Lipid MetabolismProf. Dr. rer physiol. Dr.h.c. Ulrike Beisiegel

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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

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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

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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

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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

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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

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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

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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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