Pathophysio Of Lipid Metabolism

Pathophysiology p y gy of lipid p metabolism • Major plasma lipids are: – Cholesterol – Triglycerides – Fatty acids

Cholesterol ƒ Essential component of cell membranes ƒ Required for biosynthesis of hormones „

ƒ ƒ

progesterone, cortisol, testosterone, estradiol

Absorbed 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 ƒ Essential during active growth or when dietary

ƒ ƒ

intake is limited Increases with a high-energy diet and in obesity Enzyme responsible (HMG-CoA reductase) can be inhibited „ „

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

Triglycerides ƒ Ideal means of energy storage ƒ Stored in fat cells: Adipose cell is made up of a rim

ƒ ƒ

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 muscle Triglycerides stored in fat around internal organs serve as “cushions” and also provide layer of insulation

Fatty Acids ƒ Triglycerides are synthesized from fatty acids

ƒ ƒ

(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 activity resynthesized and stored as a fuel source in adipocytes taken up by the liver or resynthesized back into triglycerides

What are Lipoproteins? ƒ Cholesterol and triglycerides are insoluble, therefore

ƒ ƒ

are transported by lipoproteins Polar surface of phospholipd allows lipoproteins to travel in aqueous environments Lipoproteins are complex molecules that carry dietary and stored fat in plasma „ „

ƒ

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? ƒ Proteins associated with lipoproteins ƒ Involved in: „ „ „ „

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

Size & Density of Particles

Lipoprotein Classification Lipoprotein

Source

Major Lipid Component

Apolipoproteins

Chylomicrons

Intestine

TG

A-I, A-II, A-IV, Cs, B-48, E

Very low density lipoprotein (VLDL)

Liver

TG

B-100, Cs, E

Intermediate density lipoprotein (IDL)

Catabolism of VLDL

CE

B-100, Cs, E

Low density lipoprotein (LDL)

Catabolism of IDL

CE

B-100

High density lipoprotein (HDL)

Liver, intestine, other

CE, PL

TG=triglyceride; CE=cholesteryl ester; PL=phospholipid

A-I, A-II, A-IV, C-I, C-II, C-III, D

Lipoprotein Classification

Chylomicrons ƒ ƒ

Largest lipoprotein particle

ƒ ƒ

Triglyceride-rich particle

ƒ

Remnant particles removed by apoE receptors

Produced in gut following absorption of digested fat Hydrolyzed by lipoprotein lipase

VLDL-Cholesterol ƒ

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

ƒ ƒ

Triglyceride-rich particle

ƒ

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

Undergoes hydrolysis by lipoprotein lipase to render IDL

LDL-Cholesterol ƒ

Small enough to cross the capillary endothelium - the most atherogenic lipoprotein

ƒ

LDL receptors migrate to cell surface to attract LDL

ƒ

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

HDL-Cholesterol ƒ ƒ ƒ ƒ

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

Apolipoproteins - Examples ƒ ApoE (E2, E3, E4) „

ƒ

ApoB-100 „

ƒ

mediates uptake of remnant particles, either chylomicron remnants or VLDL (or IDL) remnants present in VLDL and LDL - acts as ligand for the LDL receptor

ApoB-48 „

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

Apolipoproteins - Examples ƒ ApoC (CI, CII, CIII) „

ƒ

ApoAI „

ƒ

found on chylomicrons and VLDL particles. ApoCII activates lipoprotein lipase, catabolizing triglycerides. ApoCIII may inhibit action of lipoprotein lipase present 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)? ƒ Lp(a) consists of one LDL particle covalently bound

ƒ ƒ

to one or two molecules of apo(a) Structurally very similar to plasminogen -appears to have both atherogenic and thrombogenic properties Associated with increased cardiovascular disease risk

Pathways of Lipid Metabolism ƒ Exogenous „

ƒ

Endogenous „

ƒ

digestion and absorption of dietary fat cholesterol synthesis by the liver

“Reverse” Cholesterol Transport „

delivery of cholesterol from the tissues to the liver

4. Decrease synthesis

5. Increase LPL activity

3.Receptor uptake of LDL & remnant particles 1.Rate limiting enzyme-HMGCoA

2.Fecal excretion of bile acids

HDL Cholesterol Transport

Putting it all together…...

Primary Dyslipidemia ƒ Attributed to genetic causes ƒ Physical manifestations of dyslipidemia important

ƒ ƒ

aspect of diagnosis May only be expressed in the presence of exogenous or environmental factors (obesity, alcohol) Fredrickson Classification developed in the 1960’s

Fredrickson classification of h hyperlipidemias li id i Phenotype yp

I

Plasma Plasma Lipoprotein(s) elevated l t d cholesterol h l t l TG TGs

Chylomicrons Norm. to ↑

↑↑↑↑

Atherogenicity i it

Rel. f freq.

Treatment

– pancreatiti <1% Diet control s

IIa

LDL

↑↑

Norm.

+++

Bile acid 10% sequestrants, statins, niacin

IIb

LDL and VLDL

↑↑

↑↑

+++

40%

III

IDL

↑↑

↑↑↑

+++

<1% Fibrates

IV

VLDL

Norm. to ↑

↑↑

+

V

VLDL and chylomicrons

45% Niacin, fibrates

+ ↑ to ↑↑

↑↑↑↑

pancreatiti s

Statins, niacin, fibrates

5%

Niacin,, fibrates

Primary y hypercholesterolemias yp Disorder

Genetic G ti defect

Familial hypercholesterolemia LDL receptor

Familial defective apo B-100

Inheritance

dominant

Prevalence

Clinical features

heteroz.:1/500 premature CAD (ages 30– 50) TC: TC 7-13 7 13 mM M 5% of MIs <60 yr homoz.: 1/1 million

CAD before age 18 TC > 13 mM

dominant

1/700

premature CAD TC: 7-13 mM

Polygenic multiple hypercholestero defects and lemia mechanisms

variable

common 10% of MIs <60 yr

premature CAD TC: 6.5-9 mM

Familial hyperalphalipoprotein emia

variable

rare

less CHD, longer life elevated l d HDL

apo B-100

unknown

Primary y hypertriglyceridemias yp gy Disorder

Genetic defect Inheritance

LPL deficiency endothelial LPL

Prevalence

Clinical features

recessive

rare 1/1 million

hepatosplenomegaly abd. cramps, pancreatitis TG: > 8.5 mM

Apo C C-II II deficiency

Apo C-II

recessive

rare 1/1 million

abd cramps, abd. cramps pancreatitis TG: > 8.5 mM

Familial hypert i l triglyceridemia id i

unknown enhanced h hepatic ti TG TGproduction

dominant

1/100

abd. cramps, pancreatitis TG 2 TG: 2.3-6 3 6 mM M

Primary y mixed hyperlipidemias yp p Disorder Familial dysbetalipoproteinemi a Familial combined

Genetic defect A Apo E high VLDL, chylo.

Inheritance

Prevalence

Clinical features

recessive rarely dominant

1/5000

premature CAD TC: 6.5 -13 mM TG: 2.8 – 5.6 mM

dominant

1/50 – 1/100 15% of MIs <60 yr

premature CAD TC: 6.5 -13 mM TG: 2.8 – 8.5 mM

unknown high Apo B100

Secondary Dyslipidemia ƒ Primary disease affects lipid metabolism, increasing

ƒ ƒ ƒ

serum lipid concentrations Increases levels of circulating lipoproteins, but may also alter chemical and physical properties May 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… ƒ

Endocrine „ „ „ „

ƒ

„

ƒ

diabetes thyroid disease pituitary disease pregnancy

Renal „

„

Cholestasis/ cholelithiasis hepatocellular disease

Drugs „ „ „ „

ƒ

nephrotic syndrome chronic renal failure

Hepatic „

ƒ

Nutitional „ „

ƒ

ß blockers thiazide diuretics steroid hormones retinoic acid derivatives Obesity alcohol

Immunoglobulin „ „

myeloma SLE

Secondary y hyperlipidemias 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 B 100 ↑ LPL ↓ LDL LDL-rec rec. ↓

Uremia, dialysis

↑↑↑

-

↓

LPL ↓, HTGL ↓ (inhibitors ↑)

Pregnancy

↑↑

↑↑

↑

oestrogen ↑ VLDL production ↑, LPL ↓

Biliary obstruction PBC

-

-

↓

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 Syndrome Risk Factor

Defining Level*

Abdominal Obesity

Waist 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 levels of oxidized LDL in the sub-endothelial space • Scavenger Receptor (protein) on macrophages -binds to LDL particle that has b been modified difi d • Monocytes and macrophages will function as Pac-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 Proteins

- carbohydrates - 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 levels of oxidized LDL in the sub-endothelial space • Scavenger Receptor (protein) on macrophages -binds to LDL particle that has b been modified difi d • Monocytes and macrophages will function as Pac-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 Proteins

- carbohydrates - 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 Endothelium produces:

Ç PGI2 Ç NO

Maintaining an anti-coagulant, anti-thrombotic surface

A Dysfunctional Endothelium has decreased:

È PGI2 È NO

Inc pro-inflam mo Ç

ÇT ÇVCA Shifting to a pro-coagulant, pro-thrombotic surface

…

…

Endothelial dysfunction y is one of earliest changes g in AS Mechanical, chemical, inflammatory mediators can trigger endothelial dysfunction: † High

blood pressure † Smoking S ki (f (free radicals di l that h oxidatively id i l damage d endothelium) † Elevated eva ed homocysteine o ocys e e † Inflammatory stimuli † Hyperlipidemia

Endothelial Dysfunction ( endothelial activation,, impaired p endothelial-dependent vasodilation) …

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

…

…

PGI2 = vasodilator, Èplatelet adhesion/aggregation NO = vasodilator, dil t Èplatelet È l t l t & WBC (monocyte) ( t ) adhesion dh i

Ç Adhesion of monocytes y onto endothelium --> transmigration into subendothelial space (artery wall) --> change to macrophages Endothelial dysfunction --> increased flux of LDL into artery wall

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atherosclerosis

Atheroma

Atherosclerotic Plaque q … … …

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

…

smoothh muscle l cells, ll additional WBC’s (macrophages, T-lymphocytes) Calcific deposits Change in extracellular proteins, fibrous tissue formation

High risk = Ç VLDL (ÇTG)

Ç LDL

È HDL