1Cholesterol Homeostasis and HyperlipidemiaDec 7, 2005(Chem. 153C)Peter A. Edwards Departments of Biological Chemistry and Medicine>50% of all deaths in USA result from atherosclerosis and cardiovascular disease.Obesity in the USA is increasing dramatically, often leading to type II diabetes. >50% diabetics have cardiovascular disease andthe major cause of death for diabetics is atherosclerosis. Hyperlipidemia (elevated blood cholesterol and/or triglycerides) is linked to: atherosclerosis, MI (myocardial infarct)/heart attack (50% arefatal) and diabetes.Diabetes, hyperlipidemia.Angiographyidentifieslesions andplaques. (lesions<80%occlusion are often asymptomatic)Man exercising19961991Obesity Trends* Among U.S. AdultsBRFSS, 1991, 1996, 2004(*BMI ≥30, or about 30 lbs overweight for 5’4” person)No Data <10% 10%–14% 15%–19% 20%–24% ≥25%20042LumenPlaque shoulder;siteof rupture & thrombus(1stsymptom for many is death)Normal human arteryHuman atheroscleroticplaqueDying muscleAtherosclerosis, plaque formation, thrombus and MIAtherosclerosis:Risk factors include:high levels of plasma LDL (cholesterol)low levels of plasma HDL (cholesterol) obesitydiabetes (and metabolic syndrome)smoking male, or menopausal femalehigh levels of plasma LP(a)high blood pressure (BP)geneticshigh homocysteineMillions of Americans take drugs to lower LDL, raise HDL, lower BP, treat diabetes, all at the cost of billions of dollars. Treatments for obesity,including surgery is now also very common and costly. Plasma Lipoproteins (transport insoluble/hydrophobic lipids)Pro-atherogenic LDLChylomicrons (lipid absorption from intestine)VLDL (high in metabolic syndrome)HDL is athero-protective (levels higher in females>males)LDLEpitope for LDL receptor3Cholesterol synthesis and endocytosis (via LDL receptors)LDL (cholesterol ester-rich)LDL receptorPlasma membraneTarget of Statin drugs(>$16B in 2004)BloodVVVVLDLRTriglycerideFatty acids and glycerol(high fat diet leads to obesity)(muscle and fat)TGLipoproteins transport insoluble lipids in the blood to tissues for storage (adipose tissue), energy use (muscle), or structure (cholesterol)TGHDLUnload cholesterolfrom cellsLipoprotein lipase: is bound to endothelial cells lining the blood vessels in adipose tissue and muscleTriglyceride (TG)(in lipoprotein core)Hydrolysis of Triglycerides by Lipoprotein Lipase.4How important is the LDL receptor? Answer: VERY important.(LDLR binds and internalizes cholesterol-ester rich LDL from the blood)Outside the cellLDLPatients with mutations in both LDL receptor genes (Familial Hypercholesterolemia; FH)have blood cholesterol levels ~1000 mg/dl (vs normal values <200) and have heart attacksin pre-teens.Importantly from a clinical view, Statins(a class of drugs) increase the expression of LDL receptors in the liver of “normals”resulting in ~50% decrease in plasma LDLlevels and decreased riskof heart attack/MI.Inside the cellHomozygousFH (no LDLRs) XS cholesterol, derived from synthesis or endocytosis of LDL (via LDLR)represses transcription of the LDLR and HMG-CoA reductase genes pH~6pH<5proton pump(acidification)HMG-CoA reductaseCholesterol (signal)RecyclingreceptorrepressorCholesterol ester (CE) in LDL coreFatty acidC18:1Lipase (lysosomal)Fatty acid +Cholesterol (regulatory signal)Fatty acyl-CoA+cholesterolACAT: Acyl CoA Cholesterol Acyl TransferaseACATHydrolysis of cholesterol ester in LDL core by a lysosomal
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