Block 3 Cholesterol Transport & Homeostasis Flashcards
What are 3 effects of rapid CM uptake by liver?
Increased liver cholesterol supply, induces down regulation of liver LDL-R, increased circulating LDL
How does LDL deliver cholesterol to peripheral tissues?
Endocytosis by LDL-R, contains only ApoB100 and high concentration chol and CE (major plasma chol carrier)
How is NPC1 involved in chol transport?
Facilitates transport of chol to ER (ACAT activated, esterifies, deposits cytoplasmic lipid droplets) and PM (incorporated as free chol)
What is Niemann-Pick type 2 (C & D)?
Autosomal recessive (French Acadians of Nova Scotia) mutation in NPC1 -> hepatomegaly (acc chol in lysosomes), ataxia, progressive dementia
How is LDL-R regulated?
SRE in promoter regulated like HMG-CoA Red: dietary chol enters liver cells in CM remnants and represses synthesis of LDL-R
How does SREBP enter the nucleus?
Transported from ER to Golgi, binding to SCAP chaperone to get to Golgi (act by low chol), & 2 proteolysis (S1P, S2P)
What is PCSK9?
Proprotein convertase subtillisin/kexin type 9; reduces recycling & increases degradation of LDL-R via lysosomes, increasing plasma [LDL]
What is reverse cholesterol transport?
Mediates transport from per tissues to liver for conversion to bile acids, using HDL to acquire free chol
What are the major and minor mechanisms of release of free chol from cells?
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
What is NCEH? What are the functions of ABCA1 and ABCG1?
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
How does LDL-derived chol regulate intracellular chol?
Decreases synth HMG-CoA Red & de novo synth LDL-R, increases ACAT activity to esterify chol and store in lipid droplets
How do dietary cholesterol and aging affect LDL-R activity?
Dietary: suppresses LDL-R activity when CM remnants taken up by liver
Decreases with aging
What are hyperlipidemias?
Circulating levels of chol, TG, or both are elevated; polygenic and familial types
What is polygenic hypercholesterolemia?
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
What is familial hypercholesterolemia?
High total chol and LDL, premature atherosclerosis, dominant, depressed LDL-R activity; 4 classes of genetic mutations
What are the 4 classes of mutations causing familial HChol-emia?
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
What are the clinical manifestations of familiar HChol-emia?
High total, normal TG, premature athero, xanthomas of extension tendons in hands, Achilles tendon, eyelids, corneal arcus
How are homozygotes and heterozygotes affected differently in familial HC-emia?
Homo: 650-1200 total C, xantomas in early childhood, CHD death before 20
Hetero: 350-550 total C, xanthoma and CHD after 20
How is hypercholesterolemia treated?
Dietary restriction of chol and sat fat (to up reg LDL-R act), drugs (bile acid sequestrants, statins, chol absorption inh, combined)
How do dietary restrictions affect hypercholesterolemia patients?
Dietary-induced: efficient
Familial: drug treatment mandatory to up reg LDL-R act
How do bile acid sequestrates work?
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)
How do statins work?
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)
What is Ezetimibe, and how does it work?
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
What 4 groups of individuals should be treated with statins?
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%
What is oxidized LDL?
Modified LDL (lipid or ApoB) from free radicals; may be decreased by vit C, E
What are scavenger receptors? How are they affected by intracellular [chol]?
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
What is an MI?
Advanced atherosclerotic plaque that occludes >50% cor a ruptures -> thrombosis and total occlusion of blood flow
What is the atherogenic lipid profile?
High VLDL/TG, small size LDL, low HDL
In what types of patients are low HDL-C levels usually seen?
Smokers, sedentary, obese, insulin resistant or diabetic, hyper-TG-emia, chronic inflammatory disorders
What are the goal changes to the atherogenic lipid profile?
Reduce LDL, increase HDL, induce formation of large LDL vs. small, reduce total ApoB chol (CM, VLDL, LDL)
What treatments may help improve the atherogenic lipid profile?
CETP inhibitors (delay catabolism HDL, increase HDL and Apo-A1, lower LDL), fibrates (lower plasma TG, shift LDL toward larger particles, increase HDL)
How do fibrates work?
^ 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
How might HDL be anti-atherogenic other than reverse chol transport?
Antioxidant effects, inh adhesion molecule exp, inh platelet act, prostacyclin stabilization, promotion of NO production
How do aerobic exercise, tobacco cessation, weight loss, alcohol consumption, and dietary factors (n-3 and n-6 PUFAs, MUFAs) affect HDL levels?
Ex: ^ nascent HDL, ^ LPL Tob: ^ LCAT, CETP Weight: ^ LCAT, LPL Alc: ^ ABCA1, ApoA1, CETP Diet: v LDL/HDL ratio
What are primary causes of low HDL?
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)
What is Tangier disease?
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
