wk4- APOE

Plasma LDL-chol levels depend crucially on _______, which in turns req proper binding of _______, the presence of LDLR accessory protein 1 (LDLRAP1) & intracellular LDLR degradation by _____

-LDLR -APOB -PCSK9

Genetic variants affecting plasma lipoprotein distrubtuin

-freq of the traits LDL-chol., HDL-chol., & TGs levels -The extremes of the distrubution represent homozygous monogenic disorders, the less extremes heterozygous mutations & the center common variants (SNPs or targeted re-seuencing)

The APOE e2 allele has been shown to greatly increase the risk of a rare condition called

-hyperlipoproteinemia type III (characterized by increased blood levels of cholesterol, TGs, and beta-very low-density lipoproteins (beta-VLDLs), which carry cholesterol and lipoproteins in the bloodstream. A buildup of cholesterol and other fatty materials can lead to the formation of small, yellow skin growths called xanthomas and the development of atherosclerosis) *Most people w/this disorder have 2 copies of the APOE e2 allele --> the e2 allele plays a critical role in the development of the condition*

What are the 10 warning signs of Alzheimer's?

1) memory loss that disrupts daily life 2) challenges in planning/solving problems 3) difficulty completing familiar tasks at home, work, or leisure 4) confusion w/time or place 5) trouble understanding visual images & spatial relationships 6) new problems w/words in speaking or writing 7) misplacing things and losing the ability to retrace steps 8) decreased/poor judgement 9) withdrawal from work or social activities 10) changes in mood and personality

Inverse correlation between HDL levels (cause increase in TG levels) & risk of CHD is dur to the importance of

HDL-chol in reverse cholesterol transport from the periphery to the liver *initiated search for HDL raising compounds (CEPT inhibitors) -far less efficient in preventing CVD than statins

PCSK9 binds to

LDLR & induces its degradation, which reduces the metabolism of LDL-chol & can lead to hypercholestemia

Atherosclerotic plaques contain cholesterol crystals that induce the ______________ porter proteins & promote apoptosis of the foam cells.

NLRP3 inflammasome

BP varies w/

PA and depends on diseases (obesity)

BP is tightly regulated by signals from the:

SNS, in order to permit uninterrupted blood perfusion of all vital organs

the e4 allele of the APOE gene is associated w/an increased # of protein clumps (amyloid plaques) in the brain of affected people. A build-up of ______ & _____________ may lead to the death of neurons & the progressive signs & symptoms of Alzheimer's disease

amyloid -beta peptide & amyloid plaques

-->Since genes ABCA1 & ABCG1 are regulated by the __________, synthetic LXR antagonists have a high potential for the treatment of atherosclerosis. Another therapeutic strategy would be to polarize macrophages to the M2 phenotype that would regress atherosclerotic plaques via the secretion of anti-inflammatory cytokines, such as IL 10, promote tissue remodeling, & clear of dying cells & debris

oxysterol sensor LXR

Chylomicrons, VLDLS, & particular LDLs deposit cholesterol in

peripheral tissues

The susceptibility to CVD is associated w/levels of

plasma lipids and lipoproteins [the genetic basis of the cardiometabolic traits such as lipoprotein levels, can be explainable to a minor part on a monogenetic basis causing a large effect & to a larger part by commong genetic variants w/minor effects on the trait]

The density of lipoproteins depends on

the abundance of apolipoproteins

Importantly, the transporter proteins (_____ & ____) are able to mediate reverse cholesterol transport.

--ABCA1 & ABCG1 *ABCA1 promotes chol. efflux to lipid-poor APOA1 of HDLs, whereas ABCG1 stimulates the efflux to mature HDLs. .

Majority of hypercholesterolemia cases is based on common variants in the genes _____________________________ for LDL-chol & chol that displat low ORs or epigeneitc programmain

-APOe -LDLR -APOB -PCSK9 -HMGCR

in TG metabolism,

-hydrolyzed dietary fats enter intestinal cells via fatty acid transporters. -Through a vescular pathway, microsomal triglycerole transfer protein (MTTP) packs reconstituted TG w/cholesteryl esters & APOB48 into chylomicrons. (Chylomicrons also contain apolipoproteins APOA5, APOC2, & APOC3) -in adipocytes, the enzymes diacylglycerol O-acyltransferase 1 (DGAT1) re-snythesizes TGs that have been hydrolzyed by PNPLA2 & hormone sensitive lipase (LIPE) -chylomicron remanents are taken up by hepatic LDLR or LDLR-related protein 1 (LDLR1) -in liver cells, TGs are packaged w/chol & APOB100 into VLDLs -The TGs in VLDLs are hydrolyzed by LIPC yielding LDLs. Sterols in the intestinal lumen enter intestinal cells via the transporter Nieman-Pick C1-like protein 1 (NPC1L1) & some are re-secreted by ABCG5 &ABCG8. -in intestinal cells, chol is packaged w/TGs into chylomicrons -in hepatocytes, chol is recycled or synthesized de novo by a pathway in which HMGCR is rate limiting/ LDLS transport chol from liver to the periphery where hey are endocytosed -In HDL-chol metabolism, APOA1 in HDLs mediates reverse chol transport by interacting w/ABCA! & ABCG1 transporters on non-hepatic cells. LCAT esterifies chol for the use in HDL-chol, which is remodeled by CETP & by endothelial lipase (LIPG), in order to enter hepatocytes

Macrophage retention & emigration in plaques

-imbalances in the lipid metabolism of macrophages , within progressing plaque, can lead to the retention of the cells & subsequently chronic inflammation -retention molecules (netrin 1 & its receptor unc-5 homolog B -UNC5B, semaphorin 3E & cadherins) are expressed by lipid-laden macrophages& promote macrophage chemostasis -This inflammatory milieu causes ER stress, leads to apoptosis, & results in the formation of the necrotic core -lipid unloading via ABCA1 & cholesterol efflux can reverse foam cell accumulation (in parallel, in myeloid-derived cells the chemokine receptor CCR7 is up-regulated & the expression of retention factors is decreased)

what are the 4 main types of lipoproteins?

1) chylomicrons 2) VLDLs 2) LDLs 4) HDLs *differentiated based on density & size

Lowering of plasma LDLs

1) drugs (statins) = target HMGCR (rate-limiting enzyme in the production of cholesterol) can prevent subendothelial retention of lipoproteins & thereby decrease inflammatory atheroscletotic disease 2) inhibitory antibodies against the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9) were developed & are expected to show efficient chol lowering effects in pt

Steps of atherosclerosis development (detailed)

1) hyperlipidemia increases the # of monocytes recruited to atherosclerotic plaques (initiated by cholesterol-rich LDLs that become pro-inflammatory) 2) Pro-inflammatory LDLs stimulate endothelial cells to produce different chemokines (CCL2, CCL5, CXCL1), glycosaminoglcyams, & P-selectin for the recruitment of monocytes 3) Promotes the overproduction of monocytes, which lead to production of endothelial adhesion molecules (selectins, ICAM1, & VCAM1), that mediate the infiltration of the monocytes into the intima 3) monocytes differentiate into macrophages or dendritic cells & interact w/atherogenic lipoproteins (mod. LDL) 4) macrophages take up normal & oxidized LDL via. macropinocytosis or scavenger receptors (MSR1 & CD36) resulting in formation of foam cells [in CHRONIC 5) these foam cells secrete pro-inflammatory cytokines (IL1B, IL6, & TNF-alpha) & chemokines (CCL2, CCL5, & CXCL1) as well as macrophage retention factors (netrin1 & semaphorin 3E) that amplify the inflammatory response 6) foam cells persist into plaques

What control systems work in an integrated fashion, in order to ensure adequate perfusion of all tissues despite widely varying metabolic demand?

1) renin-angiotensin-adlosterone system 2) baroreceptors 3) natiuretic peptides 4) kinin-kallikrein system 5) the adrenergic receptor system 6) factors produced by blood vessels causing vasodilation (such as NO) or contraction (endothelin)

What are the complications associated w/hypertension?

1)stroke 2)vision problems 3) heart attack 4) kidney failure 5) blood vessel damage`

Steps of atherosclerosis development

1. Endothelial Dysfunction 2. Initiation of Fatty Streak 3. Fatty Streak 4. Fibrous Atheroma/Plaque

an increased of total chol of ______ is associated w/a threefold elevated risk of death from heart attack, while a HDL-chol level lower than _______ is the most common lipid disturbance of pt below the age of 60

5.2-6.2mM 0.9mM

Each cycle of heart contraction pumps

70ml blood into systemic arterial system to supple all cells/tissues w/oxygen & nutrients *the pulsation creates pressure on vascular walls that depends on the amount of pumped blood & resistance created by vasculature -this pressure is higher at the peak of a passing amount of blood (systolic) & lowest after its passage (diastolic) [for healthy adults= 120 systolic & 80 diastolic]

Some studies have suggested that having at least one copy of the ________ may help protect against the age-related macular degeneration or delay the onset of vision loss, while having at least one copy of the __________ may increase the risk of this disease or cause symptoms to appear earlier.

APOE e4 allele; APOE e2 allele -->However, other studies have not found these associations. More research is needed to clarify what role, if any, APOE gene variants play in the development of age-related macular degeneration.

15% of the US population has the

APOE e4 gene (risk of getting Alzheimer's is tripled) 1/50 that have genes from both parents -lead to 9 times the risk -Nigerian blacks have the highest freq of APOE e4 allele but lowest Alzheimer's rates

Due to the decreased ability to handle these fats and increased risk of cardiac events for those with _______________, high fat diets, such as ketogenic diets, are not appropriate for individuals with this mutation.

APOE polymorphisms

Healthy & unhealthy BP ranges

BP varies during each heartbeat between a max (systolic) & min (diastolic) value -pressure displays circadian rhythm w/highest values in afternoon & lowest at night -mean blood flow depends on BP & resistance to flow caused by mechanics of the blood vessel walls (it decreases w/distance from the heart, due to narrowing of small arteries & arterioles) -BP is also affected by hydrostatic forces (during standing-orthostasis-, valves in veins, breathing & skeletal muscle contractions

the ratio of APOB to APOA1 is the strongest predictor of

CHD risk, but the ratio of cholesterol to HDL-chol is equally predictive

___________ elevates the risk of ischemic heart disease, stroke, peripheral vascular disease & other CVDs (heart failure, aortic aneurysms, atherosclerosis, & pulmonary embolism)

Chronically elevate BP

Dysregulation of lipid metabolism (chol. esterification & efflux) in foam cells contributes to

ER stress ultimately resulting in apoptotic cell death -result in necrosis & in the release of cellular components & lipids that form the necrotitc core

Apolipoprotein E combines with fats (lipids) in the body to form molecules called _____. _______ are responsible for packaging cholesterol and other fats & carrying them through the bloodstream. -Maintaining normal levels of __________ is essential for the prevention of disorders that affect the heart and blood vessels (cardiovascular diseases), including heart attack and stroke.

Lipoproteins -cholesterol

Lipoprotein uptake & efflux in macrophages

Macropinocytosis (phagocytosis of aggregated LDLs & scavenger receptor-mediated uptake), macrophages within plague internalize native LDLs & VLDLs as well as oxidized lipoproteins -internalized lipoproteins & associated lipids are digested in lysosome releasing free cholesterol -latter moves to plasma or ER membrane & can be effluxed -enzyme ACAT1 in ER membrane esterified the free cholesterol w/FA for their storage within cytosolic lipid droplets -via lipophagy resulting in the delivery of lipid droplets to lysosomes for efflux of via lipolysis by neural cholestrol ester hydrolase 1 (NCEH1), these lipids can be mobilized -LXR is activated by accumulation of cellular choesterol & up-regulates the expression of ABCA1 & ABCG1 (these genes mediate the transfer of free cholesterol to lipid-poor APOA1 to form nascent HDLs or mature HDLs, in which free cholesterol is esterified & stored in the core of the accumulation & can activated the NLRP3 inflammasome, promotes ER stress, & leads to apoptosis) -lipid rafts are enriched in sphingomyelin form a complex w/free cholesterol & promote TLR4 signaling -->activation of NF-kB and in the production of pro-inflammatory cytokines & chemokines

The endothelium is composed of __________.

a single layer of enodthelial cells that covers blood vessels & serves as a barrier between circulating blood & subendothelial tissues

A first sign of atherosclerotic lesion formation is the

accumulation of cholesterol within the arterial wall (fatty streaks) *initated by the sequestration of cholesterol-rich APOB-containing lipoproteins called LDLs *when LDLs are modified by oxidation, enzymatic/nonenzymatic cleavage, and/or aggregation, they become pro-inflammatory & stimulate endothelial cells to produce chemokines (CCL5 & CXCL1, gycosaminoglycans, & P-selectin) for the recruitment of monocytes *hypercholesterolemia & cholesterol accumulation in hematopoietic stem cells promotes overproduction of monocytes --> increased adherence to endothelial cells (mediated by the molecules intefrain, alpha 4 (ITGA4), beta 2 (ITGB2) in monocytes binding to vascular cell adhesion molecule 1 (VCAM1) & intercellular adhesion molecule 1 (ICAM1) in endothelial cells *monocytes move into space below endothelial cells (intima) where they differentiate into macrophages *macrophages ingest normal/modifies lipoproteins (such as oxidized LDL), which at the onset of the inflammatory response us a beneficial clearance *when inflammation turns CHRONIC, macrophages transform into cholesterol-laden foam-cells *these cells persist into plaques (lost their ability to migrate & cannot resolve inflammation)

Hypobetalipoproteinemia (HBL)

almost no LDL-chol is present due to different homozygous loss-of-function mutations in genes APOB & PCSK9

The APOE gene provides instructions for making a protein called:

apolipoprotein E

People who carry at least one copy of the APOE e4 allele have an increased chance of developing

atherosclerosis (which is an accumulation of fatty deposits and scar-like tissue in the lining of the arteries) --> This progressive narrowing of the arteries increases the risk of heart attack and stroke.

________ sense acute changes in the pressure of blood vessels

baroreceptors

Artery wall can become rigid (sclerotic & fragile) due to

calcification of plaques

Levels of _______ & _______ are key risk factors for CVD

certain plasma lipids lipoproteins *10% of cases of hypercholesterolemia have a monogenic basis (such as heterozygous familial hypercholesterolemia that is based on a gain of function of the PCSK9 gene)

More than 30 common SNPs w/small effects on BP are known to

change net renal salt balance *emphasizes salt homeostasis in the kidney as a key risk factor for hypertension *~1/3 of hypertensive pt are responsive to sodium intake (humans originated from a salt-poor environment providing a strong adaptive advantage for gene variantss that promoted salt & water retention) -after migrating to salt-rich environments, the same variants now contribute to elevated BP *thus dietary intake (such as salt intake) significantly influence BP and reduced salt intake as well as increased consumption of fruits & low fat food, exercise, wt.loss, & reduced alcohol intake can reduce hypertension

Long-term changes in plasma cholesterol can lead to

changes in ApoE expression

In atherosclerosis, __________ below the endothelium causes a macrophafe-dominated inflammatory response in large/medium arteries

cholesterol deposition *95% of humans by age 40 have some type of atherosclerotic lesion -clinical manifestations don't occur before age 50-60yr -the distribution of the plaques (the core) is not randomly, but they tend to accumulate at the inner curvatures & branch points of arteries (at positions where laminar flow is either disturbed/insufficient) in order to maintain the normal state of the endothelium

Composition of the 4 types of lipoproteins:

chylomicrons: 50-200nm (diameter); represent largest lipoproteins & show low density (<1.006g/mL); composed of ~85% TG, 9% phospholipids, 4% cholesterol, & 2% protein [APOB48] VLDLS: very low density (0.95-1.006g/mL) of 30-70nm (diameter) cotaining ~50% TG, 20% cholesterol, 20% phospholipids, & 10% proteins [APOB100] LDLs: Low density (1.016-1.063g/mL) of 20-25nm (diameter) composed of ~45% chol, 20% phospholipids, 10% TGs, & 25% protein [APOB] HDLs: high density (1.063-1.210g/mL) w/diameter of 8-11nm formed of ~40-55% protein (APOA1), 25% phospholipids, 15% cholesterol, & 5% TGs

_________ is the key determinant of lipoprotein levels

diet *early dietary interventions are the most efficient & economic strategies for CVD prevention

There are 299 AA in the ApoE protein. Thus, the great possibility for variations such as:

e2 (residue- cysteine), e3 (residue- cysteine (112)/arginine (158))-MOST common, e4 (residue-arginine) Representations within society: e3- 40-90% e2- 7% e4- 14% *vary in the AA that exist at residue 112 & 158

What are the major different versions (alleles) of the APOE gene?

e2, e3, and e4. ---> The most common allele is e3, which is found in more than half of the general population.

The APOE _____ allele may also be associated with an earlier onset of memory loss and other symptoms.

e4

What allele of the APOE gene increases an individual's risk for developing late-onset Alzheimer's disease?

e4 -->People who inherit one copy of the APOE e4 allele have an increased chance of developing the disease; those who inherit two copies of the allele are at even greater risk. *it is not known how this allele is related *INHERIT the risk of developing the disease, NOT the disease itself [not all people w/Alzheimer's have the e4 allele & not all people who have this allele will get this disease] *this allele is associated with an increased number of protein clumps, called amyloid plaques, in the brain tissue of affected people. A buildup of toxic amyloid-beta peptide and amyloid plaques may lead to the death of neurons and the progressive signs and symptoms of this disorder.

The risk for Alzheimer's disease that from ___________ seems to be greater than that from the APOE e4 allele

elevated total cholesterol & BP *controlling a person's lifestyle factors can reduce a person's risk (even if they have the double gene) down to just 2

What cell types contribute to the process of atherosclerotic plaque formation?

endothelial cells, monocytes, dendritic cells, lympocytes, eosinophils, mast cells, & smooth muscle cells

Chronic inflammation stimulates the migration of smooth muscle cells into the intima region, where they transform into

fibroblasts that proliferate & produce larger amounts of EXM -->lead to formation of fibrous atherosclerotic plaques

-the main lipids in lipoprotein are

free & esterified chol & Tg

systolic BP indicates:

how much pressure blood is exerting against the artery walls while the heart is pumping blood

a Westernized-diet can lead to:

hypercholesterolemia & atherosclerosis , esp in genetically predisposed individuals

What is the most important PREVENTABLE risk factor for pre-mature death?

hypertension

the BP level above which therapeutic intervention has clinical benefit *90-95% is primary (i.e. essential) _________ that results from a complex interaction of genes & environmental factors * chronic ____ in combo w/atherosclerosis is the major risk factor for stroke, CHD, congestive heart failure, & end-stage renal disease

hypertension

increased salt reabsorption in kidneys (after salty meal) req increased water reabosprtion [to maintain plasma Na conc. at 140mM]. This results in:

increased intravascular volume venous blood return to the heart. Thus, cardiac output RAISES --> elevated BP. *a central point for salt absorption in the Na channel SCNN1 in the cortical collecting tubule of the kidney.

chol. & cholesteryl esters are

insoluble in olasma, which req that their transport in spheroidal macromolecules (lipoproteins) *lipoproteins have a hydrophobic core formed by phospholipids, fat-soluble antioxidants, vitamins, & cholesteryl esters, & a hydrophilic coat that contains free cholesterol, phospholipids, & apolipoproteins

Atherosclerosis is both a ______ & ____________, in which macrophages play a central role

lipid disorder & inflammatory disease

The cytogenetic Location of APOE is 19q13.32, which is the:

long (q) arm of chromosome 19 at position 13.32.

cholesterol is essential for

membrane structure & fluidity is a precursor to steroid hormones, vit. D3, oxysterols, & bile acids that are ligands of nuclear receptors *a small amount originates from nutrition; while ~80% dervies from endogenous synthesis

___________ produced in both the brain & heart in response to increased BP in these organs

natriuretic peptides

Blood pressure ranges

normal: <120 & <80 Pre-hypertension: 120-139 OR 80-89 Hypertension stage 1: 140-159 OR 90-99 Hypertension stage 2: 160 or higher OR 100 or higher Hypertensive crisis: >180 OR >110 *in individuals >50, hypertension is present when BP is consistently > 140 OR 90

_________ can increase the risk of hypertension fivefold as compared w/normal weight , & more than 85% of hypertension cases can be attributed to a BMI>25

obesity

Increased _____________ of the artery wall promotes modification of LDLs, which are primarily oxidations that are recognized by macrophages via scavenger receptors (MSR1 & CD36). These receptors internalize the lipoproteins & cholesteryl esters of the lipoproteins that are hydrolyzed to free cholesterol & FA. Scavenger receptors are not down-regulated by cholesterol via negative-feedback mechanisms, such as in the cased of LDLR. Free chol. is transported to ER, where it is re-esterified by the enzyme ACAT1 providing foam in foam cells. In addition, the # of other mechanisms (pinocytosis by macrophages), contributes to foam cell formation. Enrichment if ER mechanisms w/free chol. can lead to defective chol esterification by ACAT1 in macrophages, promoting the accumulation of free chol. Moreover free chol. enrichment in lipid raft within the cell membranes can enhance inflammatory signaling via TLR4 & Nf-kbeta.

oxidative stress

tangier disease (TD)

rare monogenic disorder that affects HDL levels & based on homozygous mutations in the ABCA1 gene or def. in the genes APOA1, LCAT, CETP, or LIPC

Plaque macrophages are subject to

retention & emigration signals & a misbalance of these processes contributes to a net accumulation of plaque macrophages

Rare monogenic disorders can cause:

severe hypertriglycerolemia (HTG) that are due to homozygous loss-of-function mutations of the genes LPL, APOC2, & APOA5

Abetalipoproteinemia (ABL)

similiar to HBL disease; homozygous mutation in MTTP that cause almost no LDL-chol to be present

growth lesions & inward arterial remodeling that gradually narrow the diameter of the blood vessels & thus reduces the blood flow

stenosis -when applies to >80% of coronary arteries, the heart muscle becomes ischemic, esp when a high cardiac workload increases oxygen demand *original stable lesion changes to unstable vulnerable plaque that can easily rupture endothelium ---> formation of intravascular blood clots that can cause MI or stroke

Atherosclerosis is a chronic inflammatory disease characterized by:

the accumulation of choloesterol-laden macrophages in the artery wall (based on dyslipidemia & the overreaction of the immune system) -central cells: macrophages (their programming to M1 & M2 types, which influences both disease progression & regression)

____________ affects vascular tone & renal salt handling, cardaic contraction, & vascular tone

the kinin-kallikrein system

ApoE main role is:

the principle cholesterol carrier in the brain [Nigerian blacks that had high freq of APOE e4 but lowest Alzhimer's rates pointed to the fact that their diet seemed to trump their genes -from low intake of animal fat]

HDLs have high amounts of APOA1 & mediate

the reverse cholesterol transport to the liver *high levels , sometimes referred to as "good cholesterol" & assocaited w/reduced risk for CVD

cholesterol levels are tightly regulated by the coordinated actions of

transcription factors SREBF1 *at low levels, SREBF1 activates genes that are involved in endogenous chol. production & chol. uptake (LDLR). Since already low conc of free chol. can be toxic, chol. is mostly esterified w/FA.

Decreased delivery of salt -->increased secretion of the aspartyl protein renin = secretion of peptide hormone angiotension. This causes

vasoconstriction & subsequent increase in BP. *Angiotension binds to its specific G protein-coupled receptor in the adrenal gland, inducing production of aldosterone(the ligand of the nuclear receptor mineralocortcoid receptor-MR). MR then up-regulates SCNNI gene expression ---> increase of salt-reabsorption

both HBL & ABL are found in pt with

very low TG levels

diastolic blood pressure measures the pressure

while the heart is resting between beats

What cell is central to the patho-physiology of atherosclerosis?

foam cells