8/8/2019 Lipids-2 Mechanisms of Atherosclerosis and beyond

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2 Mechanisms of Atherosclerosis

Chronic Endothelial Injury Elevated Lipids

Endothelium (epithelial lining of blood vessels (damaged byvarious mechanisms-----smoking, hypertension, microbialinfection drugs etc

Increased adhesion of platelets and the chemotaxis of monocytes and T lymphocytes to the site of injury---migrationof smooth muscle cells---plaque formation (“fatty”) plaquecells loaded with lipids)

Elevation of plasma LDL levels results in penetration of LDL into the arterialwall---lipid accumulation in smooth muscle cells and local macrophages (fatty streak)

Plaque becomes “fibrous”

Oxidized LDL---chemotactic---migration of monocytes---inflammatory lesion

Oxidized LDL---also cytotoxic to endothelial cells; loses its ability to removecholesterol from atherosclerotic plaques

Risk Factors for CADLipids Levels Hypertension Smoking Diabetes Mellitus

Elevated levels of LDL, Lp(a)and reduced levels of HDL

Associated withendothelial damage

Provides initial lesions intowhich inflammatory cellsinfiltrate

If LDL levels are elevated,fatty streak begins toform

Increases the risk of CAD and peripheralartery disease

Nicotine and other tobacco-derivedchemicals are toxic to vascular endothelium

Smoking---increases LDL, decrerases HDLlevels, raises blood carbon monoxide(produces endothelial hypoxia), promotevasoconstriction, increases plateletthrombus formation, and increases plasmafibrinogen concentration

Promotes formation of peroxides

Hyperinsulinemia---damagesvascular endothelium

Obesity Homocysteine Oxidative Stress

Hypertriglyceridemiacommonly associated withobesity

A diet that is high in saturatedfatty acids or calories willcontribute tohypertriglyceridemia

Promotes vascularendothelial injury thatpredisposes blood vesselsto atherosclerosis

Formation of reactiveoxygen spp w/c are thenable to oxidize lipids,multiplying theiratherogenic potential

Promote thrombosisformation

Increased production of reactive oxygen spp ordeficiency of antioxidantdefenses---amplify the risk of CAD

Exercise Inflammation

Detected by CRP (C-reactiveprotein)

Disorders of Lipid MetabolismHyperlipoproteinemias: (Hyperlipidemia):

Primary of Familial HLP Secondary HLP

No apparent underlying disease present

Related to inherited disorder

Caused by underlying disorder

Fredrickson-Levy Classification

Elevated Chylomicrons(Familial Chylomicronemia or Fredrickson Type I)

Increased LDL/ Primary Hypercholsterolemia(Fredrickson Type II)

Formed at the intestinal wall following a meal, cleared from theby the lipoprotein lipase (LPL)

Apoprotein CHI---required as cofactor for LPL

Accumulation of chylomicrons results in extremely elevatedtriglycerides---may result in xanthoma formation

Mild to severe pancreatitis, hepatosplenomegaly

Sera of patients w/ chylomicronemia---creamy layer forming atthe surface of a fasting specimen

Elevated: triglycerides, VLDL, cholesterol

Decreased HDL

Familial hypercholesterolemia

2 major forms:

Homozygous (type IIa)o Early or premature atherosclerosis

o Increase occurrence of MI before age 30

o Drug therapy to reduce LDL

Heterozygous (thype IIb)o  Treatable w/ dietary changes

o Elevated VLDLIncreased IDL

(Familial Dysbetalipoproteinemia or Fredrickson Type III)Increased VLDL

(Familial Hypertriglyceridemia or Fredrickson Type IV)

Inherited disorder characterized by the inability to degradechylomicron remnants and IDL

Elevated total cholesterol and triglycerides, IDL, VLDL andchylomicrons

Relatively common

Primary---autosomal recessive

Secondary disorder---may be the result of drug therapy, estrogen therapy,alcoholism, GSD, obesity, DM, or hypothyroidism

Elevated triglycerides and cholesterol, VLDL

Increased VLDL with Increased Chylomicrons(Fredrickson Type V)

Absent LDL(Abetalipoproteinemia)

Results in markedly elevated triglycerides levels either due toan impaired ability to remove the triglyceride-rich lipoproteins

Familial form

Associated with increased apoC-III which inhibits lipoproteinlipase

Symptoms over age of 20: xanthomas, episodic bouts of abdominal pain w/ or w/o pancreatitis

Elevated: Chylomicrons, VLDL

LPE (lipoprotein electrphoresis)---heavy chylomicron and pre-beta bands are the prominent features

Autosomal recessive trait results in no LDLs due to a lack of apolipoproteinemia Bo Homozygous

No detectable triglycerides, phospholipids and apoB; low total cholesterol,HDL

o Heterozygotes

Appear normal, low LDL levels

Cannot absorb fats and accumulate large lipid-filled vacuoles in the intestinal

mucosal cells that block the absorption of the essential fat soluble vitamins Result in failure to thrive in infancy, progressive degeneration of nervous system,loss of night vision

Lack of Vit. K---prolonged prothrombin time

Unabsorbed fats---metabolized by microbial intestinal organisms---producesteatorrhea, foul-smelling, soft stools

Peripheral blood smears---50-70% of erythrocytes w/ spiny projections(acanthocytosis)

Decreased HDL(Hypoalphalipoproteinemia)

Tangier Disease

Low levels of HDL; very high triglycerides

Obesity, diet, excessive alcohol consumption, lack of exercise---reduced HDL levels

Complete absence of HDL; low levels of Apo A1 and ApoAII

Cholesterol esters ten to accumulate in various tissues (liver, spleen, lymphnodes, cornea, skin)

Heterozygotes---reduced HDL; do not accumulate the cholesterol esters intissues

Major problem---increased risk of atherosclerosis

Low LDL and total cholesterol levels; normal to slight Hypertriglyceridemia

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Lipid Lysosomal Abnormalities Gaucher’s Disease

Manifest in early childhood

Abnormal accumulation of the intermediate substrates of thelipid pathways (toxic to the cells)

Psychomotor deterioration and developmental retardation

Accumulates in REC (liver, spleen)---hepatosplenomegaly andlipid-laden cells in bone marrow, CNSo LAMP-1 (lysosome-associated membrane protein)

Increased in plasma in 70% of individual with lysosomestorage disorder

o LAMP-2

Most common LSD

Caused by deficiency of beta-glucocerebrosidase---accumulation of glucocerebrosideo  Type 1 (chronic, nonneuropathic)

more common

occurs primarily in adults

normocytic or hypochromic anemia w/ thrombocytopenia, leucopenia,bone pain, hepatosplenomegaly

Pigmentation of the skin, associated w/ better prognosiso  Type II (infantile neuropathic)

Survive no more than 2 yearso  Type III (juvenile neuropathic)

May survive into adolescence Presence of Gaucher’s cells---lipid-laden macrophages, in the BM and elevated

serum acid phosphatase

Niemann-Pick Disease(Sphingomyeline Lipidosis)

Krabb’s Disease(Galactocerebroside Lipidosis or Globoid Cell Leukocystrophy)

Deficiency of sphingomyelinase result in accumulation of sphingomyelin

 Types A, B,C D

 Types A, C, and D--being more acute neuropathic disorder resulting infatal psychomotor and intellectual deterioration

Splenomegaly and hepatomegaly

Niemann-Pick cells—macrophages loaded with sphingomyelino  Type A

▪Affect newborn infants

o  Type C

▪Later onset

o  Type B▪Chronic with no neurologic involvement

 The result of galactocerbroside accumulation due to a deficiency of the enzymegalactocerebroside-beta-galactosidase

Affects the CNS and results in severe mental and motor deterioration

Blindness and deafness

Laboratory: elevated protein and the (+) of globoid cells (large multinucleatedmacrophages) in the CSF

Fatal within 6 and 12 months of onset

Fabry’s Disease(Angiokeratoma Corporis Diffusum Universale)

Tay-Sachs Disease(Gm2 Gangliosidosis)

Deficient α-galactosidase

Accumulation of ceramide trihexoside in CNS

Severe pain in the extremities and characteristicangiokeratoma (reddish lesions) on buttocks and around thenavel

Hypertension and heart problem---ceramide trihxosidepromotes narrowing of the arteries

 Jewish ancestry

Accumulation of Gm2 ganglioside in the neurons of CNS due to deficiency of hexosaminidase A

Psychomotor deterioration and dementia

Blindness associated with a cherry red spot in the retina