Basics of Lipid andLipoprotein Metabolism

John R. Guyton, M.D.Associate Professor of Medicine

Duke UniversityDurham, NC

Lipid Structure

HO

Cholesterol

COOH

COOH

COOH

HO

HO

HO

+

Fatty Acids

Glycerol

COO

COO

COO

Triglycerides

COO

COO

OPOON

Phospholipid: Lecithin

+

HMG CoA Reductase(More Than Cholesterol Synthesis)

Acetyl CoA

HMG CoA

Mevalonate

Farnesyl Pyrophosphate

Cholesterol

HMG CoA ReductaseIsopentenyl

adenine(transfer RNA)

Prenylation ofsignalling peptides(ras, rho, etc.)

Ubiquinones(CoQ-10, etc.)Dolichols

Inhibition of other key products of mevalonate may relate tononlipid effects & rare side effects of statins.

NORMAL CHOLESTEROL METABOLISM

Tissuepools70G

0.8 GSYN CHOL*

*SYN CHOL = CHOLESTEROL SYNTHESIS

0.4 G CHOL

NORMAL CHOLESTEROL METABOLISM

Tissuepools70G

.65 G

.20 G

.20 G CHOL 0.65 G CHOL

0.85 GABS CHOL

50%

0.4 G CHOL

0.8 GSYN CHOL*

*SYN CHOL = CHOLESTEROL SYNTHESIS

1.3 GCHOL

Key concepts: synthesis– Primary synthetic sites are extrahepatic, but liver

is key regulator of homeostasis

Key concepts: absorption– Largest source is biliary secretion, not diet.– Normal absorption: 50%– For cholesterol to be absorbed it must:

• undergo hydrolysis (de-esterification by esterases)

• be incorporated into micelles

• be taken up by cholesterol transporter

• be re-esterified and incorporated into chylomicrons

NORMAL CHOLESTEROL METABOLISM

400 mg/day

1,300 mg/day

NORMAL CHOLESTEROL ABSORPTION

Oil phase

400 mg/day

1,300 mg/day

17,400 mg/day

NORMAL CHOLESTEROL ABSORPTION

Plant sterols competeFor cholesterol here

Oil phase

STRUCTURE OF PLANT STEROL ESTERS

HO

Cholesterol

Sitosterol

HO

O

C - O

Sitosterol Ester

400 mg/day

1,300 mg/day

17,400 mg/day

850 mg/day

NORMAL CHOLESTEROL ABSORPTION

Ezetimibe competesFor cholesterol here

Oil phase

400 mg/day

1,300 mg/day

17,400 mg/day

850 mg/day

NORMAL CHOLESTEROL ABSORPTION

Defect in ABCG5/G8transporter causesphytosterolemia

Oil phase

Role of Bile Salts, cholesterol, phospholipids in gall stone formation.

Importance of Bile Salts for cholesterol absorption

NORMAL CHOLESTEROL METABOLISM

Key concepts: bile salt absorption inhibitors– Bile acid binding compounds:

• Welchol

• Cholestyramine

• Colestipol

• Fiber

– Surgery: Partial ileal bypass.

Bile Acid Synthesis

HO

Cholesterol

OH

OH

OH

COOH

OH OH

COOH

OH

COOH

OH

OH

COOH

ChenodeoxycholicAcid

LithocholicAcid

CholicAcid

DeoxycholicAcid

NORMAL CHOLESTEROL METABOLISM

Tissuepools70G

0.8 GSYN CHOL

.65 G

.20 G

0.85 GABS CHOL

50%

0.4 G CHOL

1.3 GCHOL

.20 G CHOL 0.65 G CHOL

17 GBA*

NORMAL CHOLESTEROL METABOLISM

Tissuepools70G

0.8 GSYN CHOL

17.35 GBA*

0.85 GABS CHOL

0.35 G BA*

.35 G

.65 G

.20 G

1.20 GCHOL + BA

50% 95%

0.4 G CHOL

1.3 GCHOL

* BA = BILE ACIDS

.20 G CHOL 0.65 G CHOL

Key concepts: absorption– Triglyceride (i.e. energy) assimilation is key to

the survival of the organism.– Dietary triglyceride must be hydrolyzed to fatty

acids, mono-glycerides and glycerol prior to absorption.

– Fatty acids must partition to micellar phase for absorption.

– For transport, triglyceride must be reconstituted from glycerol and fatty acid and incorporated into chylomicrons.

NORMAL TRIGLYCERIDE METABOLISM

Structures of Fatty Acids

CHO

O

CHO

O

CHO

O

CHO

O

CHO

O

18:0

cis-18:1 -6

trans-18:1 -6

18:2 -6

18:3 -3

Structures of Fatty Acids

CHO

O

CHO

O

CHO

O

CHO

O

CHO

O

16:0 (palmitic)

cis-18:1 -6 (oleic)

trans-18:1 -6 (elaidic)

18:2 -6 (linoleic)

18:3 -3(alpha linolenic)

CHO

O 20:5 -3 (EPA)

FATTYACIDS

(ALBUMIN)

TG (VLDL)

TG (CHYLO-MICRONS)

LIPO-PROTEINLIPASE

Fatty Acid and Triglyceride Flux

PlasmaTriglyceride

(VLDL)

Dietary Carbohydrate Increases VLDL Production

DietaryCarbohydrate

Effect of Carbohydrate Restriction on Carbohydrate-induced Hypertriglyceridemia

0

500

1000

1500

2000

2500

3000

Initial Level End of Fast Inpatient LowCHO Diet

OutpatientLow CHO Diet

Reisell et al., Am J Clin Nutr 1966;19:84

Treatment: Fast for average 5 days, then consume low CHO diet.

Compositionof diet:

7-15% CHO25-30% Prot60-65% Fat

Lipoprotein Metabolism

Cholesterol Ester Synthesis

HO

Cholesterol

COOH

COO

COO

OPOON+

CholesterolEster

COO

COO

COO

OPOON+

Lysolecithin

Lecithin-Cholesterol Acyl Transferase (LCAT)

Acyl-Cholesterol Acyl Transferase (ACAT)

Lipoproteins:Separation by –

Electrophoresis

Density

Size by Electron Microscopy

Pancreatic Lipase Movement

Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

Most pancreatic lipase is secreted into the pancreatic duct, but some moves back into capillaries.

Chylomicron Role in Pancreatitis

Pancreatic lipase actson chylomicrons adherent to capillaryendothelium, producingfatty acid anions, or soaps. By detergentaction, cell membranesare disrupted, releasingmore lipase, and additional fatty acidanions are produced ina vicious cycle.

Pancreatic lipase actson chylomicrons adherent to capillaryendothelium, producingfatty acid anions, or soaps. By detergentaction, cell membranesare disrupted, releasingmore lipase, and additional fatty acidanions are produced ina vicious cycle.

Apolipoproteins

B/E receptor ligand *E2:IDL; *E4: Diet ResponsivityapoE

LpL inhibitor; antagonizes apoEapoC-III

LpL activatorapoC-II

Inhibit Lp binding to LDL R; LCAT activatorapoC-I

apoB-48

Structural protein of all LP except HDL

Binding to LDL receptor

apoB-100

Tg metabolism; LCAT activator; diet responseapoA-IV

HL activationapoA-II

HDL structural protein; LCAT activator;RCTapoA-I

Metabolic RelationshipsAmong Lipoproteins

LDL

1.

3.2.

LipoproteinLipase`

TG

HDL

VLDL

TRIGLYCERIDES

HDLSMALL

DENSE LDL

Role of CETP in Triglyceride/Cholesteryl Ester Exchange

VLDL CETP HDL

TG

CE

LDLCETPHDL

TG

CE

Role of Triglycerides in Producing Small Dense LDL or HDL

TGTG TG

CE CE CECETP Lipase

1. CE exchanged for TG 2. TG removed

FREE FATTYACIDS

Dyslipidemia of Metabolic Syndrome

VLDL CETP

TG

CE

HDL LDLCETP

TG

CE

LIPASEsdLDL

FATTY ACIDSGLYCEROL

HDL CATABOLISM

UNINHIBITEDLYPOLYSIS

Distribution of LDL Size Phenotypes According to Triglyceride Levels

01020304050

60708090

100

0 50 100 150 200 250 300

Phenotype A(light fluffy LDL)

Phenotype B(small dense LDL)

Cum

ulat

ive

perc

ent o

f ca

ses

Triglyceride (mg/dl)

Austin et al, Circulation 1990; 82:495

Peroxisome Proliferator-Activated Receptor:

A Nuclear Receptor for Metabolic Genes

a, Basic mechanism of action of nuclear hormone receptors: bind to a specific sequence in the promoter of target genes (called hormone response elements), and activate transcription upon binding of ligand. Several nuclear hormone receptors, includingthe retinoic acid receptor, the vitamin D receptor and PPAR, can bind to DNA only as a heterodimer with the retinoid X receptor, RXR, as shown. b, some PPAR and PPAR ligands.

Kersten et al. Roles of PPARs in health and disease. Nature 2000; 405: 421-424

Role of PPAR* and in VLDL, LDL

and HDL metabolism

* Peroxisome Proliferator Activated Receptor

PPAR Tissues: Liver, kidney, heart,muscle.Ligands: fatty acids, fibrates

Actions: Stimulate productionof apo A I, lipoprotein lipase,increase expression of ABC A-1, increase FFA uptake andcatabolism, decrease FFAand VLDL synthesis.

PPAR Tissues: Adipose tissue andintestine.Ligands: arachidonic acid, GlitazonesActions: increase expression ofABC A-1, increase FFA synthesisand uptake by adipocytes, increaseinsulin sensitivity (?)

HDL and Reverse Cholesterol Transport

HDL and Reverse Cholesterol Transport

Tangier DiseaseTangier Disease

HDL and Reverse Cholesterol Transport

HDL and Reverse Cholesterol Transport

HDL and Reverse Cholesterol Transport

LDL-R

HDL and Reverse Cholesterol Transport

LDL-R

50% of HDL C mayReturn to the liverOn LDL via CETP

HDL and Reverse Cholesterol Transport

• An atherogenic lipoproteincontaining apo(a) and apoB.

• 20-30% of people have levelssuggesting C-V risk.

• Black subjects have Lp(a)normal range twice as highas white and Asiatic subjects.

• Apo(a) sequence similar to plasminogen, and Lp(a)interferes with spontaneous thrombolysis.

• Lp(a) levels highly genetic, resistant to diet and drugtherapy, although niacin may help.

““LDL”LDL”

Apo(a)Apo(a)

-S-S--S-S-

Lipoprotein(a), or Lp(a)

Summary – Lipid and Lipoprotein Metabolism

• Cholesterol absorption, synthesis, and disposition

• Triglyceride/fatty acid transformations and energy metabolism

• Lipoprotein core and surface components• Lipoprotein origins and destinations governed

by apo’s• Derangement in the metabolic syndrome• Reverse cholesterol transport – the dominant

direction• Lipoprotein(a)• Lipoproteins in the arterial wall