20:4 5, 8, 11, 14 Eicosapentaenoic, C 20:5 5, 8, 11, 14, 17
5 - desaturase
(C 22:4n-6) (C 20:5n-3)
elongase
C 22:4 7, 10, 13, 16 C 22:5 7, 10, 13, 16, 19
(C 20:4n-6) (C 22:5n-3)
(C 22:5n-6) (C 22:6n-3)C 22:5 4, 7 10, 13, 16 C 22:6 4, 7, 10, 13, 16, 19
4 -desaturase
-2H
C2
C2
-2H
-2H
EPA
DHA
FISH OIL
Docosahexaenoic
C2+2C3
(Ac.CoA) C2 C2 - C (MALONYL CoA)
ATP + CO2
CO22NADPH2
C2 - C2
2NADPH2
CO2
C2 - C2 - C2
3
2
1
2CO2
CH3- CH2 - CH2 - CH2 - CH2 COOH C6 : 0
C6 : 1 3 CH3 CH2 - CH = CH - CH2 COOH + C2
C8 : 1 5 CH3 CH2 - CH = CH - CH2 CH2 CH2 COOH
3 2 1
5 4 3 2 1
DESATURATION : -H2 , NADPH2STEARIC ; CH3 : -(CH2)7 - CH2 - CH2 - (CH2) 7 COOH (C18 : 0)
OLEIC ; CH3 : -(CH2)7 - CH = CH - (CH2)7 COOH (C18 : 1 9)9 PLANT -2H ANIMAL, คน
LINOLEIC(ω-6) C18 : 2 9, 12 C18:2 6 , 9 (ω-9)
(ω-3) -2HLINOLENIC C18 : 3
9, 12, 15 C18 : 3 3, 6, 9
6 5 4 3 2 1
SUMMARY OF FA SYNTHESIS + ELONGATION
Triacylglycerol synthesis
Glycerol phosphate production
1. Liver and adipose tissuesynthesized from dihydroxyacetone phosphate (DHAP) by glycerol phosphate dehydrogenase
2. Liversynthesized from glycerol by glycerol kinase
3. Conversion of free fatty acid to its activated form
- Attached to CoA by fatty acyl CoA synthetasebefore 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: กระตุน NADPH oxidase
reactive oxygen species (ROS)
T2DM, CAD, cancer
• NEFA ยับยั้ง glycosis ในกลามเนื้อ และกระตุน
gluconeogenesis ท่ีตับ ทําใหเกดิ hyperglycemia
Insulin resistance
T2DM
Fatty liverก. steatosis โดยเฉพาะในตับ ทําใหเกดิ insulin
resistance ยังไมมีอาการของตับ
risk factor 1. DM2. protein mulnutrition3. hypertension4. obesity5. anoxia6. alcohol7. cell toxin
Alcohol and FA synthesis
Ethanol + NAD+
Acetaldehyde + NADH
Acetyl CoA+ NADH
Alcohol DH
Aldehyde DH
ข. non-alcoholic steatohepatitis (NASH)มีอาการตับอักเสบเรื้อรังเกิดจาก TNF-α ทีไ่มไดเกิดจาก
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)
CHOLESTEROLSYNTHESIS
Regulation of cholesterol synthesis- HMG CoA reductase is allosteric enzyme
- feedback-inhibited by free cholesterol- insulin stimulates HMG CoA reductase
EXOGENOUSDIET
CHOLESTEROLสมองไขแดงตับเนยหอยนางรม
ไขมันสัตวกะทิ
CHOLESTEROL
ENDOGENOUS
SYNTHESIS PERIPHERALLIVER C2 TISSUEINTESTINE
LDL-RECEPTOR
SAT. FA
HORMONES:STEROIDSEXCELL MEMB.
CATABOLISM
BILE ACIDS
EXCRETION
COPROSTEROL
FECES
HMG CoA REDUCTASE INHIBITORS
RESIN
CHOLESTEROL METABOLISM