IBHS 527 lecture 3

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IBHS 527 lecture 3
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2011-01-16 19:04:45
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Lipids: lipoproteins, cholesterol, arteriosclerosis. munson
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  1. 5 examples of lipids
    • 1. fatty acids
    • 2. triglycerides
    • 3. phospholipids/glycolipids
    • 4. eicosanoids/prostaglandins
    • 5. steroids
  2. what are 5 things lipids are good for?
    • 1. cell membranes - affect fluidity
    • 2. energy source/ storage
    • 3. insulation/protection - for internal organs
    • 4. hormones
    • 5. chemical messengers
  3. lypolysis
    • lipid catabolism (breaking down)
    • Triglycerides --> glycerol + 3 fatty acids
  4. 2 components of triglycerides break down
    • 1. glycerol
    • 2. 3 fatty acids
  5. context: 2 components of triglycerides break down
    glycerol's fate
    glycerol --> pyruvic acid (PA) --> acetyl-CoA --> goes into TCA cycle --> make NADH and FADH2
  6. context: 2 components of triglycerides break down
    3 fatty acids' fate
    3 fatty acids --(beta-oxidation)--> acetyl-CoA --> enters TCA cycle --> lots of ATP
  7. 2 types of energy sources
    • 1. lipids
    • 2. carbohydrates
  8. context: 2 types of energy sources
    lipids
    • 18 carbon fatty acid = net 144 ATP molecules
    • compact storage = hard to access = cannot produce ATP quickly (slow)
    • used in absence of glucose
  9. context: 2 types of energy sources
    carbohydrates
    • 3 * 6 carbon sugars = net 108 ATP molecules
    • less compact storage = easy to access = can produce ATP quickly
    • use preferentially
  10. lipogenesis
    • lipid synthesis (creating)
    • glycerol (dihydroxyacetone phosphate) + fatty acids (acetyl-CoA from lipids, amino acids, and carbohydrates) = triglycerides
  11. T/F
    you can break down anything and you can synthesize everything
    • FALSE. you CAN'T synthesize everything.
    • ex: essential fatty acids required for prostaglandin synthesis and cell membranes must be acquired through diet (plant-based fatty acid)
  12. 2 ways to get cholesterol
    • 1. synthesis
    • 2. dietary
  13. context: 2 ways to get cholesterol
    synthesis
    • endogenous - 1.0 g/day
    • 1. liver: HMG-CoA reductase (rate-limiting step)
    • 2. bile: 95% of bile reabsorbed
    • 3. HDL: scavenged from blood stream
  14. context: 2 ways to get cholesterol
    dietary
    • exogenous - 0.5 g/day
    • 1. meat, eggs, dairy
    • 2. 80% of serum cholesterol
    • 3. high saturated fats --> into elevated serum cholesterol
  15. context: lipid transport
    free fatty acids
    • easily diffuse across membranes because they are lipophilic
    • bound to albumin in blood
    • utilized for energy in glucose starved cells
  16. context: lipid transport
    lipoproteins
    • large lipid-protein complexes that houses triglycerides and cholesterol that insoluble (aggregate)
    • cannot diffuse across membranes due to large size
  17. context: lipid transport
    If triglycerides and cholesterol aggregate and are insoluble how do they get into the cell?
    • composition of lipoproteins:
    • 1. surface (hydrophilic) due to:
    • a) phospholipids (PL)
    • b) apoproteins (APO)
    • -increase solubility of lipids in circulation
    • -determine cellular destination of lipids based on protein
    • -stimulate or inhibit enzymes involved in lipid metabolism
    • 2. inside (hydrophobic)
    • a) triglycerides (TG) and cholesterol (Chol)
    • b) fat soluble vitamins
  18. how are lipoproteins classified (2)?
    based on shape and lipid:protein ratio
  19. 5 types of lipoproteins
    • 1. chylomicrons - largest
    • 2. very low density lipoproteins (VLDL)
    • 3. intermediate density lipoproteins (IDL)
    • 4. low density lipoproteins (LDL)
    • 5. high density lipoproteins (HDL) - smallest
    • *densities of lipoproteins depend on their relative amounts of protein and lipids
  20. context: 5 types of lipoproteins
    chylomicrons
    • composition:
    • 90% triglycerides, 4% cholesterol, 5% phospholipids, 1% protein
    • origin:
    • produced by intestinal epithelial cells (enterocytes)
    • function:
    • carry absorbed lipids from GI tract (ditet) into the blood stream via lymph capillaries (lacteals)
  21. context: 5 types of lipoproteins
    process of chylomicron production
    dietary lipids (fatty acids and cholesterol absorbed through the brush border of the small intestines) + pancreatic lipase + bile salts --> in the endoplasmic reticulum of intestinal epithelial cells, lipid products (lipoproteins, cholesterol, triglycerides) are assembled into chylomicrons --> enter lacteal ("milky") --(lipoprotein lipase) --> breakdown of chylomicrons --> TGs to muscles and adipose tissue; cholesterol to liver
  22. lipoprotein lipase (LPL)
    • enzyme on capillary epithelium in adipose, muscle, or liver tissue
    • process:
    • apoproteins (APO) on chylomicron surface --> allows correct delivery of chylomicron to tissue and lipase activation --> lipase turns triglycerides to glycerol and fatty acids --> glycerol and fatty acids enter cell for use; chylomicron remnant (CR) which is primarily cholesterol travels to hepatocytes (liver)
  23. context: 5 types of lipoproteins
    very low density lipoproteins (VLDL)
    • composition:
    • 60% triglycerides, 15% cholesterol, 15% phospholipids, 10% proteins
    • origin:
    • -triglycerides synthesized by liver and from conversion of excess carbohydrates
    • -cholesterol synthesized by liver and from degraded chylomicron remnants
    • function:
    • primary source of triglycerides for the body and transport the lipids (mainly TG) from the liver to the tissues
  24. context: 5 types of lipoproteins
    process of very low density lipoproteins (VLDL)
    released into circulation --> (1) apoproteins on the surface target the VLDLs to muscle and adipose tissue (2) activate lipoprotein lipase in capillary walls to remove triglycerides from VLDL --> VLDL remnants/intermediate density lipoprotein (IDL)
  25. context: 5 types of lipoproteins
    intermediate density lipoproteins (IDL)
    • composition:
    • 35% triglycerides, 30% cholesterol, 20% phospholipids, 15% proteins
    • origin:
    • VLDL remnants
    • function:
    • transport lipids from blood stream to the liver and circulation
  26. context: 5 types of lipoproteins
    process of intermediate density lipoproteins (IDL)
    transported from bloodstream --> (1) ~50% of IDL converted to LDL by lipoprotein lipase removing TGs, (2) ~50% binds to LDL receptor on liver via apoproteins which then enters cell via receptor mediated endocytosis --> (a) removal of TGs = degraded into LDLs, (b) addition of TGs = recycled into VLDLs --> both released into circulation
  27. context: 5 types of lipoproteins
    low density lipoproteins (LDL)
    • composition:
    • 10% triglycerides, 50% cholesterol, 20% phospholipids, 20% proteins
    • origin:
    • IDL process
    • function:
    • main carrier of endogenous cholesterol from liver to tissues
  28. context: 5 types of lipoproteins
    process of low density lipoproteins (LDL)
    • circulation -->
    • (1) 75% LDL binds to LDL receptors in the liver via apoprotein (specific) --> receptor mediated endocytosis --> degraded (components recycled/consumed), (2) 24% bind to LDL receptors in the peripherals --> degraded/consumed for cell metabolism and maintenance --> excess cholesterol diffuses out of cells to INC. serum (blood) cholesterol, (3) 1% becomes oxidized --> enters endothelium of blood vessels --> start of atherosclerosis which is "bad"
  29. context: 5 types of lipoproteins
    high density lipoproteins (HDL)
    • composition:
    • 5% triglycerides, 20% cholesterol, 25% phospholipids, 50% proteins
    • origin:
    • self assemble in the plasma from (a) free cholesterol (lecithin-cholesterol acyl transferase [LCAT] esterifies free cholesterol, (b) lipoprotein fragments
    • function:
    • transports cholesterol from tissues to liver ("good" as a scavenger)
  30. context: 5 types of lipoproteins
    process of high density lipoproteins (HDL)
    apoprotein specific, receptor-mediated endocytosis in the liver --> cholesterol is (a) consumed (into cell membrane or make LDLs) or (b) excreted in the bile --> HDLs released back into blood stream
  31. 9 steps in the distribution of lipoproteins by liver
    • 1. liver cells synthesize VLDLs for discharge into the bloodstream
    • 2. in peripheral capillaries, lipoprotein lipase removes many of the triglycerides from VLDLs, leaving IDLs; the triglycerides are broken down into fatty acids and monoglycerides
    • 3. when IDLs reach the liver, additional triglycerides are removed, and the protein content of the lipoprotein is altered. This process creates LDLs, which are transported to peripheral tissues to deliver cholesterol.
    • 4. LDLs leave the bloodstream through capillary pores or cross the endothelium by vesicular transport
    • 5. once in the peripheral tissues, the LDLs are absorbed by means of receptor-mediated endocytosis. The amino acids and cholesterol then enter the cytoplasm
    • 6. the cholesterol not used by the cell (in the synthesis of lipid membranes or other products) diffuses out of the cell
    • 7. the cholesterol then reenters the bloodstream, where it is absorbed by HDLs and returned to the liver
    • 8. in the liver, the HDLs are absorbed and their cholesterol is extracted. Some of the cholesterol that is recovered is used in the synthesis of LDLs; the rest is excreted in bile salts
    • 9. the HDLs stripped of their cholesterol are released into the bloodstream to travel into peripheral tissues and absorb additional cholesterol
  32. 8 steps for regulations of cholesterol synthesis
    • 1. LDL and IDL bind to LDL receptor (-R)
    • 2. LDL-R cluster in clathrin coated pits on cell membrane
    • 3. LDL-R vesicles pinch off and internalized = coated vesicles --> clathrin shed and recycled, LDL-R recycled
    • 4. endosome fuses with lysosome
    • 5. LDL disassembled into amino acids (apoproteins), cholesterol and triglycerides which is used for metabolism and maintenance of the cell
    • 6. cholesterol esterified by acyl-CoA cholesterol acyltransferase (ACAT)
    • 7. cholesterol stored in the endoplasmic reticulum (ER)
    • 8. increased intracellular cholesterol causes:
    • (a) INC. ACAT
    • (b) DEC. synthesis of HMG-CoA reductase
    • (c) DEC. synthesis of LDL-R (don't need anymore)
    • *net effect: decreased storage, decreased production, decreased uptake
  33. context: clinical interest
    hypercholesterolemia
    • INC. serum (blood) cholesterol
    • 2 ways:
    • 1. high fat/cholesterol diet
    • 2. familial hypercholesterolemia
  34. context: 2 ways to get hypercholesterolemia
    high fat/ cholesterol diet
    • -chylomicron remnants take cholesterol to the liver
    • -high intracellular cholesterol levels (causes DEC. LDL receptors which causes INC. serum cholesterol)
    • *desirable level is <200 mg/dl so anything above is at high risk
  35. context: clinical interest of hypercholesterolemia
    cholesterol: pros and cons
    • 2 pros (the good):
    • 1. important component of cell membranes
    • 2. precursor of:
    • a) bile salts (for digestion of fats and lipids)
    • b) steroid hormones (corticosteroids, mineralocorticoids, sex hormones)
    • c) vitamin D3
    • 2 cons:
    • 1) cardiovascular disease
    • 2) gallstones (gallbladder)
  36. arteriosclerosis
    • arteri/o = artery
    • -sclerosis = hardening
  37. 2 types of arteriosclerosis
    • 1. focal calcification
    • 2. atherosclerosis
    • *can lead to: hypertension, occlusion, hemorrhage, thrombosis, embolus
  38. context: 2 types of arteriosclerosis
    focal calcification
    • cause:
    • smooth muscle degeneration in tunica media followed by Ca2+ deposition
    • trigger:
    • age, diabetes mellitus, atherosclerosis
  39. context: 2 types of arteriosclerosis
    atherosclerosis
    • athero = porridge; yellow fatty plaque
    • sclerosis = hardening
    • cause:
    • lipid deposits in tunica media and damage to endothelial lining
    • trigger:
    • elevated lipids, diabetes, high blood pressure, smoking
    • * complications:
    • 1. brain = stroke, TIA
    • 2. heart = angina, heart attack
    • 3. male organ = erectile dysfunction
    • 4. legs = peripheral artery disease
  40. process of atherosclerosis development
    endothelial compromise --> fatty streaks and/or LDL infiltration --> endothelium responds - oxidizes LDL, release cytokines --> infiltration of monocytem/macrophages - ingest oxidized LDL --> foam cells --> foam cells attach to endothelia and release (1) cytokines - more monocytes/macrophage, (2) growth factors - smooth muscle proliferation --> foam cells slowly die, release Ca2+ stores = calcification --> cells start phagocytosins lipids = fatty plaque --> endothelium damaged, collagen exposed - platelet adhesion and aggregation = clotting
  41. dyslipidemia
    improper amounts of lipids or ratios of lipids
  42. hyperlipidemia
    elevated levels of lipid (cholesterol)
  43. measuring cholesterol
    cholesterol = LDL + HDL + triglycerides/5
  44. 5 treatments of dyslipidemia and hyperlipidemia
    • * goal:
    • 1. decrease LDL, TG, total cholesterol
    • 2. increase HDL
    • treatments:
    • a) Therapeutic Lifestyle Changes (TLC)
    • b) statins
    • c) cholesterol absorption blockers
    • d) Niacin
    • e) Bile acid sequestering agents
  45. context: 4 treatments of dyslipidemia and hyperlipidemia
    Therapeutic Lifestyle Changes (TLC)
    • 1. Decrease total fat, saturated fat and cholesterol consumption
    • -13-20% of calories in American diet from saturated fat even though recommended 7%
    • -350 -450 mg/day cholesterol in American diet even though recommended < 200 mg/day
    • -nutritionally balanced, "low fat", "low cholesterol" diet
    • -exercise
    • -weight loss
  46. context: 4 treatments of dyslipidemia and hyperlipidemia
    statins
    • inhibit HMG-CoA reductase
    • -DEC. cholesterol synthesis
    • -INC. LDL receptor synthesis
    • -INC. HDL
    • ex:
    • 1. Atorvastatin (Lipitor)
    • 2. Simvastatin (Zocor)
    • 3. Rosuvastatin (Crestor)
  47. context: 4 treatments of dyslipidemia and hyperlipidemia
    cholesterol absorption blockers
    • inhibits absorption of dietary cholesterol
    • ex:
    • 1. Ezetimibe (Zetia)
    • -less cholesterol inserted into chylomicrons
    • 2. Ezetimibe + Simvastatin (Vytorin)
    • -less cholesterol inserted into chylomicrons
    • -DEC. synthesis of cholesterol
  48. context: 4 treatments of dyslipidemia and hyperlipidemia
    Niacin
    • decreased TG breakdown in adipose tissue
    • -reduces available fatty acids for uptake by liver:
    • a) DEC. fatty acids in liver
    • b) DEC. TG synthesis in liver
    • c) leads to decreased VLDL (and LDL)
    • -inhibits HDL breakdown and lead to increase HDL by 15-35%
    • ex:
    • 1. immediate release Niacin (Niacor)
    • 2. extended release Niacin (Niaspan)
    • 3. Simvastatin (INC. HDL) + Niacin (Simcor)
  49. context: 4 treatments of dyslipidemia and hyperlipidemia
    bile acid sequestering agents
    • reduced enteroheptic recycling of bile acids
    • -large polymeric cation exchange resins
    • -bind bile acids and prevent reabsorption
    • -resin + bile acids (contain cholesterol) excreted
    • -more cholesterol used to make new bile
    • ex:
    • 1. Cholestyramine (Questran)
    • 2. Colestipol (Colestid)
    • 3. Colesevelam (Welchol)
    • *unpopular use because of side effects:
    • -GI distress
    • -excretion of vitamins (lose vitamins = acidic proile)
    • -INC. LDL receptor synthesis
  50. context: 2 ways to get hypercholesterolemia
    familial hypercholesterolemia
    • autosomal dominant deficiency of functional LDL receptors
    • -heterozygotes (1:500): 50% of normal LDL receptors (~3x increase in serum/blood cholesterol at birth)
    • -homozygotes: (1:1*106): complete lack of LDL receptors (~6x increase in serum/blood cholesterol level at birth)
  51. context: 2 ways to get hypercholesterolemia
    4 symptoms of familial hypercholesterolemia
    • 1. xanthomas = yellowish deposits cholesterol
    • -tendons (heterozygous)
    • -skin (homozygous)
    • 2. early onset atherosclerosis (coronary, cerebral, peripheral)
    • 3. MI (heart attack) before 20 years of age (homozygous)
    • 4. INC. duration of cholesterol in blood
    • -normal: 2.5 days
    • -familial hypercholesterolemia: 4.5 days
  52. context: 2 ways to get hypercholesterolemia
    treatments of familial hypercholesterolemia
    • heterozygotes:
    • 1. statins (requires at least one functional copy of LDL-4 gene)
    • -DEC. endogenous cholesterol
    • -produce more LDL receptors (DEC. serum/blood cholesterol)
    • 2. bile acid sequestrants
    • 3. Niacin
    • homozygotes:
    • 1. large doses of bile acid sequestrants
    • 2. LDL pheresis
    • -clearing LDL by blood filtration
    • 3. liver transplant
    • -liver cells with LDL receptors (about 75% of cholesterol can be harvested !! remember how the body processes LDL - slide on lipoprotein:LDL!!

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