Block 3 Cholesterol Transport & Homeostasis Flashcards

1
Q

What are 3 effects of rapid CM uptake by liver?

A

Increased liver cholesterol supply, induces down regulation of liver LDL-R, increased circulating LDL

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2
Q

How does LDL deliver cholesterol to peripheral tissues?

A

Endocytosis by LDL-R, contains only ApoB100 and high concentration chol and CE (major plasma chol carrier)

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3
Q

How is NPC1 involved in chol transport?

A

Facilitates transport of chol to ER (ACAT activated, esterifies, deposits cytoplasmic lipid droplets) and PM (incorporated as free chol)

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4
Q

What is Niemann-Pick type 2 (C & D)?

A

Autosomal recessive (French Acadians of Nova Scotia) mutation in NPC1 -> hepatomegaly (acc chol in lysosomes), ataxia, progressive dementia

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5
Q

How is LDL-R regulated?

A

SRE in promoter regulated like HMG-CoA Red: dietary chol enters liver cells in CM remnants and represses synthesis of LDL-R

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6
Q

How does SREBP enter the nucleus?

A

Transported from ER to Golgi, binding to SCAP chaperone to get to Golgi (act by low chol), & 2 proteolysis (S1P, S2P)

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7
Q

What is PCSK9?

A

Proprotein convertase subtillisin/kexin type 9; reduces recycling & increases degradation of LDL-R via lysosomes, increasing plasma [LDL]

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8
Q

What is reverse cholesterol transport?

A

Mediates transport from per tissues to liver for conversion to bile acids, using HDL to acquire free chol

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9
Q

What are the major and minor mechanisms of release of free chol from cells?

A

Major: assembly new HDL particles upon intxn of ApoA1 with cell surface, 2 membrane transporters ABCA1 and ABCG1
Minor: non-specific chol efflux by free diffusion

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10
Q

What is NCEH? What are the functions of ABCA1 and ABCG1?

A

Neutral chol ester hydrolase, to prepare CE for export from cell
ABCA1 delivers chol to lipid-poor ApoA1 -> nascent HDL
ABCG1 delivers chol to nascent HDL or lipid-poor HDL3, but not directly to lipid-rich ApoA1

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11
Q

How does LDL-derived chol regulate intracellular chol?

A

Decreases synth HMG-CoA Red & de novo synth LDL-R, increases ACAT activity to esterify chol and store in lipid droplets

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12
Q

How do dietary cholesterol and aging affect LDL-R activity?

A

Dietary: suppresses LDL-R activity when CM remnants taken up by liver
Decreases with aging

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13
Q

What are hyperlipidemias?

A

Circulating levels of chol, TG, or both are elevated; polygenic and familial types

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14
Q

What is polygenic hypercholesterolemia?

A

Primary moderate HChol-emia, high LDL, unknown cause maybe increased absorption dietary chol, inc synth LPs by liver, decrease removal LDL; usually no physical signs

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15
Q

What is familial hypercholesterolemia?

A

High total chol and LDL, premature atherosclerosis, dominant, depressed LDL-R activity; 4 classes of genetic mutations

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16
Q

What are the 4 classes of mutations causing familial HChol-emia?

A

1: deletion, no LDL-Rs
2: defective carb arrangement in receptor so immature receptor can’t reach surface
3: impaired binding capacity of receptor
4: receptor can’t internalize bound LDL

17
Q

What are the clinical manifestations of familiar HChol-emia?

A

High total, normal TG, premature athero, xanthomas of extension tendons in hands, Achilles tendon, eyelids, corneal arcus

18
Q

How are homozygotes and heterozygotes affected differently in familial HC-emia?

A

Homo: 650-1200 total C, xantomas in early childhood, CHD death before 20
Hetero: 350-550 total C, xanthoma and CHD after 20

19
Q

How is hypercholesterolemia treated?

A

Dietary restriction of chol and sat fat (to up reg LDL-R act), drugs (bile acid sequestrants, statins, chol absorption inh, combined)

20
Q

How do dietary restrictions affect hypercholesterolemia patients?

A

Dietary-induced: efficient

Familial: drug treatment mandatory to up reg LDL-R act

21
Q

How do bile acid sequestrates work?

A

Resin like cholestyramine bind bile acids for excretion, drains hepatic supply of chol as converted to bile acid, increases LDL-R act; can reduce LDL levels 15-20% (50-75% with statins)

22
Q

How do statins work?

A

Inhibit activity of HMG-CoA red by competitive inhibition, decreases liver chol, increases LDL-R act, protective for CVD, athero, stroke; reduce plasma LDL 25-40% (50-75% with bile acid seq)

23
Q

What is Ezetimibe, and how does it work?

A

Chol absorption inh, reduces total chol by decreasing LDL levels, blocks NPC1L1 (int lumen to enterocytes); doesn’t affect FA, TG, BA, lipid-soluble vit absorption; usually with statins, fewer side effects

24
Q

What 4 groups of individuals should be treated with statins?

A

Clinical athero CVD, LDL levels >190 (familial HCE), DM (40-75 yoa) with LDL 70-189 w/o athero CVD, no evidence CVD or DM with LDL 70-189 and 10y risk athero CVD >7.5%

25
Q

What is oxidized LDL?

A

Modified LDL (lipid or ApoB) from free radicals; may be decreased by vit C, E

26
Q

What are scavenger receptors? How are they affected by intracellular [chol]?

A

On MFs, can take up ox-LDL (not rec by LDL-R) and other modified LDL; not down-reg by intracellular [chol] -> excessive lipid acc -> foam cells

27
Q

What is an MI?

A

Advanced atherosclerotic plaque that occludes >50% cor a ruptures -> thrombosis and total occlusion of blood flow

28
Q

What is the atherogenic lipid profile?

A

High VLDL/TG, small size LDL, low HDL

29
Q

In what types of patients are low HDL-C levels usually seen?

A

Smokers, sedentary, obese, insulin resistant or diabetic, hyper-TG-emia, chronic inflammatory disorders

30
Q

What are the goal changes to the atherogenic lipid profile?

A

Reduce LDL, increase HDL, induce formation of large LDL vs. small, reduce total ApoB chol (CM, VLDL, LDL)

31
Q

What treatments may help improve the atherogenic lipid profile?

A

CETP inhibitors (delay catabolism HDL, increase HDL and Apo-A1, lower LDL), fibrates (lower plasma TG, shift LDL toward larger particles, increase HDL)

32
Q

How do fibrates work?

A

^ LPL activity; ^ liver FA uptake (FA transporter, acyl-CoA synthetase) and v TG production, inhibit HSL in adipose; ^ removal LDL (make larger, ^ affinity for LDL-R); ^ HDL prod, stimulate reverse chol transport, ^ ApoA1 production in liver

33
Q

How might HDL be anti-atherogenic other than reverse chol transport?

A

Antioxidant effects, inh adhesion molecule exp, inh platelet act, prostacyclin stabilization, promotion of NO production

34
Q

How do aerobic exercise, tobacco cessation, weight loss, alcohol consumption, and dietary factors (n-3 and n-6 PUFAs, MUFAs) affect HDL levels?

A
Ex: ^ nascent HDL, ^ LPL
Tob: ^ LCAT, CETP
Weight: ^ LCAT, LPL
Alc: ^ ABCA1, ApoA1, CETP
Diet: v LDL/HDL ratio
35
Q

What are primary causes of low HDL?

A

ApoA1 deficiency/mutation, LCAT complete or partial def, ABCA1 mutation (Tangier homo or hetero, familial hypo-Apo-emia), unknown (familial HAE, fam combined hyperlipidemia with low HDL, metabolic syndrome)

36
Q

What is Tangier disease?

A

Autosomal recessive, severe HDL def, sterol dep in tissue MF and ^ athero; mutation in ABCA1 (no transport FC from cell to nascent HDL) -> foam cells