1. Atherosclerosis Part 4 Cholesterol Transport and Utilization Majority of cholesterol is transported as cholesterol ester. The ester is synthesized in the plasma from cholesterol and the acyl chain of the phosphatidylcholine (Lecithin) The intracellular cholesterol is synthetized by ACAT. (Acyl- CoA:cholesterol acyltransferase) Low density lipoprotein (LDL) transport cholesterol to peripheral tissues, and high-density lipoprotein (HDL) transport cholesterol from peripheral tissues to the liver. Lecithin + Cholesterol LCAT Lysolecithin + Cholesterolester LCAT(Lecthin:cholesterol acyltransferase) Acyl-CoA + cholesterol ACAT Cholesterolester + HS- CoA

2. Control of Cholesterol Biosynthesis 1) HMG-CoA reductase The enzyme synthesis inhibited Hydroxy cholesterols  Phosphorylation dephosphorylation (active) 2) Hormonal regulation: insulin  cortisol, glucagon  3) Dietary cholesterol intake "feedback inhibitory" 4) LDL (Low-density Lipoprotein) receptor regulation 5) n-3 polyunsaturated fatty acids  6) Drug action on HMG-CoA reductase (statins) 

3. The LDL receptor pathway

4. The LDL receptor pathway (cont.) Plasma LDL is taken up by cells via LDL receptors in clathrin-coaated pits. LDL are separated from their receptor in endosomes (pH 5 to 6) then undergo digestion in lysosomes (pH ~3). The LDL receptors recycle back to the cell surface making <100 trips in their lifetime. Lysosomal enzymes breakdown apoB100 in LDL to amino acids and liberate cholesterol for cellular needs. The cellular level of cholesterol is self-regulating. An oversupply of cholesterol has three metabolism effects: 1.inhibition of HMG-CoA reductase - The rate limiting step in cholesterol synthesis. 2.activation of ACAT, which esterifies cholesterol for storage 3.inhibition of LDL receptor synthesis

5. Hereditary Hyperlipoproteinamias Dysbetalipoproteinemia: Accumulation of IDL, VLDL and chylomicron remnant. Elevated level of total cholesterol and triglycerides. The disorder caused by Apo-E or Apo-E receptor. Diabetes, hypothyroidism are associated with type III disorders. Abetalipoproteinemia: Genetic defect in the synthesis of Apo-B. Both chylomicron and VLDL are affected. Fat malabsorbtion occurs because chylomicron can not be formed by intestine. Multiple type hyperlipoproteinemia Increased level of VLDL and LDL which is resulted from the overproduction of VLDL. The biochemical defect is unknown. Familial hypecholesterolemias: LDL receptor downregulation or receptor defects. Homozygotes do not have functioning LDL receptor. The gene defect is caused by mutation, deletions, insertions.

6. Cholesterol Homeostasis in FH FH: Familial Hypercholesterolemia LDL receptor failed to migrate from endoplasmic reticulum to Golgi Homozygous form (rare) cholesterol level above 650 mg/ 100 ml They die before age 20. Heterozygous form (one defective allele) cholesterol level 250 - 500 mg/ 100 ml high risk to have heart attack

7. Involvement of the LDL receptor in cholesterol uptake and metabolism Regulatory actions of cholesterol After the synthesis in the endoplasmic reticulum, the LDL receptor matures in the Golgi complex then migrates to the cell cell surface, where it clusters in coated pits. After internalization of LDL, multiple vesicles fuse to form endosome. Proton pumping in the endosome membrane causes the pH to drop, which in turn cause LDL to dissociate from the receptor. The LDL apolipoprotein is degraded in lysosomes. The LDL receptor remains in a vesicle, which returns to the plasma membrane to start the cycle anew.

8. Structure of the LDL receptor The structure is divided into five domains. The first domain contains the LDL binding site. This is followed by a large domain that contains homology with the epidermal growth factor (EGF) precursor. Next, is a small segment that contains a large number of O-linked carbohydrate residues. The fourth domain spans the plasma membrane. The last domain is a short segment that projects into the cytoplasm but does not have any kinase activity.

9. Hyperlipoproteinemia phenotypes PhenotypeLipoprotein elevationMajor plasma lipid elevation IChylomicronsTriglycerides IIaLDLCholesterol IIbLDL and VLDLCholesterol and triglycerides III  -VLDL and IDL Cholesterol and triglycerides IVVLDLTriglycerides VVLDL and chylomicronsTriglycerides and cholesterol

10. Diseases of Lipoprotein Metabolism Caused by Single Gene Defects Disease Lipoprotein abnormality Lipid abnormality Metabolic basisClinical implications Familial hyper- cholesterolemia LDL elevated Cholesterol elevated Decrease clearance of LDL from plasma. Familial form results from genetic deficiency or abnormality in LDL receptor. Risk factor for atherosclerosis Familial hyper- triglyceridemia VLDL elevated Triglyceride elevated Uncertain; VLDL overproduction or decreased catabolism. Questionable as to whether this is an independent risk factor for atherosclerosis Familial combined hyperlipidemia LDL and VLDL elevated Cholesterol and triglyceride elevated Uncertain; overproduction of apo-B-100Risk factor for atherosclerosis Familial dysbeta- lipoproteinemia  -VLDL and IDI elevated Cholesterol and triglyceride elevated Decreased clearance of remnants; defective binding of apo E to LDL receptor Risk factor for atherosclerosis Familial lipoprotein lipase deficiency Chylomicron s and VLDL elevated Triglycerides elevated Deficiency of lipoprotein lipase or apo-C-IIAcute pancreatitis Hypoalpha- lipoproteinemia HDL reduced None Uncertain; occasionally caused by genetic apo- A-I/apo-C-II deficiency Risk factor for atherosclerosis

11. Dietary Therapy of High Blood Cholesterol Level Nutrient Recommended Intake Step-One DietStep-Two Diet Total fatLess than 30% of total calories Saturated fatty acidsLess than 10% of total caloriesLess than 7% of total calories Polyunsaturated fatty acids Up to 10% of total calories Monounsaturated fatty acids 10% to 15% of total calories Carbohydrates50% to 60% of total calories Protein10% to 20% of total calories CholesterolLess than 300 mg/dLess than 200 mg/d Total calories To achieve and maintain desirable weight