S67: Cholesterol Metabolism and Statins!Learning Objectives 1) Learn the physiological roles of cholesterol and the importance of maintaining healthy cholesterol levels. 2) Understand how cholesterol biosynthesis is regulated. 3) Recall how cells take up cholesterol thru the LDL receptor. 4) Learn how statin drugs are used to treat hypercholesterolemia. 1) Learn the physiological roles of cholesterol and the importance of maintaining healthy cholesterol levels. - Cholesterol is essential for humans - essential component of cell membrane, but not an essential nutrient (we can make it)!- precursor for syn. of steroid hormones, bile acids, Vit D!- Excess: forms deposits on blood vessels --> atherosclerotic plaques --> heart attack and stroke!- Sources of Ch (= cholesterol) - Diet or biosynthesis!- all cells can syn., liver does most (20-50%)!- dietary: animal products-- meat, dairy, eggs, etc.!- aka vegans don't get any from diet, can syn. all they need!- Best- <300 mg/day!- When Ch is bad!- insoluble in aq envis, so carried as part of lipoprotein!- high levels of Ch (hypercholesterolemia), esp. in LDL lipoproteins --> increases risk for atherosclerosis!- Ch and Ch-Esters accum. in plauqes that form in blood vessels!- Relationship between LDL levels and coronary heart disease: increase LDL, increase CHD events!- Cholesterol Esters!- Most Ch not in membranes is in Ch-esters (esterified hydroxyl group with a fatty acid)!- Ch-Esters formed by ACAT= acyl CoA: cholesterol acyltransferase --> now is even less soluble!- Ch -- (ACAT)---> Ch-E! 2) Understand how cholesterol biosynthesis is regulated. - Regulation of Systemic Ch Levels - We DO NOT oxidize Ch to derive E or metabolize it to degrade it!- Only way to get rid of excess: thru loss of cells (skin, intestinal) and thru excretion (Ch or bile acids)!- Liver secretes Ch into bile w/bile acids --> small intestine during digestion!- 40-50% of Ch and 90-95% of bile acids secreted into bile are reabsorbed and go back to liver thru enterohepatic circulation!- Inhibit Ch resorb. by: Ezetimide (Zetia, Ezetrol)!- Ch Biosyn from Acetyl CoA req. 20 enzymes!- ALL of the C's in Ch come from acetyl CoA!- Whole pathway uses: 6 ATP, 8 NADPH - HMG-CoA Reductase= rate limiting step/enzyme (enzyme is in cyto) !1) Condensation of 3 acetates --> 6 C mevalonate !- acetates are from HMG-CoA!- 1st committed step of Ch biosyn.2) Mevalonate + 3 ATPs --> activated 5C isoprene units 3) Polymerization of six 5 C isoprenes --> 30 C linear squalene 4) Cyclization of squalene --> 4 ring steroid nucleus, oxidations and removal or migration of methyl groups!- Feedback inhibition of Ch synthesis - Ch inhibits HMG-CoA reductase (feedback inhibition)!- Regulation of HMG-CoA reductase 1) Enzyme activity (covalent mod--phosphorylation inactivates)!- AMP high (low E in cell) --> activates AMP-activated protein kinase --> phosphorys HMG-CoA --> is inactive --> no Ch made (insulin is opposite)!2) Protein degradation - getting ubiq.!- HMG - CoA Reductase is in ER and has a sterol sensing domain that interacts w/lanosterol (precursor of Ch) --> recruitment of ubiquitin ligase --> triggers proteasomal degradation !- half life of HMG CoA reductase is 12 hours w/o sterols, and less than 1 hr. w/high sterols!3) Transcriptional regulation = making the enzyme!- SREBP= a txn factor in the ER, assoc. w/SCAP (sterol sensing protein) when Ch is present!- When Ch falls --> SREBP moves to golgi --> cleaved by proteases --> active txn factor is released --> translocated to nucleus and binds upstream of gene of HMG-CoA reductase !--> stimulates its expression 3) Recall how cells take up cholesterol thru the LDL receptor. - Familial Hypercholesterolemia= genetic disorder, fams have high Ch levels (325-500 mg/dL) and early onset cardivascular disease!- Most common mut= gene for LDL receptor!- LDL receptor= allows liver to take up Ch delivered from other tissues and then dipose of it in the bile !- LDL receptor is another target for SREBP induction!- LDL Receptor Mutations increase LDL and Atherosclerosis!- Homozyg. patients have 5x normal LDL, dev. atherosclerosis and MIs in adolescence!- Heterozy. pateints have 2-3x higher LDL and dev. symptoms around 40 !- They don't internalize LDL ! 4) Learn how statin drugs are used to treat hypercholesterolemia. - Hypercholesterolemia!- people w/total Ch levels > 200 mg/dL or LDL > 160 mg/dL have greatly increased risk for dev. CHD!- Preventative med.= reduce Ch levels below those!- diets w/less Ch and less sat. fatty acids, exercise!- drugs to lower Ch syn. or absorption!- Statins= class of drugs that are competitive inhibitors of HMG-CoA Reductase!- reduced Ch biosyn. + low fat diet --> decrease in whole body Ch levels!- slow progression of atherosclerosis, reduce risk of acute coronary events!- liver= site of action!- has a part of enzyme that looks like mevalonate and gets stuck in active site of enzyme!- Actions of Statin in Liver!- Statin acts to reduce Ch levels in liver by inhibiting HMG-CoA reductase --> Ch feedback reg pathway kicks in --> activates SREBP --> increases txn of LDL receptor gene and increases levels of LDL receptor on pm --> enhanced uptake of Ch from blood and increased excretion of Ch and bile acids into bile!- can low plasma Ch levels by 20-40%!!S68: Lipoprotein Metabolism and Atherogenesis!Learning Objectives 1) Understand the general composition and organization of serum lipoproteins. 2) Learn the different classes of serum lipoproteins and their distinct roles in the transport of triglycerides and cholesterol. 3) Appreciate the role of lipoprotein lipase in metabolism of lipoprotein particles. 4) Know the role of HDL in reverse cholesterol transport and its relation to atherogenesis and coronary heart disease. 1) Understand the general composition and organization of serum lipoproteins. - Lipoproteins= specialized lipid transport particles!- lipids= hydrophobic, hard to transport, have to bind them to more soluble molecule (like albumin) or package into specialized lipid transport particles!- contain both lipid and protein components, ratio varies!- protein comp= apolipoproteins= structural comp. of the particle and baggage tag for fate of particle and enzyme cofactors!- core= hydrophobic neutral lipids!- shell= amphipathic lipids and proteins 2) Learn the different classes of serum lipoproteins and their distinct roles in the transport of triglycerides and cholesterol. - Classes of Lipoprotein Particles -
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