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AHS 2013 Digestion and Metabolism Sarah Harney 4. Liver and Gall Bladder, Fuel Metabolism • Functions of the Liver and Gallbladder • Cholesterol synthesis and metabolism • How are nutrients utilised? Differences between absorptive and post-absorptive states 1 4. Liver and Gall Bladder Functions of the Liver • Metabolic regulation/normalisation – Glucose, fat, protein • Blood protein regulation – Production and removal of waste products • Hormonal function – Production and removal • Bile secretion • Synthesis and modification of hormones • Plasma protein synthesis • Cholesterol metabolism • Metabolism of many drugs Reading: Stanfield pp 577-580 2 1 AHS 2013 Digestion and Metabolism Sarah Harney Blood flow to/from the liver • The liver receives blood from 2 sources: - the hepatic artery -the hepatic portal vein • Blood from the GI tract is carried via the hepatic portal vein to the liver • Nutrients and other substances absorbed in the small intestine are processed or detoxified by the liver before the blood flow is returned to the heart (via the hepatic vein) 3 Anatomy of the Liver • The liver is organized into functional units known as lobules 3 vessels at each corner of the lobule: Branches of the hepatic portal vein and hepatic artery + a bile duct Blood flows from both veins and arteries into expanded capillaries called sinusoids Bile is secreted into bile canaliculi which drain into the bile ducts 4 2 AHS 2013 Digestion and Metabolism Sarah Harney Blood flow though liver lobules • Flow of nutrients from hepatic portal vein • Concentration gradient of nutrients from hepatic portal vein to central vein 5 Role of the Liver in Metabolic Regulation Metabolic processing of all major nutrient groups (carbohydrates, proteins, lipids): • Glucose converted to glycogen for storage (glycogenesis) • Amino acids converted to fats • Amino acids converted to glucose (gluconeogenesis) • Amino acid catabolism to urea • Free fatty acids converted to triglycerides and cholesterol 6 3 AHS 2013 Digestion and Metabolism Sarah Harney Plasma Proteins Plasma proteins are synthesized by the liver Albumins • Most abundant plasma proteins • Transport lipophilic molecules e.g. steroid + thyroid hormones Globulins • and globulins • -globulins – bind hydrophobic substances for transport in the blood • - and -globulins – blood clotting factors ( -globulins i.e. antibodies are produced by lympohocytes and not by the liver) Fibrinogen • Soluble precursor of fibrin, forms blood clots 7 Plasma Proteins — deficiencies Albumins • Reduced plasma osmolarity, leading to oedema (esp. abdominal) and Globulins • clotting, increased bleeding time Fibrinogen • Impaired clotting 8 4 AHS 2013 Digestion and Metabolism Sarah Harney Liver and Hormones • Synthesises Insulin-like Growth Factor (IGF-I) – in response to Growth Hormone (GH, produced by pituitary) – Stimulates soft tissue and bone growth • Metabolism of hormones – Degradation and removal of hormones from circulation – Detoxification and removal of many drugs 9 Bile • Continuous secretion by liver, 250 ml-1l per day • Required for emulsification of fat, enables fat digestion by lipases • The sphincter of Oddi regulates entry of bile into duodenum 10 5 AHS 2013 Digestion and Metabolism Sarah Harney Gallbladder • The gallbladder stores bile • 95 % of bile salts secreted are reabsorbed and recycled • Bile is concentrated in the gall bladder • Cholesterol can precipitate out of bile to form gallstones • Gallbladder removal (cholecystectomy) can be performed to treat gallstones without seriously affecting digestion or absorption 11 Enterohepatic circulation of Bile Salts • ~ 95 % of bile salts are reabsorbed by terminal ileum • Transported back to liver via heptic portal vein- enterohepatic circulation • Bile salts are recycled multiple times during a meal • Total pool of bile salts = 3-4 g •Bile salts released during a meal = 3-15 g 12 6 AHS 2013 Digestion and Metabolism Sarah Harney Bilirubin, the waste product of red blood cell breakdown, is excreted in bile • Yellow pigment, gives bile characteristic colour • Red blood cells removed from blood by macrophages in liver and other tissues • Bilirubin is the breakdown product of the haem part of haemoglobin protein • Liver cells remove bilirubin from blood and excrete it into bile 13 Bilirubin accumulation causes Jaundice Bilirubin accumulation may result from: • Excessive breakdown of red blood cells (prehepatic) • Liver disease resulting in inefficient excretion of bilirubin (hepatic) • Bile duct obstruction (post-hepatic) Hyperbilirubinaemia Bilirubin accumulation in tissues - Jaundice 14 7 AHS 2013 Digestion and Metabolism Sarah Harney Cholesterol — structure • Cholesterol – 3 x 6-Carbon rings + 1x 5-Carbon ring – Basic structure for steroid hormones – Essential component of all plasma membranes 15 Cholesterol — roles • Most produced in liver – inverse ratio to intake i.e. Increases dietary intake reduces synthesis and reduced intake increases synthesis by the liver • Facilitates transport between liver and other organs • Enters cells via LDL receptors – Regulation by down-regulation of LDLr and intracellular production 16 8 AHS 2013 Digestion and Metabolism Sarah Harney Steroid hormones • Based on cholesterol • Fat-soluble • Pass through cell membrane • Typically receptors are cytosolic i.e. intracellular 17 Cholesterol and Lipoproteins • Cholesterol is synthesized by the liver • Cholesterol synthesis is inversely regulated by dietary intake i.e. increased dietary intake reduces synthesis and reduced intake increases synthesis by the liver • Cholesterol is transported in the plasma as lipoproteins – complexes containing cholesterol, phospholipids, triglycerides and apoproteins (co-factors for various enzymes) Lipoproteins have a hydrophilic outer shell and a hydrophobic inner core 18 9 AHS 2013 Digestion and Metabolism Sarah Harney Cholesterol and Lipoproteins • Lipoproteins are classified depending on their density VLDLs Very low density lipoproteins, high concentration of lipid LDLs Low density lipoproteins HDLs High density lipoproteins, high concentration of protein • High plasma cholesterol levels are a major risk factor for heart disease Normal levels 200 mg/dl (mg per 100 ml, or ~ 5 mM) High levels > 240 mg/dl (> ~ 6 mM) • A high ratio of HDL to LDL reduces the risk for atherosclerosis, hence, HDL is ‘good cholesterol’ 19 Cholesterol and Atherosclerosis • Atherosclerois (hardening of the arteries) is caused by deposition of a fatty, cholesterol-rich plaque inside arteries • Narrowing of the arteries results in increased blood pressure and can lead to complete occlusion, resulting in heart attack or stroke (depending on what arteries are affected) • Statins (e. g. Lipitor, Zocor) inhibit cholesterol synthesis and are used to reduce plasma cholesterol 20 10 AHS 2013 Digestion and Metabolism Sarah Harney Cholesterol — excretion • Produced by hepatocytes (liver) • Excreted via Bile • HDLs take up and transport cholesterol from cells around the body and transport it to the liver for degradation and excretion • Supersaturation may lead to gall stones 21 Fuel Metabolism – Carbohydrate, Protein, Fat • Excess nutrients are converted to stored fuel sources • Excess glucose is stored as glycogen, in liver and skeletal muscle – once maximal storage capacity (~ 500 g) is full, excess glucose is converted to fatty acids and triglycerides • Excess amino acids are converted to glucose and fatty acids • Excess fatty acids are assembled as triglycerides All nutrients surplus to requirements are converted to fatty acids and stored as triglycerides in adipose tissue Reading: Stanfield pp 608-612 22 11 AHS 2013 Digestion and Metabolism Sarah Harney Roles of different tissues in metabolism Liver – maintains blood glucose levels by glycogen storage/breakdown and gluconeogensis Adipose tissue – main energy storage site, regulates fatty acid levels in blood Muscle – main site for amino acid storage, major energy user Brain – only uses glucose but cannot store glycogen, relies on blood glucose being maintained 23 Fuel Metabolism Process Liver Blood Glycogenesis Glucose Glycogen Blood glucose Glycogenolysis Glycogen Glucose Blood glucose Gluconeogenesis Amino acids Glucose Blood glucose Protein Synthesis Amino acids Protein Blood amino acids Protein breakdown (proteolysis) Protein Amino acids Blood amino acids Fat synthesis (lipogenesis) Fatty acids Triglycerides Blood fatty acids Fat breakdown (lipolysis) Triglycerides Fatty acids Blood fatty acids 24 12 AHS 2013 Digestion and Metabolism Sarah Harney Fuel Metabolism – Anabolism and Catabolism Anabolism - Synthesis of large macromolecules from smaller molecular subunits (Energy-requiring) Catabolism – Breakdown of large, energy-rich macromolecules (Energy-yielding) 25 Absorptive and Postabsorptive States Absorptive State (Fed) • Nutrients absorbed for ~3-4 hrs after eating • Energy input > Energy output • Energy is stored in macromolecules (anabolism) Postabsorptive State (Fasting) • Time between meals, no nutrients being absorbed • Energy output > Energy input • Energy stores are utilized (catabolism) 26 13 AHS 2013 Digestion and Metabolism Sarah Harney Feeding & Fasting — Carbohydrate Absorptive State (Fed) • Glucose is the major energy source Postabsorptive State (Fasting) • Glycogen depletion • Glycogen synthesis + storage • Glucose sparing to conserve glucose for the brain • Excess glucose converted to fat • Gluconeogenesis 27 Feeding & Fasting — Protein Absorptive State (Fed) Postabsorptive State (Fasting) • Protein synthesis • Protein catabolism • Excess converted and stored as triglycerides • Amino acids used for gluconeogenesis 28 14 AHS 2013 Digestion and Metabolism Sarah Harney Feeding & Fasting — Fat Absorptive State (Fed) • Triglyceride synthesis and storage Postabsorptive State (Fasting) • Triglyceride catabolism • Fatty acids used as energy source for non-glucosedependent tissues 29 Absorptive Metabolism Absorption of small nutrients Blood Glucose Most body cells Liver + muscle CO2 + H2O + Energy Glycogen Fatty Acids Liver + adipose tissue Glycerol Fatty acids Amino acids Liver Fatty acids Muscle etc. Protein Triglycerides Stanfield, Fig. 21.3 30 15 AHS 2013 Digestion and Metabolism Sarah Harney Postabsorptive Metabolism Stored Macromolecules Adipose tissue Muscle + oth cells Proteins Triglycerides Amino acids Liver Muscle Glycogen Glycogen Fatty Fatty acids acids Glycerol Liver Lactate, pyruvate Glucose Ketones Blood Amino acids Fatty acids Ketones Glucose Non-nervous tissue Nervous tissue CO2 + NH3 + H2O + Energy CO2 + H2O + Energy 31 Stanfield, Fig. 21.4 Appendix Summary of nutrient metabolism in different tissues From: http://www.nature.com/scitable/topicpage/dynamic-adaptation-of-nutrient-utilization-in-humans-14232807 32 16