Pathophysiology of lipid metabolism p y gy p

• Major plasma lipids are:
– Cholesterol – Triglycerides – Fatty acids

Cholesterol
Essential component of cell membranes Required for biosynthesis of hormones
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
Essential during active growth or when dietary 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
Ideal means of energy storage Stored 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 muscle Triglycerides stored in fat around internal organs serve as “cushions” and also provide layer of insulation

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

What are Lipoproteins?
Cholesterol and triglycerides are insoluble, therefore 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
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 lipoproteins 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
Chylomicrons Very low density lipoprotein (VLDL) Intermediate density lipoprotein (IDL) Low density lipoprotein (LDL) High density lipoprotein (HDL)

Source
Intestine

Major Lipid Component
TG

Apolipoproteins
A-I, A-II, A-IV, Cs, B-48, E B-100, Cs, E

Liver

TG

Catabolism of VLDL

CE

B-100, Cs, E

Catabolism of IDL Liver, intestine, other

CE CE, PL

B-100 A-I, A-II, A-IV, C-I, C-II, C-III, D

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

Lipoprotein Classification

Chylomicrons
Largest lipoprotein particle Produced in gut following absorption of digested fat Triglyceride-rich particle Hydrolyzed by lipoprotein lipase Remnant particles removed by apoE receptors

VLDL-Cholesterol
Fatty 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-Cholesterol
Small 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-Cholesterol
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
ApoE (E2, E3, E4)
mediates uptake of remnant particles, either chylomicron remnants or VLDL (or IDL) remnants

ApoB-100
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
ApoC (CI, CII, CIII)
found on chylomicrons and VLDL particles. ApoCII activates lipoprotein lipase, catabolizing triglycerides. ApoCIII may inhibit action of lipoprotein lipase

ApoAI
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)?
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 properties Associated with increased cardiovascular disease risk

Pathways of Lipid Metabolism
Exogenous
digestion and absorption of dietary fat

Endogenous
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
Attributed to genetic causes Physical manifestations of dyslipidemia important 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 hyperlipidemias h li id i
Phenotype yp Plasma Plasma Lipoprotein(s) elevated l t d cholesterol h l t l TGs TG Atherogenicity i it Rel. freq. f Treatment

I

Chylomicrons Norm. to ↑

↑↑↑↑

– pancreatiti <1% Diet control s +++ +++ +++ + + Bile acid 10% sequestrants, statins, niacin 40% Statins, niacin, fibrates

IIa IIb III IV V

LDL LDL and VLDL IDL VLDL VLDL and chylomicrons

↑↑ ↑↑ ↑↑ Norm. to ↑ ↑ to ↑↑

Norm. ↑↑ ↑↑↑ ↑↑ ↑↑↑↑

<1% Fibrates 45% Niacin, fibrates 5% Niacin, fibrates ,

pancreatiti s

Primary hypercholesterolemias y yp
Disorder Genetic G ti defect Inheritance Prevalence Clinical features

Familial hypercholesterolemia LDL receptor

dominant

heteroz.:1/500 premature CAD (ages 30– 50) TC: 7-13 mM TC 7 13 M 5% of MIs <60 yr homoz.: 1/1 million 1/700 common 10% of MIs <60 yr rare CAD before age 18 TC > 13 mM premature CAD TC: 7-13 mM premature CAD TC: 6.5-9 mM less CHD, longer life elevated HDL l d

Familial defective apo B-100

apo B-100

dominant

Polygenic multiple hypercholestero defects and lemia mechanisms Familial hyperalphalipoprotein emia unknown

variable

variable

Primary hypertriglyceridemias y yp gy
Disorder Genetic defect Inheritance Prevalence Clinical features

LPL deficiency endothelial LPL Apo C-II C II deficiency Familial hypertriglyceridemia t i l id i

recessive

rare 1/1 million rare 1/1 million

hepatosplenomegaly abd. cramps, pancreatitis TG: > 8.5 mM abd. cramps abd cramps, pancreatitis TG: > 8.5 mM abd. cramps, pancreatitis TG: 2.3-6 M TG 2 3 6 mM

Apo C-II unknown enhanced hepatic TG h ti TGproduction

recessive

dominant

1/100

Primary mixed hyperlipidemias y yp p
Disorder Familial dysbetalipoproteinemi a Familial combined Genetic defect Apo E A high VLDL, chylo. unknown high Apo B100 dominant Inheritance Prevalence Clinical features

recessive rarely dominant

1/5000

premature CAD TC: 6.5 -13 mM TG: 2.8 – 5.6 mM premature CAD TC: 6.5 -13 mM TG: 2.8 – 8.5 mM

1/50 – 1/100 15% of MIs <60 yr

Secondary Dyslipidemia
Primary disease affects lipid metabolism, increasing 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…
Endocrine
diabetes thyroid disease pituitary disease pregnancy

Drugs
ß blockers thiazide diuretics steroid hormones retinoic acid derivatives

Renal
nephrotic syndrome chronic renal failure

Nutitional
Obesity alcohol

Hepatic
Cholestasis/ cholelithiasis hepatocellular disease

Immunoglobulin
myeloma SLE

Secondary hyperlipidemias y yp p
Disorder
Diabetes mellitus Hypothyreosis Obesity Anorexia Nephrotic sy Uremia, dialysis Pregnancy Biliary obstruction PBC Alcohol Many-many drugs

VLDL
↑↑↑ ↑ ↑↑ ↑↑ ↑↑↑ ↑↑

LDL
↑ ↑↑↑ ↑ ↑↑ ↑↑↑ ↑↑

HDL
↓ ↓ ↓ ↓ ↓ ↑

Mechanism
VLDL production ↑, LPL ↓, altered LDL LDL-rec.↓, LPL ↓ VLDL production ↑ bile secretion ↓, LDL catab. ↓ Apo B-100 ↑ LPL ↓ LDL-rec ↓ B 100 LDL rec. LPL ↓, HTGL ↓ (inhibitors ↑) oestrogen ↑ VLDL production ↑, LPL ↓ Lp-X ↑ ↑ no CAD; xanthomas dep. on dose, diet, genetics

↑↑ chylomicr. ↑

-

-

Please allways see for adverse effects before any drug presciption!!!

Metabolic Syndrome
Risk Factor Abdominal Obesity Triglyceride level HDL-Chol level Blood Pressure Fasting Glucose Level
*Must have 3 or more

Defining Level* Waist circ >102cm (men) Waist circ >88cm (women) > 1.7 mmol/L < 1.0 mmol/L (men) < 1.3 mmol/L (women) > 130/85 6.2 – 7.0 mmol/L

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 been modified b 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 been modified b 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:

PGI2 NO

Maintaining an anti-coagulant, anti-thrombotic surface

A Dysfunctional Endothelium has decreased:

PGI2 NO

Inc pro-inflam mo

T VCA
Shifting to a pro-coagulant, pro-thrombotic surface

Endothelial dysfunction is one of earliest changes in y g AS Mechanical, chemical, inflammatory mediators can trigger endothelial dysfunction:
High blood pressure Smoking (free radicals that oxidatively d S ki (f di l h id i l damage endothelium) Elevated homocysteine eva ed o ocys e e Inflammatory stimuli Hyperlipidemia

Endothelial Dysfunction
( endothelial activation, impaired , p endothelial-dependent vasodilation)
PGI2 = vasodilator, platelet adhesion/aggregation NO = vasodilator, platelet & WBC ( dil t l t l t (monocyte) adhesion t ) dh i

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

Adhesion of monocytes onto endothelium --> y 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:
smooth muscle cells, h l ll additional WBC’s (macrophages, T-lymphocytes) Calcific deposits Change in extracellular proteins, fibrous tissue formation

High risk =

VLDL ( TG)

LDL

HDL

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