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Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
1The screen versions of these slides have full details of copyright and acknowledgements
Lipid Metabolism
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Prof. Dr. rer physiol. Dr.h.c. Ulrike BeisiegelDepartment of Biochemistry and Molecular Biology II
Medical Center Hamburg-Eppendorf
Lipids……. visceral fat
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…. nutritional lipids
…. serum lipids
…. lipid accumulation in the arterial wall
0 1.5 3 4.5 9 h
Karpe et al., Atherosclerosis 1994
Functions of lipids
Energy supply
Triglycerides
Fatty acids
Phospho- and shingolipids as structural membrane components
COOH
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Hormones
Regulation of gene expression
Lipophilic vitamins
Cholesterol
COOH
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
2The screen versions of these slides have full details of copyright and acknowledgements
1. Postprandial lipid metabolism
2. Hepatic lipid metabolism
3 Cellular cholesterol homoeostasis
Lipid metabolism
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3. Cellular cholesterol homoeostasis
4. Reverse cholesterol transport
EnterocytesLipid droplets
+ pancreatic lipase
Lipid absorption in the intestinenutritional lipids in:
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Lipid emulsion
+ phospholipids
+ bile acids
+ pancreatic lipase with cofactor
Micelles
bile acids→ entero-hepatic cycle
fatty acids
cholesterol
cholesterol and plant sterols NPC1L1
Intestinal sterol uptake
Niemann-Pick C1 Like 1 (NPC1L1) protein is responsible for sterol absorption in the small intestine1
Enterocytes
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plant sterolsand cholesterol
and
The secretion of sterols into bile is mediated jointly by the two ABC-transportersABCG5 and ABCG82
1) Altmann SW et al., Science 20042) Berge KE et al., Science 2000
ABCG5/G8
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
3The screen versions of these slides have full details of copyright and acknowledgements
Fatty acids
and cholesterol
CD36
Intestinal fatty acid uptake
Enterocytes
COOH
CD36 is a fatty acid translocase (FAT) with a broad ligand specificityproximal
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Fatty acidsFATP4
Stahl A et al., Mol Cell 1999; Nassir F et al., JBC 2007
Fatty acid transport protein 4 (FATP4)is a member of the large family of fatty acid transport proteins
COOH
distal
long chain FA
cholesterol Chylomicron
microsomal triglyceride transport protein (MTP)
Intestinal chylomicron formation
short chain FA albumin-bound to liver
via lymph into
Enterocyte
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DAG and MAG
lipophilic vitaminsformation
Apo B48
the blood stream
Chylomicrons = intestinal triglyceride-rich lipoproteins
Hussain et al., JLR 2003
Blood samples from a healthy young maleafter a heavy meal (1950 kcal)
Postprandial hyperlipidemia
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0 1.5 3 4.5 9 hours
Heeren and Beisiegel
Most of the day we are in the postprandial state!
Karpe et al., Atherosclerosis 1994
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
4The screen versions of these slides have full details of copyright and acknowledgements
Lipoprotein model
cholesterol esters
triglycerides
amphipatic ß sheet
10Löffler/Petrides/Heinen, Textbook on `Biochemie & Pathobiochemie‘; Springer publishing house
free cholesterol
phospholipids
amphipatic helices
Major lipoproteins and apoproteins
Intestinal derived chylomicrons - mainly apo B48
CR …. hydrolyzed in blood to chylomicron remnants
CMB-48
Liver derived very low density lipoproteins (VLDL) -B-
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y y p p ( )Apo B100 and apo EVLDL
E3100
LDL …. hydrolyzed in blood to low density lipoproteins (LDL)
Intestinal derived precursor of high density lipoproteins(HDL) – apo AI
HDL-precursor
…. matures in blood to HDL3 and HDL2HDL3 HDL2
Apo B100 and Apo B48 are derived from one gene
Apo B100 mRNA is edited by APOBEC1 to yield apo B48
Apo B100 receptor binding site
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p
COOH
COOHNH3
NH3
Apo B48no receptor binding
Davidson et al., Annu Rev Nutr 2000
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
5The screen versions of these slides have full details of copyright and acknowledgements
oral fat intake
Postprandial lipoprotein metabolism
E
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CM
LipoproteinLipase
B-48
Beisiegel et al., PNAS 1991Heeren J et al., J Mol Med 2002
HDL
CRE
E
CRE
oral fat intake
Insulin as major postprandial hormone
Insulin
+
muscle
adipose tissue
14CR
LipoproteinLipase
CM
CR
fatty acids
EE
Sadur et al., JCI 1982
Metabolism of adipose tissue
Uptake of fatty acids
FATP1
Anabolic:Leptin
Insulin effects
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Free fatty acidrelease
HSL
Catabolic:
TNFα and IL-6
Glucagon and adrenalin effects
Trujillo ME and Scherer PE, Endocrine Reviews 2006
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
6The screen versions of these slides have full details of copyright and acknowledgements
oral fat intakeoral fat intake
Nutritional lipids are also delivered to the bone
Intestinal synthesisof chylomicrons
hepatic clearance
Hussain MM et a., JBC 1989Niemeier et al., J Bone Miner Res 2005
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CR ECR ECR ECR E
CM
LipoproteinLipase
Fatty acids
MuscleAdipose tissue
CR ECR ECR ECR E
EEEECM
EEEE
oral fat intake
Chylomicron remnants deliver Lipids and vitamin K to the bone
The vitamin K-dependent carboxylation of osteocalcin is necessary for bone formation
17CR
CM
CR EE
Niemeier et al., Bone 2008
Vit K
Vit K
Vit K
LRP1
1. Postprandial lipid metabolism
2. Hepatic lipid metabolism
3. Cellular cholesterol homoeostasis
Lipid metabolism
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4. Reverse cholesterol transport
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
7The screen versions of these slides have full details of copyright and acknowledgements
Hepatic lipid metabolism:what are the receptors responsible for CR uptake?
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E
CR
E?
Beisiegel et al., Nature 1989Rohlmann et al., JCI 1998
LDLR class A repeat
EGF like modules
β-propeller
O-linked sugar domain
LRP1I
II
NH2
α-su
buni
t
LDLR
Hepatic receptors for lipoprotein uptake
LDL Receptor
LDL Receptor-Related Protein 1
20COOH
NPXY
NPXY
III
IV
β-su
buni
t
NH2
COOH
NPXY
LDLR
EGF precursorhomology domain
ligand bindingdomain
O-linked sugar domain
Transmembrane domain
cytosolicdomain
Heeren and Beisiegel 2008
Beisiegel et al., Nature 1989Rohlmann et al., JCI 1998Lillis et al., Physiol Rev 2008
CR uptake into the liver
LRP1 Insulin
LRP1
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CRE
CRE
LDLR
CRE
Insulin
Laatsch et al., Atherosclerosis 2008
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
8The screen versions of these slides have full details of copyright and acknowledgements
Hepatic lipoprotein pathways
CM
B-48
VLDLE3
B-100
LRP1
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LipoproteinLipase
CRE3
B-48
IDL E3B-100
LDL
B-100
LDLR
Lipases
Peripheral Tissue
LDLR
Apo E
Normal hepatic VLDL IDL
LPLApo CII
LPLApo CIIINormal LDL
HL
Size of VLDL determines LDL size
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Apo B 100 FFA Apo B 100
Apo B 100
Apo E
Large VLDL IDL
LPLApo CII
LPL
FFA
Apo CIII
Apo B 100
HLSmall dense LDL
Berneis et al., JLR 2002 Packard CJ, Curr Opinion Lipidol 2006
Role of apo E in lipoprotein catabolism
CMB-48
VLDLE3
B-100
LRP1
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LipoproteinLipase
CR
IDL LDL
E3
E3
B-48
B-100 B-100
LDLR
Schaefer et al., JCI 1986
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
9The screen versions of these slides have full details of copyright and acknowledgements
H2N
Apo E polymorphism
ApoE3 (frequency 0.77)
Cys112 Arg158
COOH
Receptor Binding Domain
ApoE2 (freq enc 0 08)
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ApoE2 (frequency 0.08)
H2N
Cys112 Cys158
COOH
• reduced binding to LDL-Receptor• associated with Typ-III HLP
ApoE4 (frequency 0.15)
H2N
Arg112 Arg158
COOH
• associated with hyperlipidemia and coronary heart disease
Utermann et al., Hum Genet 1982Bennet et al., JAMA 2007
1. Postprandial lipid metabolism
2. Hepatic lipid metabolism
3. Cellular cholesterol homoeostasis
Lipid metabolism
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4. Reverse cholesterol transport
LDL receptor involved in cellular cholesterol homeostasis
Nobel Prize 1985 to J.L. Goldstein and M.S. Brown
NH2
LDLR
ligand bindingdomain
27Heeren and Beisiegel 2008
Brown and Goldstein, Science 1986
COOH
NPXY
EGF precursorhomology domain
O-linked sugar domain
cytosolicdomain
Transmembrane domain
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
10The screen versions of these slides have full details of copyright and acknowledgements
Intracellular cholesterol regulated gene expression
LDL Cholesterin
3. LDL-Receptor Synthesis ↓
LDL Receptor
1. Cholesterol-
2. Cholesterol Synthesis ↓HMG-CoA Reductase
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LDL Cholesterin
ACAT= Acyl-Cholesterin-Acyl-TransferaseSREBP = Sterol regulated element binding protein
Storage ↑ACAT
Free intracellular cholesterol regulates synthesis, storage and uptake of cholesterol via regulating the expression of the genes for HMG CoA reductase, ACAT and LDL-receptor
Goldstein and Brown, Science 1986*Brown and Goldstein, PNAS 1999*Gong Y et al., PNAS 2006
Cholesterol acts via the SREBP*
1. Postprandial lipid metabolism
2. Hepatic lipid metabolism
3. Cellular cholesterol homoeostasis
Lipid metabolism
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3. Cellular cholesterol homoeostasis
4. Reverse cholesterol transport
‘Reverse cholesterol transport‘ by HDL
PeripherySR-B1
HDL2
Apo AI
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Cholesterol
ABCA1
Von Eckardstein A et al., ATVB 2000
HDL-precursorApo AI
HDL3
Apo AI
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
11The screen versions of these slides have full details of copyright and acknowledgements
Lipid exchange proteins
HDL-precursor
PeripheryHDL2
SR-B1
LCAT
CE
Cholesterol
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PLTP
VLDL orChylomicrons
HDL3
Von Eckardstein A et al.,ATVB 2000
CETP
▲ Cholesterol
TriglyceridesPhospholipids
PLTP = phospholipid transfer proteinCETP= cholesterol ester transfer protein
Total cholesterol < 200 < 200
LDL- cholesterol < 130 < 130
Fasting Postprandial
In mg/dl; generalized from several international recommendations
Normal levels for plasmalipids
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LDL- cholesterol < 130 < 130
HDL- cholesterol > 40 > 40
Total triglycerides < 150 < 300
... relates to primary prevention and is not differentiated for gender
Dietary lipids
33Nordestgaard et al., JAMA 2007
Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel
12The screen versions of these slides have full details of copyright and acknowledgements
Thank you very much for listening!
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