Med Phys Pharm 551 L29 Hyperlipidemia Phys Lecture Notes PDF

Lecture #29: Hyperlipidemia Physiology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L29: Learning Obje...

Lecture #29: Hyperlipidemia Physiology Julia Hum, PhD Primary Course Instructor Course Meets: Monday/Wednesday/Friday: 2:00-2:50pm Office Hours: Monday/Wednesday/Friday 11:00am-12:00pm (317B or WebEx)  L29: Learning Objectives 1. Define the causes and correlations of CHD with cholesterol and triglyceride levels 2. Understand the basic biochemistry and physiology of cholesterol and lipoprotein metabolism 3. Understand the metabolism of ApoB-containing lipoproteins and the three divisions of their “lifespan” 4. Describe the formation and clearance of LDL particles; predict changes from “normal” with genetic mutations 5. List the treatment goals of CHD 6. Calculate and interpret the 10-year ASCVD Risk Unless otherwise noted, figures in today’s lecture are from: Principles of Pharmacology 3e Baca, Golan (Ch. 19), Lippincott Illustrated Reviews: Pharmacology 6e Yellepeddi (Ch. 23) L29: “Take Home” Slide  Case Study A 42-year-old man with moderately severe coronary artery disease has a body mass index (BMI) of 34, increased abdominal girth, and hypertension that is well controlled. A lipid panel is ordered: Total: LDL: HDL: Triglycerides:  Coronary Heart Disease Coronary heart disease (CHD) is the leading cause of death worldwide CHD is correlated with: elevated levels of: 1. Elevated LDL (“bad” cholesterol) 2. Elevated Triglycerides 3. Low levels of HDL (“good cholesterol”) https://www.nhlbi.nih.gov/sites/www.nhlbi.nih.gov/files/images_349 LO1 Risk Factors for CHD/CAD Coronary Heart Disease Hyperlipidemias can also result from an inherited defect in lipoprotein metabolism Combination of genetic and lifestyle factors Appropriate lifestyle changes and drug therapy can lead to a 30% to 40% reduction in CHD mortality Antihyperlipidemic drugs are often taken indefinitely to control plasma lipid levels  Love for Lipids Essential for membrane biogenesis and maintenance of membrane integrity Serve as energy sources, hormone precursors, and signaling molecules To facilitate transport through the blood nonpolar lipids (cholesteryl esters and triglycerides) are packaged within http: //ma cromole cule ma ni a.we e bl y.c om /upl oa ds/2/5/1/8/25186489/2396884_orig.jpg lipoproteins LO2  Biochemistry and Physiology of Cholesterol and Lipoprotein Metabolism Lipoproteins are macromolecular aggregates that transport triglycerides and cholesterol in the blood Circulating lipoproteins can be differentiated by: Density Size Protein content LO2  Biochemistry and Physiology of Cholesterol and Lipoprotein Metabolism Lipoproteins are microscopic particles ranging from 7 to 100 nm in diameter Consists of a monolayer of polar, amphipathic lipids that surrounds a hydrophobic core LO2 http: //www. robertba rrington.net/wp-content/uploads/2013/01/L ipoprotei ns.jpg  Biochemistry and Physiology of Cholesterol and Lipoprotein Metabolism The hydrophobic core - cholesteryl esters and triglycerides Apolipoproteins (“apoproteins”) are amphipathic proteins Intercalate into the surface coat of lipoproteins Stabilize the structure of lipoproteins Example: each LDL particle contains Engage in biological functions one apoB100 molecule which is a Act as ligands for lipoprotein receptors or may activate ligand for the LDL receptor enzymatic activities in the plasma Binding of LDL to the LDL receptor promotes cholesterol uptake into LO2 cells  Biochemistry and Physiology of Cholesterol and Lipoprotein Metabolism Lipoproteins can be divided into: 1. Participate in the delivery of triglyceride molecules to muscle and fat tissue apoB-containing lipoproteins, chylomicrons, and VLDL 2. Involved primarily in cholesterol transport HDL and apoB-containing lipoproteins HDL also serves as a reservoir for exchangeable apolipoproteins in the plasma apoAI, apoCII, and apoE LO2  Metabolism of ApoB-Containing Lipoproteins Primary function of apoB-containing lipoproteins is to deliver fatty acids to: 1. Muscle tissue Use in ATP biogenesis https ://www.ma btech. com/sites/defa ult/fil es/a polipoprotein-la ndi ng 3_2.png 2. Adipose tissue For storage Chylomicrons are formed in the intestine transport dietary triglycerides VLDL particles are formed in the liver transport triglycerides that are synthesized endogenously LO3  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles This unesterified cholesterol affects three major homeostatic pathways 1. Intracellular cholesterol inhibits HMG- CoA reductase the enzyme that catalyzes the rate-limiting step in de novo cholesterol synthesis LO4  Clinical Connection: Familial Hypercholesterolemia (FH; Type IIA) Autosomal dominant disease involving defects in the LDL receptor Mutations in the gene encoding the LDL receptor result in one of four molecular defects: 1) lack of receptor synthesis 2) failure to reach the plasma membrane 3) defective LDL binding 4) failure to internalize bound LDL particles Heterozygous individuals (1 in 500 in USA) Clinical features: LO4  Clinical Connection: Familial Hypercholesterolemia (FH; Type IIA) Homozygous FH is a much more severe but rare disorder (1 in 1 million in USA) Characterized by the absence of functional LDL receptors Clinical features: LO4 Drugs for Hyperlipidemia  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles This unesterified cholesterol affects three major homeostatic pathways 2. Cholesterol activates acetyl-coenzyme A:cholesterol acyltransferase (ACAT) increase esterification and storage of cholesterol in the cell LO4 Drugs for treatment of Hyperlipidemia Selectively inhibits absorption of dietary and biliary cholesterol in the small intestine Leads to a decrease in the delivery of intestinal cholesterol to the liver Causes a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles This unesterified cholesterol affects three major homeostatic pathways 3. LDL receptor expression is down- regulated, reducing further uptake of cholesterol into the cells The majority of LDL receptors (70%) are expressed on the surface of hepatocytes The liver is primarily responsible for the removal of LDL particles from the circulation LO4  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles LDL particles not taken up by LDL LDL and Atherosclerosis receptor-expressing tissues may migrate into the intima of blood vessels and bind to proteoglycans Subject to oxidization or nonenzymatic glycosylation Oxidation of LDL results in lipid peroxidation and may create reactive intermediates that fragment apoB100 The modified LDL is internalized by scavenger receptors (SR-A) expressed by mononuclear phagocytic cells LO4  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles LDL and Atherosclerosis Continued accumulation of oxidized LDL in macrophages can lead to foam cell formation (cholesterol-rich macrophages) Foam cells may undergo apoptotic or necrotic death releasing free radicals and proteolytic enzymes LO4  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles LDL and Atherosclerosis Oxidized LDL causes: a) up-regulation of cytokine production b) impairs endothelial function c) increases expression of endothelial adhesion molecules All of these increase the local inflammatory response and promote atherosclerosis LO4  Metabolism of ApoB-Containing Lipoproteins: Formation and Clearance of LDL Particles LDL and Atherosclerosis Foam cells are a major constituent of atherosclerotic lesions Excessive foam cell death can destabilize atherosclerotic plaques Plaque rupture is the main cause of acute ischemic cardiovascular events (heart attacks and strokes) High plasma levels of LDL are a major risk factor for the development of atherosclerosis and subsequent cardiovascular disease LO4  Top 10 List of Drugs Prescribed in America 10. Amlodipine – high blood pressure 5. Amoxicillin– infections Norvasc – Ca++ channel blocker Amoxycillin 9. Alprazolam - anxiety Xanax – short acting “benzo” 4. Lisinopril- hypertension, heart failure Zestril – ACE inhibitor 8. Atorvastatin – high cholesterol Lipitor – “Statins” 3. Prednisone– arthritis/inflammation Delasone – steroid hormone 7. Metformin - T2D Glucophage – first line of defense 2. Levothyroxine - hypothyroidism T4 vs T3 6. Gabapentin – seizures and nerve pain 1. Hydrocodone/Acetaminophen – Pain Neurontin Vicodin/Norco  Treatment Goals of Hypercholesterolemia: Effect of circulating LDL and HDL on risk of CHD The clinically important lipoproteins in decreasing order of atherogenicity: LDL VLDL and chylomicrons HDL The occurrence of CHD is positively associated with high total cholesterol and more strongly with elevated LDL High levels of HDL have been associated with a decreased risk for heart disease Total cholesterol = LDL + VLDL+ HDL Reduction of LDL is the primary goal of cholesterol- LO5 lowering therapy  Treatment Goals of Hypercholesterolemia: Effect of circulating LDL and HDL on risk of CHD Past cholesterol guidelines recommended treating to specific targets for LDL Recent cholesterol guidelines do not recommend targets but instead emphasize high-intensity or moderate-intensity statin therapy LO5  10-year risk for ASCVD is categorized as: Low-risk (