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What is the purpose of the LDLR?
- cholesterol-delivery system
- Uptake of LDL into cells via LDLR
- 70% of LDLRs on hepatocytes
- most LDL (derived from VLDL) is actually finally removed from blood by the liver
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Why does the body synthesize and secrete VLDL only to later take up LDL via endocytosis?
- deliver endogenous TGs to adipose tissue and muscle
- to then deliver cholesterol to cells via LDLR
- TG metabolism parallels the chylomicron pathway for exogenous lipids.
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Why does the liver not normally become loaded with cholesterol derived form the uptake of cholesterol-ester rich LDL?
- liver is the one organ that can convert cholesterol to bile acids
- 5% of bile acids are lost in the feces during every cycle of the enterohepatic circulation
- bile acids allow cholesterol to be excreted rather than be taken up again by transporter protein NPC1L1
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Familial Hypercholesterolemia
- dominant disorder
- mutations in the LDLR gene
- Heterozygotes are quite common ~1/200
- blood cholesterol levels ~300-450 mg/dl.
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HMG-CoA reductase
- rate limiting enzyme for cholesterol synthesis
- Statin drugs target: reduced blood LDL levels of 18-55%
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How can SREBP2, a membrane-bound protein outside the nucleus be a transcription factor in the nucleus? What is it a TF for?
- processing is increased when cells have low cholesterol levels
- release of a soluble portion of the protein that then enters the nucleus to bind promoters
- high intracellular cholesterol - genes encoding LDLR and HMG-CoA reductase (that mediate uptake of LDL or control cholesterol synthesis) are not transcribed
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Statins
- inhibit HMG-CoA reductase, reduced synthesis
- lower cholesterol levels in hepatocytes
- increased processing of SREBP2
- increased transcription and protein levels of LDLR
- liver can take up more LDL b/c of more LDLR
- lowers serum LDL
- Commonly MI patients take statins for life to reduce their risk
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Absence of LPL, ApoCII or Insulin
- Increased free fatty acids
- Diabetes
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Lipoprotein lipase (and ApoCII)
- insulin (fed state) increases LPL activity.
- hydrolysis of dietary TGs and release of fatty acids
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NAFLD
- non-alcoholic fatty liver disease
- 24-42% US population, most asymptomatic
- 66% diabetics have this
- incr. plasma triglycerides, caused by obesity
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trans fatty acids
- produced by food industry to maintain shelf life
- incr. risk of MI
- they lack a kink, more like saturated FAs
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micelles
- created in the intestinal lumen by bile salts +dietary lipids, incr. SA
- pancreatic lipases, cholesterol esterase
- facilitate absorption of A,D,E,K
- CE+TGs in center, monoglycerides, PLs, bile salts, cholesterol on outer shell
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lipid digestion/absorption
- micelles -> FAs + monoglycerides get absorbed by diffusion
- chylomicron assembly (resynthesis of TG, phospholipids, cholesterol ester)
- cholesterols taken up by NPC1L1 then esterified in enterocyte
- secretion into lymph
- HDL donates ApoCII and ApoE
- chylomicron goes thru blood vessels, LPL hydrolyzes to deliver FFA +glycerol
- ApoCII is delivered back to HDL
- chylomicron remnant is recognized by the liver thru ApoE receptor
- Liver secretes VLDL
- ApoCII and apoE transfer from HDL to VLDL
- LPL hydrolyzes
- ApoCII and ApoE go back to HDL
- LDL is the remaining lipid
- LDLR on liver or extrahepatic tissues
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LPL
- hydrolyze chylomicron triglycerides to FFA, glycerol
- located on endothelium surface/adipose tissue
- without LPL, there are no chylomicron remnants that can be taken up by apoE receptors in the liver
- ApoCII is not returned to HDL
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cardiovascular lesions: HDL and LDL
- LDL enters intima, is oxidized, taken into macrophages via
- scavenger receptor depositing lipid (CE) in cells= foam cells.
- Cells eventually die releasing lipid=necrotic core of lesions.
- HDL-prevents LDL oxidation and unloads cholesterol from
- foam cells
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HDL
- secreted by liver (80%) and small intestine (20%), take up free cholesterol
- reabsorbed by liver
- good because it removes cholesterol from cells (like foam cells) and returns to the liver
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bile acid sequestrants
- less than 95% bile acids reabsorbed
- cholesterol 7 alpha hydroxylase is not inhibited
- more conversion of cholesterol into bile acids, low cholesterol in hepatocytes, increased SREBP2, incr. expression LDLR
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Treatments for Hyperlipidemia/atherosclerosis/MI
- Statins (HMG-CoA reductase inhibitors); lower LDL cholesterol 20-50%
- Inhibitors of NPCL1, reduce cholesterol absorption from the intestine
- Niacin (Nicotinic acid); decreases VLDL secretion (lowers TGs) and increases HDL.
- Bile acid sequestrants; lower LDL levels by increasing LDL receptors.
- Fibrates (PPARa agonists) lower plasma TGs ( a minor risk factor).
- Aspirin: Anti-thrombolitic (reduces blood clotting).
- Thrombolytic therapy. E.g. treatment with tissue plasminogen activator(tPA) to dissolve the blood clot/thrombi at the site of the infarct.
- By-pass surgery
- Angioplasty (balloon) +/- stents.
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Lysosomal storage disease
- Wolman’s disease: inactive esterase = CE accumulates
- Niemann-Pick C: cholesterol exporter mutated = cholesterol accumulates
- after LDL is internalized via LDLR, it goes to lysosomes for degradation
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I cell disease
- defect in PGlcNAc transferase.
- loss of the M6P lysosomal targeting signal.
- Result: “Lysosomal proteins” are secreted and high levels of Hex in blood & urine.
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Tay-Sachs
- defect in degradation of ganglioside GM2
- high turnover in infant brain -> neuro effects
- mutation in HexA gene
- diagnostic test based on temperature sensitivity difference between HexA and B
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treatments for lysosomal storage disease
- Removal of stored product (cysteamine for cystinosis)
- Substrate reduction for glycosphingolipid storage diseases
- BMT, gene therapy
- Replacement of missing enzyme: enzyme w/M6P for targeting. Doesn't reach the brain, which is often the organ most affected
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