Pathophysiology of lipid metabolismp y gy p

• Major plasma lipids are:Major plasma lipids are:– Cholesterol

Triglycerides– Triglycerides– Fatty acids

Cholesterol Essential component of cell membranesRequired for biosynthesis of hormones

progesterone, cortisol, testosterone, estradiolAbsorbed through lumen of the gut, also secreted back to intestine as component of bile In addition to dietary sources, cholesterol is also synthesized by body tissues - liver

Cholesterol Synthesis Essential during active growth or when dietary intake is limited Increases with a high-energy diet and in obesityEnzyme responsible (HMG-CoA reductase) can be inhibited

down-regulated when tissues are supplied with cholesterol in abundancesite of action for “statin” drugs

TriglyceridesIdeal means of energy storageStored in fat cells: Adipose cell is made up of a rim of cytoplasm around a central droplet of energy-rich triglyceride Light in weight relative to energy content when compared to glycogen stores in liver or muscleTriglycerides stored in fat around internal organs serve as “cushions” and also provide layer of insulation

Fatty AcidsTriglycerides are synthesized from fatty acids (circulating or from glucose)Enzyme lipoprotein lipase causes fatty acids to be released from glycerol (to which they are bound in the stored triglycerides)Free fatty acids bind to serum albumin

used as fuel/energy for muscle activityresynthesized and stored as a fuel source in adipocytestaken up by the liver or resynthesized back into triglycerides

What are Lipoproteins?Cholesterol and triglycerides are insoluble, therefore are transported by lipoproteinsPolar surface of phospholipd allows lipoproteins to travel in aqueous environmentsLipoproteins are complex molecules that carry dietary and stored fat in plasma

triglyceride - rich (chylomicrons, VLDL-C)cholesterol - rich (LDL-C, HDL-C)

Each class varies in size, weight, lipid composition, density, apolipoprotein content

What are Apolipoproteins?Proteins associated with lipoproteinsInvolved in:

secretion of lipoproteinsstructural integrity of lipoproteinco-activate enzyme reactions necessary for lipoprotein processing facilitate receptor-mediated uptake of lipoproteins and remnants

Size & Density of Particles

Lipoprotein Source Major LipidComponent Apolipoproteins

Chylomicrons Intestine TG A-I, A-II, A-IV, Cs,B-48, E

Very low densitylipoprotein(VLDL)

Liver TG B-100, Cs, E

Intermediatedensitylipoprotein (IDL)

Catabolism of VLDL CE B-100, Cs, E

Low densitylipoprotein (LDL) Catabolism of IDL CE B-100

High densitylipoprotein (HDL)

Liver, intestine,other CE, PL A-I, A-II, A-IV, C-I,

C-II, C-III, DTG=triglyceride; CE=cholesteryl ester; PL=phospholipid

Lipoprotein Classification

Lipoprotein Classification

ChylomicronsLargest lipoprotein particle

Produced in gut following absorption of digested fat

Triglyceride-rich particle

Hydrolyzed by lipoprotein lipase

Remnant particles removed by apoE receptors

VLDL-CholesterolFatty acids bound to albumin in plasma are taken up by the liver and packaged into VLDL particles

Triglyceride-rich particle

Undergoes hydrolysis by lipoprotein lipase to render IDL

About half of IDL is converted to LDL by hepatic lipase; remaining IDL is taken up by liver

LDL-CholesterolSmall enough to cross the capillary endothelium - the most atherogenic lipoprotein

LDL receptors migrate to cell surface to attract LDL

Heterogeneity in particle composition arises from differences in the amount of cholesterol per particle (small, dense LDL (“B”) vs. buoyant LDL (“A”)

HDL-CholesterolReceives excess chol from tissues and transfers to liver LCAT increases the capacity of HDL to receive cholesterolThe esterification of free cholesterol into cholesteryl ester produces a more hydrophobic core - enhances HDL densityCETP mediates transfer of cholesterol ester form HDL core between HDL and other lipoproteins

Apolipoproteins - ExamplesApoE (E2, E3, E4)

mediates uptake of remnant particles, either chylomicron remnants or VLDL (or IDL) remnants

ApoB-100present in VLDL and LDL - acts as ligand for the LDL receptor

ApoB-48found in chylomicrons and intestinal cells; lipoproteins coming from intestinal metabolism have ApoB-48; hepatic lipoproteins have ApoB-100

Apolipoproteins - ExamplesApoC (CI, CII, CIII)

found on chylomicrons and VLDL particles. ApoCII activates lipoprotein lipase, catabolizing triglycerides. ApoCIII may inhibit action of lipoprotein lipase

ApoAIpresent in chylomicrons and HDL particles. Activates LCAT enzyme and provides structure to HDL particles

ApoAII present in chylomicrons and HDL particle. Activates hepatic lipase which results in HDL2 HDL3 nascent HDL

What about Lipoprotein(a)?Lp(a) consists of one LDL particle covalently bound to one or two molecules of apo(a)Structurally very similar to plasminogen -appears to have both atherogenic and thrombogenic propertiesAssociated with increased cardiovascular disease risk

Pathways of Lipid MetabolismExogenous

digestion and absorption of dietary fatEndogenous

cholesterol synthesis by the liver“Reverse” Cholesterol Transport

delivery of cholesterol from the tissues to the liver

4. Decrease synthesis

3.Receptor uptake of LDL & remnant particles

1.Rate limiting enzyme-HMGCoA

2.Fecal excretion of bile acids

5. Increase LPL activity

HDL Cholesterol Transport

Putting it all together…...

Primary DyslipidemiaAttributed to genetic causesPhysical manifestations of dyslipidemia important aspect of diagnosisMay only be expressed in the presence of exogenous or environmental factors (obesity, alcohol)Fredrickson Classification developed in the 1960’s

Fredrickson classification of h li id ihyperlipidemias

PhenotypeLipoprotein(s)

l t dPlasma

h l t lPlasma

TGAthero-

i itRel.f Treatmentyp

elevated cholesterol TGs genicity freq. Treatment

I Chylomicrons Norm. to ↑ ↑↑↑↑–

pancreatiti <1% Diet controls

IIa LDL ↑↑ Norm. +++ 10%Bile acid sequestrants, statins, niacinstatins, niacin

IIb LDL and VLDL ↑↑ ↑↑ +++ 40% Statins, niacin, fibrates

III IDL ↑↑ ↑↑↑ +++ <1% Fibrates

IV VLDL Norm. to ↑ ↑↑ + 45% Niacin, fibrates

VVLDL and

↑ to ↑↑ ↑↑↑↑

+

5% Niacin, fibratesVchylomicrons

↑ to ↑↑ ↑↑↑↑ pancreatitis

5% ,

Primary hypercholesterolemiasy yp

G ti Disorder

Genetic defect

Inheritance Prevalence Clinical features

heteroz.:1/500 premature CAD (ages 30–50) TC 7 13 MFamilial hyper-

cholesterolemia LDL receptor dominant5% of MIs <60 yr

homoz.: 1/1 million

50) TC: 7-13 mM

CAD before age 18

TC > 13 mM

Familial defectiveapo B-100

apo B-100 dominant 1/700premature CADTC: 7-13 mM

Polygenic multiple commonpremature CAD

hypercholesterolemia

defects and mechanisms

variable 10% of MIs <60 yr

premature CADTC: 6.5-9 mM

Familial hyper-alphalipoprotein unknown variable rare

less CHD, longer lifel d

alphalipoproteinemia

unknown variable rareelevated HDL

Primary hypertriglyceridemiasy yp g y

Disorder Genetic defect Inheritance Prevalence Clinical features

LPL deficiency endothelial LPL recessiverare

1/1 million

hepatosplenomegalyabd. cramps, pancreatitis

TG: > 8.5 mM

Apo C-II rare abd cramps pancreatitisApo C IIdeficiency

Apo C-II recessiverare

1/1 millionabd. cramps, pancreatitis

TG: > 8.5 mM

Familial hyper-t i l id i

unknownenhanced

h ti TGdominant 1/100

abd. cramps, pancreatitisTG 2 3 6 Mtriglyceridemia hepatic TG-

production

dominant 1/100TG: 2.3-6 mM

Primary mixed hyperlipidemiasy yp p

DisorderGenetic defect

Inheritance Prevalence Clinical features

Familial A EFamilial dysbeta-

lipoproteinemia

Apo E

high VLDL, chylo.

recessiverarely

dominant1/5000

premature CADTC: 6.5 -13 mM

TG: 2.8 – 5.6 mM

unknownFamilial

combined

unknown

high Apo B-100

dominant1/50 – 1/100

15% of MIs <60 yr

premature CADTC: 6.5 -13 mM

TG: 2.8 – 8.5 mM

Secondary DyslipidemiaPrimary disease affects lipid metabolism, increasing serum lipid concentrationsIncreases levels of circulating lipoproteins, but may also alter chemical and physical propertiesMay accelerate the progress of the primary disease (e.g. renal, liver disease)May increase morbidity and mortality (e.g. diabetes, renal disease)

Causes of Secondary Dyslipidemia…Endocrine

diabetesthyroid diseasepituitary diseasepregnancy

Renal nephrotic syndromechronic renal failure

Hepatic Cholestasis/ cholelithiasishepatocellular disease

Drugsß blockersthiazide diureticssteroid hormonesretinoic acid derivatives

NutitionalObesityalcohol

ImmunoglobulinmyelomaSLE

Secondary hyperlipidemiasy yp p

Disorder VLDL LDL HDL Mechanism

Diabetes mellitus ↑ ↑ ↑ ↑ ↓ VLDL production ↑,LPL ↓, altered LDL

Hypothyreosis ↑ ↑ ↑ ↑ ↓ LDL-rec.↓, LPL ↓

Obesity ↑ ↑ ↑ ↓ VLDL production ↑

Anorexia - ↑ ↑ - bile secretion ↓, LDL catab. ↓

Nephrotic sy ↑ ↑ ↑ ↑ ↑ ↓ Apo B-100 ↑ LPL ↓ LDL-rec ↓Nephrotic sy ↑ ↑ ↑ ↑ ↑ ↓ Apo B 100 ↑ LPL ↓ LDL rec. ↓

Uremia, dialysis ↑ ↑ ↑ - ↓ LPL ↓, HTGL ↓ (inhibitors ↑)

Pregnancy ↑ ↑ ↑ ↑ ↑ oestrogen ↑Pregnancy ↑ ↑ ↑ ↑ ↑ VLDL production ↑, LPL ↓

Biliary obstructionPBC - - ↓ Lp-X ↑ ↑

no CAD; xanthomas

↑ ↑Alcohol ↑ ↑chylomicr. ↑ - ↑ dep. on dose, diet, genetics

Many-many drugs Please allways see for adverse effects before any drug presciption!!!

Metabolic SyndromeRisk Factor Defining Level*

Abdominal ObesityWaist circ >102cm (men)Waist circ >88cm (women)

Triglyceride level > 1.7 mmol/L

HDL-Chol level< 1.0 mmol/L (men)< 1.3 mmol/L (women)

Blood Pressure > 130/85

Fasting Glucose Level 6.2 – 7.0 mmol/L

*Must have 3 or more

LDL Oxidation

High levels of LDL may result in higher levelsHigh levels of LDL may result in higher levelsof oxidized LDL in the sub-endothelial space• Scavenger Receptor (protein) on• Scavenger Receptor (protein) onmacrophages -binds to LDL particle that hasb difi dbeen modified• Monocytes and macrophages will function asPac-mans and clean cholesterols

Oxidation of LDL (oxLDL)( )

Oxidation = process by which free radicals (oxidants) attack /and damage target molecules / tissues

Targets of free radical attack: DNA - carbohydrates Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s

LDL can be oxidatively damaged: PUFA’s are oxidized and trigger oxidation of apoB100 protein --> oxLDL

OxLDL is engulfed by macrophages in subendothelial space

LDL Oxidation

High levels of LDL may result in higher levelsHigh levels of LDL may result in higher levelsof oxidized LDL in the sub-endothelial space• Scavenger Receptor (protein) on• Scavenger Receptor (protein) onmacrophages -binds to LDL particle that hasb difi dbeen modified• Monocytes and macrophages will function asPac-mans and clean cholesterols

Oxidation of LDL (oxLDL)( )

Oxidation = process by which free radicals (oxidants) attack /and damage target molecules / tissues

Targets of free radical attack: DNA - carbohydrates Proteins - PUFA’s>>> MUFA’s>>>>> SFA’s

LDL can be oxidatively damaged: PUFA’s are oxidized and trigger oxidation of apoB100 protein --> oxLDL

OxLDL is engulfed by macrophages in subendothelial space

Atherosclerosis

Atherosclerosis

A Healthy Endotheliumproduces:

PGI2PGI2NO

Maintaining anMaintaining ananti-coagulant, anti-thromboticsurface

A Dysfunctional Endotheliumhas decreased:

PGI2PGI2NO

Incpro-inflam

momo

TVCA

Shifting to a

VCA

pro-coagulant, pro-thrombotic surface

Endothelial dysfunction is one of earliest changes in y gASMechanical, chemical, inflammatory mediators can trigger endothelial dysfunction:

High blood pressure S ki (f di l h id i l d Smoking (free radicals that oxidatively damage endothelium)Elevated homocysteineeva ed o ocys e eInflammatory stimuliHyperlipidemia

Endothelial Dysfunction( endothelial activation, impaired ( , pendothelial-dependent vasodilation)

endothelial synthesis of PGI2 (prostacylcin), & NO y 2 (p y ),(nitric oxide)

PGI2 = vasodilator, platelet adhesion/aggregationNO = dil t l t l t & WBC ( t ) dh iNO = vasodilator, platelet & WBC (monocyte) adhesion

Adhesion of monocytes onto endothelium --> ytransmigration into subendothelial space (artery wall) --> change to macrophages

Endothelial dysfunction --> increased flux of LDL into artery wallartery wall

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atheroma

Atherosclerotic Plaqueq

Continued endothelial dysfunction (inflammatory response)Accumulation of oxLDL in macrophages (= foam cells) Migration and accumulation of:

h l llsmooth muscle cells, additional WBC’s (macrophages, T-lymphocytes)Calcific depositsChange in extracellular proteins, fibrous tissue formation

High risk = VLDL ( TG) LDL HDLHigh risk VLDL ( TG) LDL HDL