Lipoprotein Metabolism - Mansoura National University - Level 2 - Semester 3 - PDF

Mansoura National University Faculty of Medicine Level: 2 Semester: 3 2024-09-15 Mansoura National University 1  Lipoprotein metabolism By Dr. Wesam Sameer El-Saeed...

Mansoura National University Faculty of Medicine Level: 2 Semester: 3 2024-09-15 Mansoura National University 1  Lipoprotein metabolism By Dr. Wesam Sameer El-Saeed Lecturer of Medical Biochemistry and Molecular Biology Department Email: [email protected] 2024-09-15 Mansoura National University 2  Contents Plasma lipoproteins: structure – functions – classification. Metabolism of chylomicrons. Metabolism of VLDL. Metabolism of LDL. Metabolism of HDL. 2024-09-15 Mansoura National University 3  Learning Outcomes (LOs) At the end of this session, the students should be able to: Classify lipoproteins and identify their functional significance. Recognize metabolism of different types of plasma lipoproteins. Correlate their knowledge to the clinical case. 2024-09-15 Mansoura National University 4  Case scenario (Clinical correlate) A 38-year-old male came to the general practitioner with yellow skin lesions on his forearm and palmar surfaces of the hands. His father passed away from myocardial infarction at the age of 52 years. Physical examination revealed severe xanthomas in the upper and lower extremities. Laboratory investigations showed elevated LDL-C, total cholesterol and decreased HDL levels. What is your provisional diagnosis? What are possible complications? 2024-09-15 Mansoura National University 5  LO 1 Classify lipoproteins and identify their functional significance. 2024-09-15 Mansoura National University 6  Lipoproteins 2024-09-15 Mansoura National University 7  Plasma lipoproteins  Plasma lipoproteins are complex molecules organized as micelles of nonpolar core and a single layer of amphipathic lipids.  Lipid part: Triglycerides , cholesterol , phospholipids.  Protein part (apolipoprotein or apoprotein). 2024-09-15 Mansoura National University 8  Plasma lipoproteins  Nonpolar core (hydrophobic):  Triglycerides (TG).  Cholesterol ester (CE).  Outer layer (hydrophilic):  Free cholesterol.  Phospholipids.  Apoproteins. 2024-09-15 Mansoura National University 9  Plasma lipoproteins Functions:  The primary function of plasma lipoproteins is to transport lipids in circulation. Lipids are insoluble in water, so it bind to proteins to form water- soluble lipoproteins to be transported in the blood. 2024-09-15 Mansoura National University 10  Plasma lipoproteins Functions:  These lipoproteins play a key role in: Transport of dietary lipids from the small intestine, Transport of lipids from the liver to peripheral tissues, Transport of lipids from peripheral tissues to the liver. 2024-09-15 Mansoura National University 11  Plasma lipoproteins Classification: Lipoproteins differ in lipid and protein composition, size, density and electrophoretic mobility. Based on density, the main 4 types are: 1) Chylomicrons. 2) Very low density lipoproteins (VLDL). 3) Low density lipoproteins (LDL). 4) High density lipoproteins (HDL). 2024-09-15 Mansoura National University 12  Plasma lipoproteins Classification: According to electrophoretic mobility, the main 4 types are: 1) Chylomicrons. 2) β-lipoproteins (LDL). 3) Pre β-lipoproteins (VLDL). 4) α-lipoproteins (HDL). 2024-09-15 Mansoura National University 13  Plasma lipoproteins Classification: 2024-09-15 Mansoura National University 14  Plasma lipoproteins 2024-09-15 Mansoura National University 15  Plasma lipoproteins 2024-09-15 Mansoura National University 16  LO 2 Recognize metabolism of different types of plasma lipoproteins 2024-09-15 Mansoura National University 17  Chylomicrons  Site of synthesis: intestinal mucosa.  The largest lipoproteins.  Composition: Lipid core (TG 85-90% and CE). Outer layer of phospholipids and cholesterol. Apolipoprotien, mainly apoB-48 (1-2%).  Function: transport dietary TG from intestine to peripheral tissues (liver, muscle and adipose tissue). 2024-09-15 Mansoura National University 18  Chylomicrons  Metabolism:  Dietary TG are digested in the gut to fatty acids and monoglycerides.  Fatty acids and monoglycerides are absorbed into the enterocytes where they are re synthesized in TGs and packaged into chylomicrons (CM).  Subsequently, CM enter the circulation and receive apoC-II and apoE from HDL, forming mature chylomicrons.  Lipoprotein lipase (LPL), enzyme anchored to capillaries endothelium, breaks down TGs of mature chylomycrons and release large amounts of fatty acids.  Part of the fatty acids is taken up by skeletal and cardiac muscle for oxidation and by adipose tissue for storage and part is bound to albumin and circulates in plasma as free fatty acids (FFAs).  Chylomicron remnants are formed, rich in cholesterol, and removed from the circulation by the liver by LDL receptor (apoE receptor). 2024-09-15 Mansoura National University 19  Chylomicrons  Metabolism: 2024-09-15 Mansoura National University 20  VLDL (Pre β-lipoproteins)  Site of synthesis: liver.  Composition: Lipid core (TG 55% and CE). Outer layer of phospholipids and cholesterol. Apolipoprotien, mainly apoB-100 (7-10%).  Function: transport TG from liver to extrahepatic tissues (muscle and adipose tissue). 2024-09-15 Mansoura National University 21  VLDL (Pre β-lipoproteins)  Metabolism:  In the hepatocytes, TG and CE are transferred to apoB-100, forming nascent VLDL that is released to the circulation.  Nascent VLDL, similar to chylomicrons, obtains apoC-II and apoE from circulating HDL and is now termed mature VLDL.  The apoC-II in mature VLDL activates LPL to cleave their stored TG into fatty acids and monoglycerides, releasing them from the VLDL.  The core of the VLDL gets reduced, and the VLDL remnant is now called intermediate density lipoproteins (IDL).  The remnants may be taken up by the liver by the LDL receptor (apoB- 100, apoE receptor), or they may be further metabolized to LDL in the circulation.  VLDL transports endogenous lipids from the liver to extrahepatic tissues (unlike chylomicrons which carry exogenous dietary lipids from intestine). 2024-09-15 Mansoura National University 22  VLDL (Pre β-lipoproteins)  Metabolism: 2024-09-15 Mansoura National University 23  VLDL (Pre β-lipoproteins)  Metabolism: Cholesteryl ester transfer protein (CETP) 2024-09-15 Mansoura National University 24  VLDL (Pre β-lipoproteins)  Metabolism: 2024-09-15 Mansoura National University 25  LDL (β-lipoproteins)  Site of synthesis: in blood from VLDL.  Composition: Lipid core (TG 13% and CE 48%). Outer layer of phospholipids (28%) and cholesterol. Apolipoprotien, mainly apoB-100 and apoE (20%).  Function: transport cholesterol from liver to extrahepatic tissues. 2024-09-15 Mansoura National University 26  LDL (β-lipoproteins)  Metabolism:  The liver and many extrahepatic tissues express the LDL receptor (apoB- 100, apoE receptor).  Approximately 70% of circulating LDL (rich in CE and PL) is cleared by liver and 30% taken up by extrahepatic tissues.  LDL plays a key role in the formation of atherosclerotic plaques that leads to atherosclerotic cardiovascular disease (bad cholesterol). 2024-09-15 Mansoura National University 27  LDL (β-lipoproteins)  Metabolism: 2024-09-15 Mansoura National University 28  LDL (β-lipoproteins)  Metabolism: 2024-09-15 Mansoura National University 29  HDL (α-lipoproteins)  Site of synthesis: liver and intestine.  The smallest lipoproteins.  Composition: Lipid core (TG 3% and CE 15%). Outer layer of phospholipids (25%) and cholesterol. Apolipoprotien, mainly apoA (50%). 2024-09-15 Mansoura National University 30  HDL (α-lipoproteins)  Functions: 1. A source of apoC and apoE required in the metabolism of chylomicrons and VLDL. 2. Uptake of free cholesterol from extrahepatic tissues and esterifying it using lecithin cholesterol acyl transferase (LCAT) enzyme, activated by apoA1. 3. Carry cholesterol ester to liver (reverse cholesterol transport). LCAT 2024-09-15 Mansoura National University 31  HDL (α-lipoproteins)  Metabolism:  Nascent HDL consists of discoid phospholipid bilayers containing apo A and free cholesterol.  Free cholesterols are converted into cholesteryl esters by LCAT enzyme (activated by apoA1), forming mature spherical HDL.  The cholesterol ester carried in the core of HDL particles may be transferred to apoB containing particles in exchange for TG by CETP enzyme.  HDL cholesterol is primarily delivered to the liver via Scavenger receptor B1 (SR-B1), which promotes the selective uptake of HDL cholesterol.  Hepatic lipase hydrolyzes both TG and PL in HDL.  The apoA1 from the degradation of HDL is recycled for new HDL formation. 2024-09-15 Mansoura National University 32  HDL (α-lipoproteins)  Metabolism: 2024-09-15 Mansoura National University 33  HDL (α-lipoproteins)  Metabolism: Bile cholesterol and bile acids 2024-09-15 Mansoura National University 34  Lipid transport 2024-09-15 Mansoura National University 35  LO 3 Correlate their knowledge to the clinical case 2024-09-15 Mansoura National University 36  Case scenario (Clinical correlate) A 38-year-old male came to the general practitioner with yellow skin lesions on his forearm and palmar surfaces of the hands. His father passed away from myocardial infarction at the age of 52 years. Physical examination revealed severe xanthomas in the upper and lower extremities. Laboratory investigations showed elevated LDL-C, total cholesterol and decreased HDL levels. What is your provisional diagnosis? What are possible complications? 2024-09-15 Mansoura National University 37  Case scenario (Clinical correlate) A case of familial hypercholesterolemia with xanthomas. Complications of hypercholesterolemia include atherosclerosis, myocardial infarction, ischemic cardiomyopathy, sudden cardiac death, ischemic stroke and acute limb ischemia. 2024-09-15 Mansoura National University 38  References Lippincott’s Biochemistry. 6th Edition, Chapter 18, Lippincott Williams & Wilkins, eds. Vasudevan's Textbook of Biochemistry For Medical Students, 6th Edition. Harper's Illustrated Biochemistry. 31e, Chapter 25-26, Botham & and Mayes, eds. Agirbasli, D., Hyatt, T., & Agirbasli, M. (2018). Familial hypercholesterolemia with extensive coronary artery disease and tuberous and tendinous xanthomas: A case report and mutation analysis. Journal of Clinical Lipidology, 12(4), 863-867. 2024-09-15 Mansoura National University 39 2024-09-15 Mansoura National University 40