Lipid metabolism
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The document outlines lipid metabolism, detailing processes such as lipolysis, beta-oxidation, ketogenesis, and their regulatory mechanisms. It also addresses conditions related to abnormal lipid metabolism, such as fatty liver disease, obesity, and atherosclerosis, including their symptoms, causes, and treatments. Additionally, it highlights the importance of ketone bodies in energy production, particularly during fasting or in metabolic disorders like ketoacidosis.
Lipid metabolism
- 1. 1 Prepared by: Ms. Shivanee Vyas Assistant Professor SVKM’s, NMIMS, School of Pharmacy and Technology Management
- 2. Lipid metabolism is the synthesis and degradation of lipids in cells. • It involves the breakdown or storage of fats for energy and the synthesis of structural and functional lipids, such as those involved in the construction of cell membranes. • In animals, these fats are obtained from food or are synthesized by the liver. Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise and usually occurs in fat adipocytes. • The most important regulatory hormone in lipolysis is insulin. • lipolysis can only occur when insulin action falls too low levels, as occurs during fasting. Other hormones that affect lipolysis include glucagon, epinephrine, norepinephrine, growth hormone, atrial natriuretic peptide, brain natriuretic peptide, and cortisol. LIPOLYSIS 2
- 3. The three separate steps of hydrolysis are involved in lipolysis. In the first step, triacylglycerol is hydrolyzed to make diacylglycerol and this is catalyzed by adipose triglyceride lipase (ATGL). In the second step, diacylglycerol is hydrolyzed to make monoacylglycerol and this is catalyzed by hormone-sensitive lipase (HSL). In the last step, monoacylglycerol is hydrolyzed to make glycerol and this is catalyzed by monoacylglycerol lipase (MGL). 3
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- 5. Beta-oxidation is the process in which fatty acid molecules are broken down to produce energy. • For beta-oxidation to take place, fatty acid must first enter the cell through the cell membrane, then bind to coenzyme A (CoA), forming fatty acyl CoA in the case of eukaryotic cells, enter the mitochondria, where beta-oxidation occurs. The beta-oxidation of fatty acids involves three stages: 1. Activation of fatty acids in the cytosol 2. Transport of activated fatty acids into mitochondria (carnitine shuttle) 3. Beta oxidation is proper in the mitochondrial matrix BETA-OXIDATION OF FATTY ACIDS 5
- 6. 1. Fatty acid activation • Fatty acids are activated to acyl CoA by thiokinases. The reaction occurs in two steps and requires ATP, coenzyme A and Mg2+. • Fatty acid reacts with ATP to form acyl adenylate which then combines with coenzyme A to produce acyl CoA. 6
- 7. 2. Transport of acyl CoA into mitochondria • The inner mitochondrial membrane is impermeable to fatty acids. A specialized carnitine carrier system operates to transport activated fatty acids from the cytosol to the mitochondria. • This occurs in four steps 1. The Acyl group of acyl CoA is transferred to carnitine, catalysed by carnitine acyltransferase I (present on the outer surface of the inner mitochondrial membrane). 2. The acyl-carnitine is transported across the membrane to the mitochondrial matrix by a specific carrier protein. 3. Carnitine acyl transferase II (found on the inner surface of the inner mitochondrial membrane) converts acyl- carnitine to acyl CoA. 4. The carnitine released returns to the cytosol for reuse. 7
- 8. 3. β-Oxidation proper Each cycle of β-oxidation, liberating a two-carbon unit-acyl CoA, occurs in a sequence of four reactions 1. Oxidation: Acyl CoA undergoes dehydrogenation by a FAD- dependent flavoenzyme, acyl CoA dehydrogenase. A double bond is formed between D and E carbons (i.e., 2 and 3 carbons). 2. Hydration: Enoyl CoA hydratase brings about the hydration of the double bond to form β-hydroxyl acyl CoA. 3. Oxidation: β-Hydroxyacyl CoA dehydrogenase catalyses the second oxidation and generates NADH. The product formed is β-ketoacyl CoA. 4. Cleavage: The final reaction in β-oxidation is the liberation of a 2-carbon fragment, acetyl CoA from acyl CoA. This occurs by a thiolytic cleavage catalysed by β-ketoacyl CoA thiolase (or simply thiolase). The process continues till the fatty acid is completely oxidized. Complete oxidation of one molecule of palmitic acid produces 130 moles of ATP 8
- 9. Ketogenesis is a metabolic pathway that produces ketone bodies, which provide an alternative form of energy for the body. The synthesis of ketone bodies occurs in the liver. The ketone bodies can make 22 ATP. The synthesis of ketone bodies occurs in the liver. The enzymes for ketone body synthesis are located in the mitochondrial matrix. Ketogenesis occurs through the following reactions. KETOGENESIS 9
- 10. 1. Two moles of acetyl CoA condense to form acetoacetyl CoA. This reaction is catalysed by β-ketothiolase. 2. Acetoacetyl CoA combines with another molecule of acetyl CoA to produce β-hydroxyl-β-methyl glutaryl CoA. HMG CoA synthase, catalysing this reaction, regulates the synthesis of ketone bodies. 3. HMG CoA lyase cleaves HMG CoA to produce acetoacetate and acetyl CoA. 4. Acetoacetate can undergo spontaneous decarboxylation to form acetone. 5. Acetoacetate can be reduced by a dehydrogenase to β- hydroxybutyrate. 10
- 11. • Biological Importance: 1. Ketogenesis is used to get energy by the brain, heart and skeletal muscles under fasting conditions. 2. The ketogenic diet is used these days to lose weight. The idea is to utilize excess fat stored in the body to get energy. 3. In ketoacidosis conditions, the kidneys excrete extra ketone bodies with the water resulting in fluid loss. 4. Diabetic patients are greatly affected by ketoacidosis because the insulin hormone is the main regulator of the process. 5. Symptoms of ketoacidosis include frequent urination, breath smelling like fruits or acetone, nausea, shortness of breath, fatigue, excessive thirst, etc. 6. The level of ketone bodies present in the body can be tested by blood serum or urine sample analysis. 11
- 12. KETOLYSIS Ketolysis is the process of catabolizing ketones. Ketone bodies produced in the liver reach peripheral tissues through circulation. The heart, kidney cortex, brain and skeletal muscles use ketone bodies for energy production. Biological Importance: • The heart and kidney cortex prefer to use ketone bodies instead of glucose for energy production. • During prolonged starvation, the brain obtains most of its energy from ketone bodies. 12
- 13. KETOACIDOSIS Ketoacidosis is a metabolic state caused by the uncontrolled production of ketone bodies that cause metabolic acidosis. In ketoacidosis, the body fails to regulate ketone production causing severe accumulation of keto acids. • Symptoms: Excessive thirst, Nausea and vomiting, Weakness or fatigue, Fruity-scented breath, Frequent urination, Stomach pain, Shortness of breath, and Confusion. • Causes: Diabetes Mellitus, Prolonged ether anaesthesia, Alkalosis, Injection of anterior pituitary extract • Treatment: 1. Insulin through an IV to bring ketones down. 2. Electrolyte replacement through an IV to replace key minerals like sodium, potassium, and chloride to keep the heart, muscles, and nerves working properly. 3. Antibiotics. 13 Diseases related to abnormal metabolism of lipid
- 14. 14 It is a reversible condition where large molecules of triglyceride fat accumulate in liver cells. • Symptoms: Obesity, High blood pressure, One or more abnormal cholesterol levels - high levels of triglycerides, a type of blood fat, or low levels of HDL cholesterol. • Causes: Fatty liver is commonly associated with alcohol or metabolic syndrome (diabetes, hypertension, obesity and dyslipidemia). • Diagnosis of Fatty Liver: In routine blood screening or images of the liver obtained by an ultrasound test, CT (computed tomography) scan, or MRI (magnetic resonance imaging) may suggest the presence of a fatty liver or liver biopsy, in which a small sample of liver tissue is obtained through the skin and analyzed under the microscope. • Treatment: The treatment of fatty liver is related to the cause. The benefit of weight loss, dietary fat restriction, and exercise in obese patients is inconsistent. Reducing or eliminating alcohol use can improve fatty liver due to alcohol toxicity. Controlling blood sugar may reduce the severity of fatty liver in patients with diabetes. FATTY LIVER
- 15. 15 Obesity is a condition in which too much fat is deposited in the body resulting in being overweight. • Causes: obesity occurs when people regularly eat and drink more calories than they use, lack physical activity, lack sleep, genetics and use certain medications that can cause weight gains or water retention, such as corticosteroids, antidepressants or some seizure medications. Modern culture and conveniences also, contribute to obesity. • Symptoms: Coronary heart disease, High blood pressure, Stroke, Type II diabetes, Some cancers (breast, colon, endometrial, gallbladder, kidney, and liver), Sleep apnea, High LDL cholesterol, low HDL cholesterol, or high levels of triglycerides. • Treatment. People may need to see several health professionals, including a dietitian, behavioural therapist, and exercise to achieve a healthy weight and adopt healthier eating habits. OBESITY
- 16. Atherosclerosis is a condition where the arteries become narrowed and hardened due to a buildup of plaque around the artery wall and can result in a shortage of blood and oxygen in various tissues of your body, plaque can also lead to a blood clot. If left untreated, atherosclerosis can lead to heart attack, stroke, or heart failure. Fatty material called atheroma builds up in the lining of artery walls and narrows your arteries. Over time it can grow bigger until arteries become so narrow that they can’t let enough blood through. Treatment: • Lifestyle changes focus on weight management, physical activity, and a healthy diet. eating foods high in soluble fibre and limiting the intake of saturated fats, sodium, and alcohol. • Medication: Antiplatelet medications can prevent the build-up of plaque or help prevent blood clots. such as statins, might be prescribed to lower cholesterol & angiotensin-converting enzyme (ACE) inhibitors can help lower blood pressure. • Surgery: Severe cases of atherosclerosis may be treated by surgical procedures, such as angioplasty or coronary artery bypass grafting. Angioplasty involves expanding the artery and opening the blockage so that the blood can flow through properly again 16 ATHEROSCLEROSIS