Block 3 Cholesterol Transport & Homeostasis

Question 1

What are 3 effects of rapid CM uptake by liver?

Answer 1

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

Question 2

How does LDL deliver cholesterol to peripheral tissues?

Answer 2

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

Question 3

How is NPC1 involved in chol transport?

Answer 3

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

Question 4

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

Answer 4

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

Question 5

How is LDL-R regulated?

Answer 5

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

Question 6

How does SREBP enter the nucleus?

Answer 6

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

Question 7

What is PCSK9?

Answer 7

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

Question 8

What is reverse cholesterol transport?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

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

Answer 10

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

Question 11

How does LDL-derived chol regulate intracellular chol?

Answer 11

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

Question 12

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

Answer 12

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

Question 13

What are hyperlipidemias?

Answer 13

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

Question 14

What is polygenic hypercholesterolemia?

Answer 14

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

Question 15

What is familial hypercholesterolemia?

Answer 15

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

Question 16

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

Answer 16

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

Question 17

What are the clinical manifestations of familiar HChol-emia?

Answer 17

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

Question 18

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

Answer 18

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

Question 19

How is hypercholesterolemia treated?

Answer 19

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

Question 20

How do dietary restrictions affect hypercholesterolemia patients?

Answer 20

Dietary-induced: efficient

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

Question 21

How do bile acid sequestrates work?

Answer 21

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)

Question 22

How do statins work?

Answer 22

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)

Question 23

What is Ezetimibe, and how does it work?

Answer 23

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

Question 24

What 4 groups of individuals should be treated with statins?

Answer 24

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%

Question 25

What is oxidized LDL?

Answer 25

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

Question 26

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

Answer 26

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

Question 27

What is an MI?

Answer 27

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

Question 28

What is the atherogenic lipid profile?

Answer 28

High VLDL/TG, small size LDL, low HDL

Question 29

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

Answer 29

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

Question 30

What are the goal changes to the atherogenic lipid profile?

Answer 30

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

Question 31

What treatments may help improve the atherogenic lipid profile?

Answer 31

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

Question 32

How do fibrates work?

Answer 32

^ 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

Question 33

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

Answer 33

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

Question 34

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

Answer 34

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

Question 35

What are primary causes of low HDL?

Answer 35

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)

Question 36

What is Tangier disease?

Answer 36

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