Lipid Metabolism 2024 PDF

Lipid Metabolism  Overview of Lipid Metabolism Lipid digestion & absorption Fatty Acid metabolism (Oxidation & synthesis) Triglycerides metabolism (synthesis & lipolysis) Phospholipid metabolism Cholesterol metabolism Ketone body metabolism Lipoprotein metabolism  Major Biological...

Lipid Metabolism  Overview of Lipid Metabolism Lipid digestion & absorption Fatty Acid metabolism (Oxidation & synthesis) Triglycerides metabolism (synthesis & lipolysis) Phospholipid metabolism Cholesterol metabolism Ketone body metabolism Lipoprotein metabolism  Major Biological Roles of Lipids 1. Structural components of biological membranes. 2. Triacylglycerols provide energy reserves. 3. lipids and lipid derivatives are vitamins and hormones. 4. Bile acids aid in lipid solubilization  Lipid Digestion TAG, PL, C, CE Emulsification, Hydrolysis and Micelle Formation: 1-Bile salts 2-Pancreatic lipase 3-Phospholipases 4-Cholesterol estrases & Cholesterol Acyl Transferase (ACAT) 1-Bile salts  2-Pancreatic lipase Hydrolyze TAG into 2-MAG & FFA  3-Phospholipases Convert phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D. Hydrolysis of ester linkage on carbon 2 of phospholipids gives Lysophospholipids (powerful detergents). Lysophospholipids  4-Cholesterol estrase & Acyl Transferase (ACAT) Within intestinal cells (and other body cells) some of absorbed cholesterol is esterified with FA, forming cholesterol esters. C CE ACAT Absorption and Transport into Blood  Chylomicrons Capillaries energy storage  Release Insulin from Adipose Tissue Epinephrine, Glucagon corticotropin FFA-albumin Glycerol: GK Glycerol-3P DHAP  Lipids = TAG Glycerol FFA Acetyl DHAP COA Glycolysis Gluconeogenesis Kreb’s cycle  β-Oxidation of Fatty Acids Activation and transfer of fatty acid Fatty acids must be activated in cytoplasm before being oxidized in mitochondria. FA + ATP + CoASH ---> Acyl-CoA+ AMP+ PPi+ H2O Activation is catalyzed by acyl-CoA ligase (acyl-CoA synthetase or thiokinase).  Carnitine Shuttle Malonyl-COA ‫يربط‬ ‫يفك‬ ‫يعدي‬  Carnitine is produced enzymatically from lysine and methionine. Carnitine acyltransferase I allosterically inhibited by malonyl-CoA (intermediate in FA biosynthesis), to prevent cycling between beta-oxidation and fatty acid synthesis.  Beta-Oxidation of Fatty Acids (even chain) Inside the mitochondria, β-oxidation occurs via four recurring steps: 1-Oxidation by FAD 2-Hydration 3-Oxidation by NAD+ 4-Thiolysis  Energy yield Each cycle of Beta-oxidation produced one molecule of Acetyl-CoA, one molecule of FADH2 and one molecule of NADH. Each Acetyl-CoA produce 12 ATP in the citric acid cycle. FADH2 has a P/O ratio of 2 and NADH has a P/O ratio of 3 and thus they produce 2 ATP and 3 ATP, respectively.  Example Calculations Energy yield from palmitate (16C saturated FA): 7 cycles of beta-oxidation produces 8 Acetyl-CoAs (the last step breaks the 4- carbon fatty acid into 2 Acetyl-CoAs). 8 molecules of Acetyl-CoA: 12 x 8 ATP = 96 ATP 7 molecules of FADH2 = 14 ATP 7 molecules of NADH = 21 ATP 2 molecules of ATP lost through = -2 ATP 96 + 14 + 21 - 2 = 129 ATP. Beta-Oxidation of Fatty Acids (odd chain) Propionyl-CoA (3:0) Methylmalonyl-CoA (gluconeogenesis) Succinyl-CoA  LIPOGENESIS (Fatty Acid Synthesis) Occurs in cytosol, in the liver, adipose tissue and mammary glands during lactation. Precursors are acetyl-CoA (citrate) & malonyl-CoA.  biotin Fatty Acid Synthase (FAS) Complex transacylase transacylase  Elongation Like β-oxidation, elongation occurs via four recurring reactions: Condensation (with malonyl-ACP) Reduction Dehydration Reduction In the second step of elongation, butyryl ACP condenses with malonyl ACP to form an acyl ACP compound. This continues until a C16 acyl compound is formed, at which point it is hydrolyzed by a thioesterase into palmitate and ACP.  Elongation and Desaturation The FA product released from FAS is palmitate (saturated 16:0). Elongation (>16c) & desaturation occurs in the Smooth Endoplasmic Reticulum (SER). Elongation (2C longer) involves condensation of acyl-CoA groups with malonyl-CoA (reduction, dehydration, reduction).  Desaturation occurs in the ER involves 4 broad specificity fatty acyl-CoA desaturases. These enzymes introduce unsaturation at C4, C5, C6 or C9. These enzymes cannot introduce sites of unsaturation beyond C9 they cannot synthesize either linoleate (18:2∆9, 12) or linolenate (18:3∆9, 12, 15). These fatty acids must be acquired from diet essential FA. Linoleic (18:2∆9, 12) ---→ arachidonic (20:4∆5,8,11,14)  Origin of Cytoplasmic Acetyl-CoA Acetyl-CoA is generated in mitochondria primarily from The PDH reaction In order for these acetyl units to be utilized for fatty acid synthesis they must be present in the cytoplasm. Regulation of FA Metabolism  Regulation of FA metabolism Short term regulation Long term regulation Substrate availability/ Enzyme synthesis & allosteric effector turnover rate Citrate + ACC Insulin + ACC, FAS, LPL Long acyl COA - ACC Insulin - HSL Malonyl COA - carnitine acyl transferase I Fasting (starvation) – LPL & + HSL Enzyme modification Glucagon (+PKA) – ACC (ACC-P) Insulin (+Pase) + ACC  FA synthesis FA oxidation Organ Location Liver & adipose Liver & tissue muscles Intracellular Cytosol Mitochondria location Hormonal Insulin Glucagon Stimulation Carrier between Citrate Carnitine cytosol & mitochondria Active carrier Acyl carrier protein CoASH (ACP) Coenzymes NADP FAD & NAD Two carbon Malonyl CoA Acetyl CoA donor/product Inhibitor Fatty acyl CoA Malonyl CoA Product Pathway Palmitate Acetyl CoA  Synthesis of Triglycerides Fatty acids are stored as triacylglycerols in all cells, but primarily in adipocytes. (1 molecule glycerol + 3 FA first sat, second unsat, third sat or unsat) The major building block for the synthesis of triacylglycerols, in tissues other than adipose tissue, is glycerol. Adipocytes lack glycerol kinase, therefore, (DHAP), produced during glycolysis, is the precursor for triacylglycerol synthesis in adipose tissue. Synthesis of TAG  This means that adipocytes must have glucose to oxidize in order to store fatty acids in the form of triacylglycerols. Why? 1- Glucose→ acetyl CoA→ FA synthesis 2- Glucose→ DHAP→ glycerol backbone 1 + 2 = TAG  Phospholipids phosphatidic a + polar head Phosphatidylcholine (PC) (Lecithin) Phosphatidylserine (PS) Phosphatidylethanolamine (PE) (Cephalin)  Phospholipid Synthesis One method utilizes CDP-activated polar head group for attachment to the phosphate of phosphatidic acid CDP-choline + DAG = PC + CMP DAG-CDP + choline = PC + CMP Synthesis of Phospholipids  Cholesterol synthesis Synthesis and utilization of cholesterol must be tightly regulated to prevent accumulation and deposition within the body. Clinically, cholesterol and cholesterol-rich lipoproteins are deposited in the coronary arteries leading to atherosclerosis & coronary artery diseases.  Cholesterol is synthesized by virtually all tissues in humans, although liver, intestine, adrenal cortex, and reproductive tissues, including ovaries, testes, and placenta, make the largest contributions. Cholesterol synthesis occurs in the cytoplasm and microsomes from the two-carbon acetate group of acetyl-CoA. Liver parenchymal cells contain two isoenzymes of HMG CoA synthase. The cytosolic enzyme participates in cholesterol synthesis, whereas the mitochondrial enzyme functions in the pathway for ketone body synthesis. Cholesterol Synthesis Regulation of Cholesterol Synthesis Statins: HMG CoA inhibitors Bile acids and Bile salts Synthesis of bile acids (liver)  Ketogenesis KB are acetoacetate, β-hydroxybutyrate, and acetone. When carbohydrate utilization is low or deficient (high rates of FA oxidation, primarily in liver)--→ large amounts of acetyl-CoA exceed TCA cycle capacity, resulting in ketogenesis, this increases KBs release from liver for use as fuel by other tissues. In early starvation, heart and skeletal muscle will consume primarily KBs to preserve glucose for use by brain. Ketolysis  Clinical Significance of Ketogenesis KB production occurs at low rate during normal feeding/ physiological status. CHO shortage +liver to increase KB production from acetyl-CoA (FA oxidation). Heart & skeletal muscles use KB for energy, preserving glucose for brain. In untreated IDDM, diabetic ketoacidosis (DKA) occurs decrease glucose (due to - insulin)/ increase FA oxidation (due to + glucagon) acetyl COA + KB >> tissue utilization. KB are strong acids (pKa around 3.5), lowers blood pH (impairs Hb/O2 binding)  Plasma Lipoproteins TAGs/cholesterol from diet or synthesized by liver, are solubilized in lipid-protein complexes. These complexes contain TAGs lipid droplets & CEs surrounded by polar PLs & proteins (apolipoproteins). These lipid-protein complexes vary in their content of lipid and protein.  Types of Lipoproteins Chylomicrons: synthesized in intestinal mucosa, formed mainly of exogenous TG (96%) carrying exogenous TG from intestine to hepatic tissues Very low-density lipoproteins (VLDLs) (Pre-β – lipoproteins): Synthesized mainly in liver, contain mainly hepatic TG carrying endogenous TG from liver to extra-hepatic tissues.  Low-density lipoproteins (LDLs) (β-lipoproteins) Synthesized in liver & blood circulation, its main lipid content is cholesterol carrying cholesterol to peripheral tissues, (bad cholesterol). High-density lipoproteins, HDLs (α-lipoproteins) Synthesized in intestine & liver. Its main lipid content is phospholipid rather than cholesterol. HDLs carry cholesterol from various tissues to liver.(good cholesterol) Chylomicron metabolism VLDL & LDL metabolism LDL receptor mediated endocytosis HDL metabolism