• regular, vigorous exercise raise HDL
• low fat diet that avoid red meat reduces serum cholesterol/cholesterol ester levels

• total cholesterol rises
• HDL falls

• 50% of wt composed of protein
• apoA-1 allows HDL to go from "traffic cop" to scavenger structure
  • apoA-1 forms 4 cyclic discs (dimer on top and dimer on bottom)
  • amphipathic alpha helixes subunits
  • traps cholesterol and cholesterol esters until it cant pick up anymore
• apoE3- sits on surface of HDL
  • acts as targeting protein for lipoprotein binding to cell surface receptors on liver

• function- lipid raft trafficking of caveoli (membrane structure)
• mechanism of action
  1. fission at domain bounds via apical transport center
  2. domain induced budding
  3. raft clustering

NPC-1

SCP-2

Golgi vesicles

• ABCA-1 (ATP bindin cassete) will bind to HDL
• this will activate apoA1

1. NPC-1 and SCP-2 (sterol carrier proteins) carry excess cholesterol made in smooth ER to Golgi
   1. cholesterol in vesicle insert into membrane
   2. cholesterol can be handed off to ABCA-1
   3. cholesterol can be converted to cholesterol ester via ACAT OR cholesterol ester to cholesterol via CE-hydrolase (stim by apoA1)
2. signals to HDL to activate apoA1
   1. stabilized by stabilizer protein which is activated by JAK
3. LCAT (lecithin cholesterol acyl transferase) generate cholesterol ester
4. saturate HDL particle with cholesterol ester
5. when HDL "get full", it is released from the membrane
6. recycled to liver

1. cholesterol converted to cholic acid or deoxycholic acid
2. converted to choyl CoA via ATP hydrolysis\
3. Two options
   1. add taurine to form taurocholate
   2. add glycine to form glycocholate

smooth muscle cells

fibroblasts

macrophages

cholesterol

connective tissue

1. any type of physical stress (where blood pressure increases), this causes microfractures in the tunica, exposing the vessel lumen to the fat deposits in tunica
2. causes a clotting mechanism via platelets
   1. kick out growth factors
   2. various cells (smooth muscle, fibroblasts) grow
   3. macrophages sees this damage and make lipoperoxidases and proteases
      1. kick out free radicals
      2. leads to "collateral damage" on healthy cells (ex: flipases, flopases)
      3. leads to oxidation of LDL (Lys residues in apoB100 oxidized so it cant bind to LDL receptor)
         1. oxidation of LDL lipids occurs by intimal lipo-oxygenases
   4. eventually, macrophage takes up so much cholesterol it becomes a foam cell, than will die
3. results in a large amount of scar tissue within the lumen

• see modified LDL apoB100 with negative charge
• will not bind normal LDL
• different gene product and orientation in the membrane

• increased cholesterol produced cholesterol esters
• leads to coalesced cholesterol ester deposits

NO FEEDBACK CONTROL OF CHOLESTEROL LEVELS IN MACROPHAGES

• oxidation
  • phospholipids → lysoPL + malondialdehyde + HC fragments
  • malondialdehyde + apoB100 → Schiff base with Lys in binding domain
  • Effects
    • blocks Lys-Asp interaction with normal LDL receptor
    • targets oxidized LDL to scavenger
• glycation
  • increase glucose → Lys Schiff base → retarget to scavenger receptor
• apo(a)
  • apoB100-Cys-SH + apo(a)-Cys-SH → apoB-S-S-apo(a) {LP(a)} → scavenger receptor path

• caspases activated by the inflamasome
• binding this will lead to increase in IL-1 and IL-8
• activates macrophages

• bile binding resins (cholestryamine)
• HMG-CoA reductase inhibitors (statins)
• VLDL inhibitors (nicotinic acid/niacin)
• plant sterols (inh. uptake) (ezetimibe)
• combined drug therapies (vytorin, advicor)

• prevent bile acid from being reabsorbed in the gut
  1. functional group: quarternary ammonium group w/inert styrene- divinylbenzene copolymer that binds to anionic bile acids
  2. forms insoluble complex that causes bile acids to be excreted in the feces
  3. leads to much more of plasma cholesterol being used to produce bile acid, significantly lowering plasma concentrations

1. localizes to brush border of microvilli of small intestines
2. binds to critical mediator of cholesterol absorption (NPC1L1) protein on membrane of GI epithelial cells and hepatocytes
3. causes increase in LDL-cholesterol uptake into liver (decrease circulating LDL)

1. E4 because of a SNP mutation, it folds up differently so it clears cholesterol slowly
2. increases secretase activity
3. increases amyloid protein
4. leads to increase beta amyloid plaques

Apoproteins can be made in brain and kidney as well. Originally, thought to only be in liver and intestines.

• trans fats are long and linear (looks like a saturated fat and more crystalline)
• cis fats have bends, so they can be metabolized easier

• HDL3 contains the polar coat of HDL containing apoA1 that allows for binding to cell surface
• HDL2 is the point where cholesterols esters go to the interior of HDL