Lipoprotein Physiology & Atherosclerosis BMS 150 PDF

Lipoprotein Physiology & Atherosclerosis BMS 150 Week 13 General Lipoprotein Physiology Cholesterol and triglycerides are transported through lymph and blood by a sub-cellular body known as a lipoprotein ▪ Outer envelope consists of a phospholipid monolayer...

Lipoprotein Physiology & Atherosclerosis BMS 150 Week 13 General Lipoprotein Physiology Cholesterol and triglycerides are transported through lymph and blood by a sub-cellular body known as a lipoprotein ▪ Outer envelope consists of a phospholipid monolayer interspersed with apoproteins and unesterified cholesterol ▪ Inner portion carries cholesterol esters and triglycerides Lipids are transported through the body via lipoproteins along three major routes: ▪ Exogenous pathway –gathers lipids from the digestive tract and distributes them throughout the body after a meal ▪ Endogenous pathway – the liver builds apoliproteins and secretes them into the bloodstream – also distributes lipids throughout the body ▪ Reverse cholesterol transport – scavenges cholesterol from peripheral tissues and returns it to the liver Summary – Endogenous & Exogenous Pathways, Reverse Cholesterol Transport HDL Lipids to HDL Mi Apoproteins from HDL IDL VLDL Ch VLDL Chy ChR LDL LDL IDL Chy Chy  Overview of Lipid Transport Exogenous Endogenous Reverse Cholesterol Transport Lipoprotein Enterocyte Liver Liver & Enterocyte synthesis Initial lipoprotein Chylomicron VLDL Nascent HDL (ApoA-I, ApoA- (key apoproteins) (ApoB-48, ApoE, ApoC-II, (ApoB-100, ApoA-V, ApoC-II) II, ApoC-II, ApoE) ApoA-V) Intermediate Chylomicron IDL (ApoE, ApoB-100) Mature HDL lipoproteins remnants  (ApoA-I, ApoA-II, ApoE) (key apoproteins) (ApoB-48, Apo-E) LDL (ApoB-100) Cleared by Liver Liver Liver (clearance (depends on ApoE for (LDL receptor for B-100, (SR-B1 after ApoA-I is degraded) mechanism) clearance) ApoE clearance) Function Carry dietary lipids to most Carry liver-synthesized lipids - Transfer apoproteins and lipids cells, but especially liver, to other cells between lipoproteins muscle, and adipose tissue - Clear peripheral deposits of cholesterol  Exogenous Pathway Initial lipoprotein: Chylomicrons are synthesized by the enterocyte – rich in triglycerides, less cholesterol esters, retinyl esters, phospholipids, and vitamin E ApoB-48 is inserted as a structural protein for the chylomicron Chylomicrons are secreted into the lymph and then travel to the thoracic duct to be transported into the bloodstream Intermediate forms: HDL particles transfer ApoC-II and ApoA-V to the chylomicrons These apoproteins allow the chylomicron to interact with lipoprotein lipase (LPL) LPL on the endothelial cells of capillaries cleaves TGs in chylomicrons to FFAs, which are then taken up by peripheral tissues After TGs are lost, the chylomicron becomes a chylomicron remnant HDL also transfers ApoE to the chylomicron so that the chylomicron remnant can be cleared by the liver Cleared by: Chylomicron remnants are cleared by the liver via an ApoE-dependent mechanism (LDL receptor) Summary –Exogenous Pathway HDL Mi Apoproteins from HDL Chy ChR Chy Chy  Endogenous pathway Initial lipoprotein: VLDL is synthesized by the liver – contains mostly TGs but also contains phospholipids, cholesteryl esters, vitamin E Contain ApoC-II and ApoA-V – these are important for the activity of LPL in peripheral tissues → as LPL “drains” triglycerides from VLDL, it becomes IDL and then LDL Also contains ApoB-100 – major structural protein and allows later clearance by the liver Intermediate forms: As TGs are removed from VLDL it becomes IDL – most IDL is cleared by the liver via ApoE binding to the LDL receptor (ApoE was transferred via HDL particles) IDL that loses TGs and becomes more and more cholesterol-rich becomes LDL LDL is cleared by the LDL receptor, and seems to have no useful physiologic role LDL receptor can bind to both ApoE and ApoB-100 Cleared by: Liver clears IDL and LDL via the LDL receptor on hepatocytes LDL receptor can bind to either ApoE or ApoB-100 If LDL is not cleared, it can become oxidized and becomes a major risk factor for the development of atherosclerosis Summary –Exogenous Pathway HDL Apoproteins from HDL IDL VLDL LDL VLDL LDL IDL  Summary – Reverse Cholesterol Transport Initial lipoprotein: HDL is synthesized by both hepatocytes and enterocytes – major structural proteins are ApoA-1 and Apo-A2 ApoA-1 can also allow HDL to receive cholesterol from the liver or peripheral tissues The “cholesterol-to-ApoA-1” transporter is ABC (ATP-binding cassette protein) Enzyme known as LCAT (lecithin-cholesterol acyltransferase) also aids this process by converting free cholesterol into cholesterol esters – it also associates with ApoA1 Intermediate forms & Clearance: HDL can help remove cholesterol from peripheral tissues via LCAT-ApoA-1-ABC interactions → an HDL particle “loaded” with cholesterol recirculates back to the liver The liver can remove cholesterol esters from HDL via the SR-B1receptor (scavenger receptor B1) The “unloaded” HDL can recirculate or be removed by the liver HDL can also “exchange” cholesterol between other lipoproteins via CETP (cholesterol ester transfer protein) The HDL particle “trades” its cholesterol for TGs in VLDL or chylomicrons The “traded” cholesterol in the VLDL or chylomicrons can then be removed via elimination (LDL receptor and ApoE or ApoB-100 interaction)  HDL Triglycerides from VLDL, Chy Cholesterol from HDL IDL Ch Summary –Reverse Cholesterol Transport VLDL LDL Regulation of the LDL receptor The liver can’t just receive infinite amounts of cholesterol from peripheral tissues ▪ Once hepatocytes accumulate excess cholesterol, they downregulate the LDL receptor, which reduces LDL clearance ▪ They will also secrete more cholesterol in the bile, and produce less VLDL ▪ Therefore, reducing liver cholesterol content (a major mechanism of “–statin” drugs) will result in improved clearance of IDL and LDL The LDL receptor is also degraded/removed from the hepatocyte membrane by a protein known as PCSK9 ▪ Inhibitors of this protein also improve IDL and LDL clearance Regulation of the LDL receptor Atherosclerosis Development of atheromas in a wide range of large and medium-sized arteries The leading cause of death in most Western countries Atherosclerosis - pathogenesis Endothelial injury, which causes (among other things) increased vascular permeability, leukocyte adhesion, and thrombosis ▪ Caused by inflammation, hypertension, toxins, hyperlipidemia Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall ▪ May increase free radical production by endothelial cells ▪ Activates macrophages upon binding to the scavenger receptor Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells How did the LDL get below the endothelium? Is it just leaky? ▪ Maybe a little, but likely not major reason ▪ LDL seems to bind weakly to the ECM of the intima, and will reside there for a variable amount of time It is here that they tend to become oxidized (ox-LDL) – they are “hidden” from antioxidants in the plasma AGEs may increase the binding of LDL to the matrix ▪ What is an AGE again? Atherosclerosis - pathogenesis As the plaque grows and the overlying endothelium becomes more dysfunctional → platelet adhesion Factor release from activated platelets, macrophages, and vascular wall cells → smooth muscle cell recruitment → smooth muscle cell proliferation and ECM production ▪ Development of fibrous cap ▪ Lipid-filled macrophages + smooth muscle cells = foam cells  Major Risk Factors For Atherosclerosis Dyslipidemia Lifestyle risk factors: ▪ High LDL cholesterol, ▪ Smoking low HDL cholesterol ▪ Physical inactivity Diabetes Mellitus ▪ “atherogenic” diet Hypertension Emerging risk Family history of factors: premature coronary ▪ Lipoprotein (a) heart disease ▪ Prothrombotic Age (men > 45 years, factors women > 55 years) ▪ Pro-inflammatory factors Obesity Atherosclerosis Risks are Additive Lipid Labs and Cardiac Risk Lipid Canadian Values LDL is measured indirectly: LDL Low risk: < 2.59 mmol/L LDL = TC – [(TGs/5)-HDL] Good: 2.59 – 3.34 mmol/L Borderline high: 3.37 – 4.11 Excessively high Bad: > 4.14 triglycerides skews this equation – if > TG 0.45 – 1.71 mmol/L (normal) 4.5 mmol/L, different (triglycerides) methods of determining LDL HDL Low risk: > 1.55 mmol/L need to be used High risk: < 1.04 mmol/L The TC:HDL ratio is often Total < 5.2 mmol/L (normal) used to calculate cardiac cholesterol risk from atherosclerosis (TC) Goal is < 3.5 Primary care lipid measurement Measure fasting serum TC, LDL, HDL, and TG ▪ screen with full fasting lipid profile q1-3yr in males >40 yr and females >50 yr or who are menopausal ▪ any age for adults with additional dyslipidemia risk factors Assign risk - estimate using the model for 10 year coronary artery disease risk developed from the Framingham data (Framingham Risk Score – FRS) ▪ Low risk: < 10% risk of developing coronary artery disease in the next 10 years ▪ Intermediate risk: 10 – 19% risk of developing coronary artery disease in the next 10 years ▪ High risk: > 20% risk of developing coronary artery disease in the next 10 years Primary care lipid measurement Framingham risk score is calculated based on the following factors: ▪ gender, age ▪ HDL-C, total cholesterol ▪ Systolic BP ▪ Smoking ▪ Presence of DM ▪ family history of CVD