Lipid Metabolism Summary PDF

Lipid Metabolism 1. Introduction to Lipids: a. Definition and properties: - Lipids are a large, heterogeneous group of naturally occurring organic compounds. - They are easily dissolved in organic solvents but poorly soluble or insoluble in water. - Lipids are e...

Lipid Metabolism 1. Introduction to Lipids: a. Definition and properties: - Lipids are a large, heterogeneous group of naturally occurring organic compounds. - They are easily dissolved in organic solvents but poorly soluble or insoluble in water. - Lipids are either derivatives of fatty acids or capable of binding fatty acids. b. Major biologically important lipids: i. Fatty acids ii. Triacylglycerols (TAGs or triglycerides) iii. Phospholipids iv. Sphingolipids v. Cholesterol vi. Plasmalogens 2. Fatty Acids: a. Classification: i. Saturated fatty acids: - No double bonds in the hydrocarbon chain - Examples: palmitic acid, stearic acid ii. Monounsaturated fatty acids (MUFAs): - One double bond - Examples: oleic acid, palmitoleic acid iii. Polyunsaturated fatty acids (PUFAs): - Two or more double bonds - Examples: linoleic acid, alpha-linolenic acid b. Biological functions: i. Energy source: - Major fuel for the body, especially during fasting or starvation - Can fulfill 25-50% of energy requirements during prolonged starvation  ii. Precursors for other lipids: - Used to synthesize triacylglycerols, phospholipids - Precursors for specialized products like eicosanoids (prostaglandins, leukotrienes, thromboxanes) iii. Structural components: - Incorporated into cell membranes as part of phospholipids c. Fatty acid metabolism: i. Absorption and transport: - Absorbed from the intestine - Packaged into lipoproteins (chylomicrons) - Transported in the bloodstream bound to albumin ii. Beta-oxidation: - Process of breaking down fatty acids in mitochondria to produce ATP - Longer fatty acid chains generate more ATP iii. Regulation of beta-oxidation: - Insulin inhibits beta-oxidation by increasing malonyl-CoA - Malonyl-CoA is an allosteric inhibitor of carnitine palmitoyl transferase I - Carnitine palmitoyl transferase I is the rate-limiting enzyme in fatty acid transport into mitochondria 3. Triacylglycerols (TGs): a. Structure and properties: - Composed of three fatty acid molecules esterified to a glycerol backbone - Main form of lipid storage in the body - High energy content and low molecular weight b. Biological functions: i. Energy storage: - Most efficient way for the body to store excess energy - Predominantly stored in adipose tissue ii. Thermal insulation:  - TGs deposited under the skin provide insulation against heat loss iii. Mechanical cushioning: - TGs around organs and tissues act as protective padding - Absorbs impact of potentially injurious mechanical forces c. TG biosynthesis pathways: i. Glycerol phosphate pathway: - Sequential esterification of glycerol-3-phosphate with fatty acyl-CoA - Catalyzed by glycerol-3-phosphate acyltransferase and 1-acylglycerol-3-phosphate acyltransferase ii. Monoacylglycerol pathway: - Occurs primarily in intestinal mucosa - Monoacylglycerols converted to TGs by monoacylglycerol acyltransferase iii. Regulation of TG synthesis: - Enzyme diacylglycerol acyltransferase (DGAT) is thought to be rate-limiting in most circumstances 4. Phospholipids: a. Structure and properties: - Composed of a glycerol backbone, two fatty acid chains, and a phosphate-containing headgroup - Amphipathic molecules with hydrophilic head and hydrophobic tails - Form lipid bilayers in cell membranes b. Biological functions: i. Structural component of cell membranes: - Major lipid constituents of all cellular membranes - Provide a barrier and platform for various membrane-associated proteins ii. Surfactant in the lungs: - Along with proteins, main components of alveolar surfactant - Reduces surface tension and prevents alveolar collapse 5. Cholesterol Metabolism: a. Biosynthesis of cholesterol: - Synthesized from acetyl-CoA through a series of enzymatic reactions - Occurs primarily in endoplasmic reticulum and cytosol - Rate-limiting step catalyzed by HMG-CoA reductase, converting HMG-CoA to mevalonate b. Regulation of cholesterol biosynthesis: i. Feedback inhibition: - Cholesterol and its derivatives inhibit HMG-CoA reductase activity ii. Transcriptional regulation: - Cholesterol regulates expression of genes involved in its biosynthesis iii. Posttranslational regulation: - Phosphorylation and degradation of HMG-CoA reductase c. Excretion of cholesterol: - Excreted unchanged in bile or converted to bile acids and then excreted in intestine - Bile acids reabsorbed in intestine through enterohepatic circulation 6. Lipid Transport: a. Lipoproteins: i. Chylomicrons: - Transport dietary lipids from intestine to peripheral tissues - Triglycerides hydrolyzed by lipoprotein lipase - Remnants taken up by liver ii. VLDL, IDL, LDL: - Transport endogenously synthesized lipids from liver to peripheral tissues - LDL is primary cholesterol-carrying lipoprotein iii. HDL: - Transports cholesterol from peripheral tissues back to liver for excretion - Process known as reverse cholesterol transport (RCT) b. Roles of apolipoproteins: i. Structural components of lipoproteins ii. Enzyme cofactors or inhibitors (e.g., apoC-II activates lipoprotein lipase, apoC-III inhibits it) iii. Ligands for lipoprotein receptors (e.g., apoB-100 and apoE bind to LDL receptor) c. Reverse cholesterol transport (RCT) and HDL cycle: i. HDL accepts cholesterol from peripheral tissues through ABCA1 and ABCG1 transporters ii. Cholesterol in HDL esterified by LCAT enzyme, converting HDL3 to larger HDL2 particles iii. HDL2 delivers cholesterol to liver, selectively taken up by SR-B1 receptor iv. HDL cycle involves hydrolysis of HDL2 by hepatic lipase and endothelial lipase v. Free apoA-I released for formation of new pre-beta-HDL particles 7. Lipid-Related Disorders: a. Atherosclerosis: i. Formation of fatty streaks: - Accumulation of lipid-laden macrophages (foam cells) in subintimal space of arteries - Initiated by endothelial injury and inflammation ii. Risk factors: - High levels of LDL, chylomicron remnants, and VLDL remnants - Low levels of HDL - Arterial hypertension - Smoking - Chronic hyperglycemia iii. Hypothesis of atherosclerosis pathogenesis: - Endothelial injury → monocyte recruitment and foam cell formation - Smooth muscle cell proliferation and plaque formation  - Plaque rupture and thrombosis b. Ketogenesis and ketoacidosis: i. Ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) produced by liver ii. Occurs during prolonged fasting or uncontrolled diabetes iii. Fatty acid oxidation becomes predominant metabolic pathway iv. Elevated ketone bodies can lead to diabetic ketoacidosis v. Diabetic ketoacidosis is a life-threatening condition characterized by severe metabolic acidosis vi. Regulation of ketogenesis: - More fatty acids entering liver leads to more ketone body production - Factors boosting lipolysis (e.g., prolonged fasting, starvation, uncontrolled diabetes) increase fatty acid delivery to liver and stimulate ketogenesis