HCP 7 Flashcards
what are the components of a mature atheroma
foam cells, fibrous cap, necrotic core
List the lipoproteins and what makes up the molecule
chylomicrons: Apo A (I, II), Apo B48, Apo C (I, II, III), Apo E VLDL: Apo B100, Apo C (I, II, III), Apo E IDL: Apo B100 LDL: Apo B100 HDL: Apo A (I, II), Apo C (I, II, III), Apo D, Apo E
classes of familial hypercholesterolemia
class 1: complete failure of LDL receptor protein synthesis Class 2: receptor proteins misfolded -> accumulation in ER and no transport to golgi or cell surface Class 3: defective binding domain of LDL receptor -> LDL receptor present but LDL unable to bind Class 4: No localization of receptor in clatharin pits -> no LDL internalization Class 5: failure of pH dependent separation of receptor & LDL -> receptors stuck in endosome -> receptors degraded -> receptors unable to be recycled
familial hypercholesterolemia
mutation in gene for LDL receptor with autosomal dominant inheritance (heterozygous = 50% of receptors, homozygous = no LDL receptors) -> most common mutation class 2 where proteins misfolded -> accumulates in ER and degraded and does not reach golgi or cell surface -> decreased receptors on cell surface of hepatocyte and peripheral tissue (adipose/muscle) ->
exogenous fat metabolism french fry absorbed from lumen of small intestine. Track this lipid moiety all the way to the formation of VLDL
high cholesterol, FA, phosplipid, and TAG diet -> reaches duodenum where bile acids emulsify fats and form micelles -> micelles transferred into enterocyte -> TAGs, cholesterol, and CE combine with Apo B-48 synthesized in ER and Golgi via microsomal triglyceride transfer protein -> forms nascent chylomicron in enterocyte -> particle packaged into secretory vesicle and exported to plasma membrane -> vesicle fuses with membrane and release of nascent chylomicron into interstitial space -> increased osmotic pressure -> water passively diffuses into interstitial space -> increased hydrostatic pressure -> with expansion of fluid in interstitial space anchoring filaments on lymph attached to surrounding CT open microvalves on lymphatic capillary -> nascent chylmicro travels through lymphatic lacteals because they are too large to enter blood capillaries -> drains into cisternae of chili -> drains into thoracic duct -> chylomicrons enter blood circulation via left subclavian vein -> travels through heart -> in blood nascent chylomicrons receive poE and apoC-II from circulatory HDL in exchange for phospholipids and apoA1 -> forms mature chylomicrons that travel through capillaries and Apo C-II on chylomicron activate LPL enzyme anchored via heparin sulfate -> catalyzes hydrolysis of chylomicron -> forms remnant chylomicron, FA, and glycerols -> FA enter adipocytes and muscle cells, remnant chylomicron and glycerols reach liver hepatocyte -> ApoE on remnant chylomicron binds to syndical-1 or LDL related receptor on liver hepatocyte -> remnant chylomicron enters hepatocyte via receptor mediated endocytosis -> remnant chylomicron degraded in lysosomes into free cholesterol, amino acids, FA -> FA and cholesterol re-esterified to glycerol -> formation of TAG that are packaged into VLDL -> VLDL released into circulation
endogenous fat metabolism Diagram/explain the process of LDL trafficking at the cellular level and describe regulation of this process
VLDL released into circulation -> VLDL receives Apo C-II and Apo E from HDL -> VLDL can activate LPL via Apo C-II -> VLDL hydrolyzed by LPL into IDL -> LDL -> LDL binds to LDL receptor of peripheral tissue (adipose, muscle) or liver -> LDL endocytosed and processed (apo B100 broken down into amino acids) nascent HDL receives Apo A1 from chylomicrons -> HDL 3 picks up free cholesterol in circulation -> activates LCAT (PCAT) -> converts cholesterol to CE -> exchanges CE for TAG with VLDL mediated by cholesterol ester transfer protein (CETP) or CE rich HDL 2 -> HDL 2 reaches liver and binds to SR-B1 that mediates selective hepatic uptake of CE from HDL
receptor mediated endocytosis
LDL binds to LDL receptor via ApoB100 -> forms clatharin coated pit -> clatharin stabilizes vesicle formation -> clatharin coated endocytotic LDL vesicle carries endocytose material into the cell -> followed by immediate loss of clatharin coat -> LDL vesicle fuses with endosome -> protons pumps in endosome decrease pH <6 -> LDL and LDL receptors dissociate -> receptors are recycled to cell surface and LDL vesicle transferred to lysosome -> lysosomal acid hydrolases degrade LDL to release free cholesterol, amino acids, FA and phospholipids -> increased intracellular cholesterol inhibits HMG-CoA reductase and decreases cholesterol synthesis -> inhibits LDL receptor synthesis -> free cholesterol may be stored as CE by esterification by ACAT or used for cell membrane maintenance of steroid synthesis
atherosclerosis
see map
