1. 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
  2. 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.
  3. 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
  4. Familial Hypercholesterolemia
    • dominant disorder
    • mutations in the LDLR gene
    • Heterozygotes are quite common ~1/200
    • blood cholesterol levels ~300-450 mg/dl.
  5. HMG-CoA reductase
    • rate limiting enzyme for cholesterol synthesis
    • Statin drugs target: reduced blood LDL levels of 18-55%
  6. 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
  7. 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
  8. Absence of LPL, ApoCII or Insulin
    • Increased free fatty acids
    • Diabetes
  9. Lipoprotein lipase (and ApoCII)
    • insulin (fed state) increases LPL activity.
    • hydrolysis of dietary TGs and release of fatty acids
  10. NAFLD
    • non-alcoholic fatty liver disease
    • 24-42% US population, most asymptomatic
    • 66% diabetics have this
    • incr. plasma triglycerides, caused by obesity
  11. trans fatty acids
    • produced by food industry to maintain shelf life
    • incr. risk of MI
    • they lack a kink, more like saturated FAs
  12. 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
  13. 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
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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.
  19. 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
  20. 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.
  21. 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
  22. 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
Card Set
lipid metabolism