Lipid Metabolism -III Lecture 9 - 2024 - PDF

LIPID METABOLISM III Sidrah Shams Ph. D. in Molecular Medicine Fatty Acid Metabolism Fatty Acid Oxidation Key Steps in Cholesterol Synthesis: 1. Make HMG CoA: 1.Acetyl CoA combines to form HMG CoA. 2. Convert to Mevalonate: 1.HMG CoA is r...

LIPID METABOLISM III Sidrah Shams Ph. D. in Molecular Medicine Fatty Acid Metabolism Fatty Acid Oxidation Key Steps in Cholesterol Synthesis: 1. Make HMG CoA: 1.Acetyl CoA combines to form HMG CoA. 2. Convert to Mevalonate: 1.HMG CoA is reduced to mevalonate, a crucial step that controls the cholesterol production process. 3. Form Building Blocks: 1.Mevalonate is changed into smaller units, leading to the formation of isopentenyl pyrophosphate (IPP). 4. Create Squalene: IPP units join to form larger molecules like farnesyl pyrophosphate (FPP), which combine to make squalene. 5. Form Lanosterol: Squalene is converted into lanosterol, a precursor to cholesterol. 6. Convert to Cholesterol: 1.Lanosterol goes through several steps to finally become cholesterol. Metabolism of Eicosanoids Introduction to Eicosanoids Definition: Eicosanoids are biologically active compounds derived from polyunsaturated fatty acids with 20 carbons (eicosa = 20). Types: Prostaglandins, thromboxanes, and leukotrienes. Key Functions: Regulate inflammation (physiologic and pathologic). Maintain gastric integrity and renal function. Control smooth muscle contraction and platelet homeostasis. Differences Between Eicosanoids and Hormones Local Action: Eicosanoids act locally, not like endocrine hormones that act on distant organs. Production: Made in small amounts in almost all tissues, not specialized glands. Short Half-Life: Rapidly metabolized and not stored. Biosynthesis of Prostaglandins and Thromboxanes Precursor: Arachidonic acid, an ω-6 fatty acid with 20 carbons. Location: Incorporated into membrane phospholipids and released by phospholipase A2. Synthesis: Arachidonic acid is converted to PGH2 via prostaglandin endoperoxide synthase (PGH synthase). Isozymes: COX-1 (constitutive) and COX-2 (inducible). COX-1 vs. COX-2 COX-1: Constitutively produced in most tissues. Maintains gastric tissue, renal function, and platelet aggregation. COX-2: Induced in response to immune and inflammatory stimuli. Drives pain, redness, swelling, and fever during inflammation. Inhibition of Prostaglandin Synthesis Cortisol: Inhibits phospholipase A2, reducing the availability of arachidonic acid. NSAIDs: Inhibit COX-1 and COX-2, preventing prostaglandin synthesis. Side Effects: Systemic inhibition of COX-1 can damage the stomach, kidneys, and impair blood clotting. Aspirin: Irreversibly inhibits COX-1 and COX-2. Induces anti-inflammatory compounds like lipoxins and resolvins. Selective COX-2 Inhibitors (Coxibs) Designed to reduce pathologic inflammation while preserving COX-1 functions. Increased cardiovascular risk due to reduced PGI2 synthesis, leading to heart attack risk. Leukotriene Synthesis Enzyme: 5-lipoxygenase converts arachidonic acid to leukotrienes. Function: Key mediators in allergic responses and inflammation. Clinical Relevance: NSAIDs do not inhibit leukotriene synthesis. Overproduction of leukotrienes can trigger NSAID-induced asthma. Leukotriene inhibitors are used in asthma management. Platelet Homeostasis Thromboxane A2 (TXA2): Produced by COX-1 in platelets. Promotes platelet aggregation and vasoconstriction. Prostacyclin (PGI2): Produced by COX-2 in endothelial cells. Inhibits platelet aggregation and promotes vasodilation. Aspirin and Antithrombotic Effects Mechanism: Aspirin inhibits both TXA2 and PGI2 by irreversibly acetylating COX-1 and COX-2. Clinical Application: Platelets lack nuclei, so COX-1 inhibition is permanent. Endothelial cells can regenerate COX-2, balancing the antithrombotic effect. Low-dose aspirin is used to reduce the risk of heart attacks and strokes. Key Takeaways: Eicosanoids play a crucial role in regulating physiological processes and inflammatory responses. Understanding their synthesis and inhibition is key to treating inflammation, pain, and cardiovascular diseases. NSAIDs and selective inhibitors can manage prostaglandin-related conditions but come with side effects. REFERENCES Lehninger's biochemistry 7 th Edition Lippincott Biochemistry 7 th Edition