Lipid Metabolism Disorders Lecture - D. Zhang, NYIT

Lipid metabolism Part III: lipid metabolism disorders Zhang, Dong PhD, Professor Biomedical Sciences Department [email protected] Harvey and Ferrier: Lippincott Biochemistry 8th Edition: Chapter 18, 25, and 26 Harper’s Illustrated Biochemistry, 32e: Chapter 26 Office of Academic Affairs ...

Lipid metabolism Part III: lipid metabolism disorders Zhang, Dong PhD, Professor Biomedical Sciences Department [email protected] Harvey and Ferrier: Lippincott Biochemistry 8th Edition: Chapter 18, 25, and 26 Harper’s Illustrated Biochemistry, 32e: Chapter 26 Office of Academic Affairs  Learning Objectives 1. Categorize the different hyperlipoproteinemia and hypolipoproteinemia. 2. Explain the different biochemical pathways that could potentially be targeted pharmacologically in the management of heart diseases 3. Identify the statins as the main therapeutic intervention in dyslipidemia/atherosclerosis and interpret their action in terms of the inhibition of HMG CoA reductase. 4. Explain the increasing incidence of obesity and diabetes and its impact on atherosclerosis. 5. Illustrate the risk factors of the metabolic syndrome and its specific lipid abnormalities. Disorders related to lipoproteins Or mutation in PCSK9  Strategies to identify and treat a clinical condition Find out which gene/protein is mutated/defective Review the physiological function(s) of the gene/protein Rationalize the clinical manifestations with its physiological function(s) Explore possible clinical interventions to compensate/correct the defect(s) Hyperlipoproteinemia Hyper-: too much of  Chylomicrons Hyperlipoproteinemia (Type I) – familial lipoprotein lipase (LPL) deficiency Defective: LPL – digest TG ApoCII – activate LPL Consequences: chylomicron↑, VLDL↑, LDL↓, HDL↓ Increased risk of coronary disease: No VLDL  Hyperlipoproteinemia ( Type IIa) – familial hypercholesterolemia Defective: LDL receptor ApoB100 PCSK9 Consequences: LDL↑, cholesterol ↑. Increased risk of coronary disease: Yes VLDL becomes VLDL remnant or IDL after loses TG IDL is further metabolized to become LDL LDL is rich in cholesterol LDL is taken up by liver or peripheral tissues via ApoB100 binding to LDL receptor PCSK9 regulates the turnover of LDL receptor (next slide)  Treatment of hypercholesterolemia with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor PCSK9 belongs to the proprotein convertase family of serine proteases Secreted PCSK9 binds to LDL receptors (LDLR) and targets them for lysosomal degradation PCSK9 inhibition → LDLR↑ → LDL↓ → LDL-Cholesterol↓ PCSK9 inhibitors: Alirocumab (Praluent, Sanofi/Regeneron) and Evolocumab (Repatha, Amgen) are human monoclonal antibodies that inhibit the degradation of LDLR in hepatocytes and thus enhance the uptake and clearance of circulating LDL particles. Cell Vol.169, p971-972 2017  Chylomicrons Hyperlipoproteinemia – familial Type III Defective: ApoE Consequences: chylomicron↑, VLDL↑ Increased risk of coronary disease: Yes Other clinical manifestation: xanthomas ApoE receptors VLDL  Hyperlipoproteinemia (Type IV) – familial hypertriacylglyerolemia Overproduction of VLDL often associated with glucose intolerance → VLDL↑, TG ↑. Commonly associated with coronary heart disease, type 2 diabetes, obesity, etc. Hypolipoproteinemia Hypo-: too little of  Summary of hypolipoproteinemia Disorder Type Cause Effects Tangier disease Defects in ABCA1, the transporter that supports HDL: ↓ cholesterol pickup by nascent HDLs Abetalipoproteinemia Mutations in the MTTP* (microsomal triglyceride Chylomicrons: ↓ (Beta: ApoB-containing lipoproteins) transfer protein, MTP) gene VLDL, IDL, LDL: ↓ Hypoalphalipoproteinemia Accelerated catabolism of ApoA-I and ApoA-II HDL: ↓ (Alpha: ApoA-containig lipoproteins) *: The gene MTTP encodes the protein MTP.  Hypolipoproteinemia – Tanger disease Disorder Type Cause Effects Tangier disease Defect in ABCA1, a transporter that supports HDL: ↓ cholesterol pickup by nascent HDLs ABC1 (an ATPase, also known as ABCA1): moves cholesterol from the inner leaflet of plasma membrane to the outer leaflet.  Hypolipoproteinemia - Abetalipoproteinemia Disorder Type Cause Effects Abetalipoproteinemia Mutations in the MTTP* (microsomal Chylomicrons: ↓ (Beta: ApoB-containing lipoproteins) triglyceride transfer protein) gene VLDL, IDL, LDL: ↓ IDL LDL VLDL ApoB-100 Chylomicrons *: The gene MTTP encodes the protein MTP.  Hypolipoproteinemia - Hypoalphalipoproteinemia Disorder Type Cause Effects Hypoalphalipoproteinemia Accelerated catabolism of ApoA-I and ApoA-II HDL: ↓ (Alpha: ApoA-containig lipoproteins) HDL: Synthesized mainly in the liver and intestine Nascent HDL particle is disk-shaped Contains/transfers several Apoproteins (ApoA, ApoE, and ApoCII; others) ApoA1 activates LCAT Matures after receiving TG from VLDL and cholesterol from peripheral tissues  A few more clinical issues related to lipoproteins – Wolman Disease Wolman Disease: Lysosomal acid lipases hydrolyze cholesterol esters and TGs within the cell. If these lipases are defective, as in Wolman disease, the cholesterol esters and TGs accumulate in the cells and cannot be mobilized when needed, resulting in early death. A few more clinical issues related to lipoproteins– LCAT deficiency LCAT deficiency: LCAT (lecithin - cholesterol acyl transferase) converts cholesterol to cholesterol esters in HDL. LCAT deficiency leads to low HDL levels and tissue accumulation of cholesterol resulting in anemia, corneal opacification, and renal failure.  Other clinical issues related to lipoproteins Fatty Liver: If the liver does not have adequate energy available for protein synthesis, or is starved of amino acids, or choline, resulting in decreased synthesis of apolipoproteins or phosphatidyl choline (lecithin), which are necessary for the synthesis of VLDL, then the liver cannot make VLDL; so, most of the TGs that normally are exported to peripheral tissues through VLDL will not be exported, instead will accumulate in the liver and cause the fatty liver.  Clinical goals for cholesterol levels - HDL High serum cholesterol levels are strongly correlated with cardiovascular disease Higher levels of HDL are cardio-protective, possibly through both: o prevention of oxidative damage to LDL o reverse cholesterol transport Control of serum cholesterol levels HDL Range Risk Range Risk 130 mg/dL Atherosclerosis: a disease in which plaque builds up inside the arteries. Different layers of the arterial walls intima Intima  The evolution of atherosclerotic plaques  Control of serum cholesterol levels – lifestyle/diet Lifestyle/diet modification used to lower serum cholesterol – reduced dietary intake of cholesterol and saturated fats – Increased plant stanols or sterols (soy) – increased dietary soluble fiber – weight reduction/exercise potentiates drug effects  Control of serum cholesterol levels - Drugs  HMG CoA reductase inhibitors (statins: Lipitor, Zocor, Crestor etc.)  PCSK9 inhibitors (Alirocumab and Evolocumab): slow LDL receptor degradation  Bile acid sequestrant (Colestipol, Cholestyramine): increases bile acid loss in feces  Nicotinic acid (niacin, vitamin B3)(Niaspan, Advicor (with lovastatin)): mechanism of action not completely understood (reduces Lp(a), as well as LDL-cholesterol and TAGs, and raises HDL)  Fibrate (Gemfibrizol, Clofibrate) inhibits the hepatic release of lipoproteins (particularly VLDL) potentiates the action of lipoprotein lipase (LPL) Increase HDL  Ezetimibe (Zetia) inhibits dietary absorption of cholesterol combined with a statin in Vytorin Treatment: Pharmacological  Treatment: Pharmacological (vitamin B3)  Metabolic Syndrome The metabolic syndrome (syndrome X, insulin resistance syndrome): consists of a constellation of metabolic abnormalities that confer increased risk of cardiovascular disease (CVD) and diabetes mellitus. Risk factors: o A large waistline: waist circumference >102 cm (M), >88 cm (F) o A high triglyceride level: ≥150 mg/dL o Low HDL-cholesterol: