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2022 GIT Biochemistry.pptx

  2. Objectives  At the end of this lesson You will able to describe Digestion and absorption of food  The effect of Gastrointestinal-Derived Hormones on Fuel Metabolism Liver Metabolism Liver function tests Bilirubin, ALT,AST,ALP,GGT GGT, Urea, NH3 and Albumin  Pancreatic function tests
  3. BIOCHEMISTRY OF GASTROINTESTINAL SYSTEM Definitions  Food: - is any solid or liquid which ingested & enable the body to carry out any of its life function.  Nutrients; Foods components which provide energy and serve as cofactor in different metabolic reactions  Xenobiotic: Biologically unimportant components which excrete with wastes are  Roughage: - is as dietary fibers which enable the body to get rid of waste products, which would otherwise become poisonous to the body. 3
  4. Macronutrients Contribute to the Energy Pool of the Body and Micronutrients are Cofactors (Coenzymes): Energy Pool of the body (100%) 28 March 2023 4 Micronutrient (Vitamins, ions)<0.01%) Fats 20% - 35% Proteins (10% - 35%) Macronutrients
  5. BIOCHEMISTRY OF GASTROINTESTINAL SYSTEM Cont…  Food have a little chemical different from the tissue of the animal  So how tissues of animal protected from enzymatic digestion?
  6. BIOCHEMISTRY OF GASTROINTESTINAL SYSTEM Cont…  GIT biochemistry discuss the role of GIT in peripheral energy homeostasis through digestion, assimilation and absorption of ingested nutrients.  The whole process of digestion involves hydrolytic cleavage reactions with the final absorbable monomers like: Monosaccharaides, amino acids, fatty acids and glycerol  Tissue of the animal protected from enzymatic digestion by:  Secretion of most digestive enzymes in the form of Zymogen and  Capsulation of tissues with mucus (large glycoproteins) 6
  7. Strategies that prevent premature zymogen activation  Secretion of most digestive enzymes in the form of Zymogen Capsulation of tissues with mucus (large glycoproteins) At pH>2, the peptide (44 AA) clipped of pepsinogen remains bound to pepsin, masking its active site; it is released by a drop of pH below 2 or by further degradation by pepsin Acinar cells synthesize and secrete a trypsin inhibitor that acts as a safeguard against trypsin activation within the pancreas. Pancreatic secretory trypsin inhibitor (PSTI), a small polypeptide, blocks any trypsin that is erroneously activated within the pancreas Another protective mechanism is that trypsin has a mechanism of autolysis (self-digestion) Fluid secretion by duct cells flush zymogens/active enzymes out of the pancreas into the duodenum α-1ant trypsin blocks any trypsin that is erroneously activated within the alveoli
  8. BIOCHEMISTRY OF GASTROINTESTINAL SYSTEM Cont… The Characteristics of Most Digestive Enzymes They are fairly narrow substrate specificity; e.g. Glycosidase (glycosidic bonds), proteases/peptidase (peptide bonds), Lipases (ester bonds) and Nucleases(phospodiester bond) They hydrolyzes only specific bonds based on the type of nutrients; e.g.  Salivary amylase (α-1→ 4 glycosidic bonds)  Isomaltase (α-1→ 6 glycosidic bonds)  Surcease (α-1→ 2 glycosidic bonds)  Lactase (β-1→ 4 glycosidic bonds) PH specific
  9. Salivary --amylase Lingua lipase  HCL, Gastric lipase, pepsin, rennin Pancreatic -amylase and HCO3- Pancreatic lipase. Co-lipase, phospholipase & cholesterol esterase Trypsinogen, chymotrypsinogen, proelastase and procarboxypeptidse  Glucoamylase, Lactase, Sucrase &Trehalase Enterokinase. Aminopeptidase, dipeptidase & tripeptidase Bile acid/salt
  10. Mechanisms of Carbohydrate Absorption A. Sodium-dependent transport B. Sodium-independent transport (GLUTs) 10
  11. Lipid Digestion and Absorption 11
  12. Protein Digestion and Amino Acids Absorption 12
  13.  Sodium-dependent transport and facilitated diffusion. 13 Absorption of Amino Acids
  14. The Effect of Gastrointestinal-Derived Hormones on Fuel Metabolism 14  Gastrin  Motilin  Secretin  PYY  PP  CCK  Ghrelin  GLP-1  GIP
  15. The Effect of Gastrointestinal-Derived Hormones on Fuel Metabolism  In addition to insulin and the counter regulatory hormones variety of peptides influence fuel metabolism  The following Gut” hormones have indirect influence on fuel metabolism by effects on the synthesis or secretion of insulin or the counter hormones.  For example:  Gastrin induces gastric acid secretion, which affects nutrient digestion & absorption .  Secretin stimulates pancreatic and biliary bicarbonate and water secretion but inhibits gastrin release and secretion of gastric acid  Peptide YY (PYY) inhibits gastric acid secretion, slows intestinal motility and inhibits
  16. The Effect of Gastrointestinal-Derived Hormones on Fuel Metabolism  For example:  Motilin stimulates gastric and pancreatic enzyme secretion to influences nutrient digestion and Induces gallbladder contraction  Pancreatic polypeptide (PP) reduces gastric emptying &slows upper intestinal motility  CCK inhibits proximal gastric motility to increases postprandial satiety &regulates nutrient-stimulated pancreatic enzyme secretion & gallbladder contraction  Ghrelin, is growth hormone secretagogue & appetite stimulant. Its mechanism is through the activation of the AMPK in the hypothalamus which leads to the release of neuropeptide Y, which increases appetite. Research geared toward interrupting the ghrelin/ghrelin receptor signaling system is increasing to develop new antiobesity agents.
  17. The Effect of Gastrointestinal-Derived Hormones on Fuel Metabolism  “INCRETIN” are all Insulinotropic factors from GIT which potentiating insulin release from β-pancreatic cell INCRETIN do not act as direct insulin secretagogues, they have indirect influence through fuel metabolism  They are mediating modest postprandial (After a meal) increase in serum glucose by slowing gastric empty time and increase the rate of insulin synthesis and secretion INCRETIN are accounted for the greater β-cell response(50-70%) seen after an oral glucose load as opposed to that seen after the administration of glucose intravenously
  18. The Effect of Gastrointestinal-Derived Hormones on Fuel Metabolism Several gastrointestinal peptides have INCRETIN effect , e.g.;  Glucagon like peptide-1 (GLP-1) regulate glucose homeostasis by inhibiting the secretion of glucagon  Glucose-dependent insulinotropic polypeptide (GIP) interacts with GIP receptors on adipocytes, this interaction coupled to energy storage The half-lives of GIP and GLP-1 in the circulation are on the order of 2.5 minutes. The protease DPP-4 (dipeptidyl protease 4) found on the surface of kidneys, intestine, liver, and many other tissues is responsible for inactivating GIP and GLP-1. If one wants to increase the efficacy of the incretins (GIP/GLP-1): synthetic incretin which mimics GIP/GLP-1 & with longer half-lives could be developed along with drugs which inhibit DPP-4, thereby increasing the serum half-lives of GIP and GLP-1. Such synthetic incretin/drugs have been developed & are used for treatment of type 2 DM
  19. Liver Metabolism
  20. LIVER METABOLISM Because of its wide range and diversity of synthetic functions, the liver may be considered to be the body’s factory, Taking raw materials and producing many compounds, some of which are exported for use in other tissues.
  21. Liver Metabolism Metabolic Functions  Carbohydrate metabolism (glycogen metabolism & gluconeogenesis  Lipid metabolism (cholesterol, fatty acids & TAG synthesis, bile and bile salt synthesis  Detoxification (Urea cycle, Conjugation &excretion of bilirubin),, gluconeogenesis from glycerol & lactate (Cori cycle) Vitamin storage vit. B 12, vit A and K  All proteins synthesis except gamma globulin Liver cells are responsible for conversion of preprothrombin (inactive) to active prothrombin in the presence of vit. K.  It also produces other clotting factors like factor V, VII and X. Fibrinogen involved in blood coagulation is also synthesized in liver. Right lobe Left lobe Gall bladder Bile duct Pancreas
  22. BLOOD CELLS LIVER Bilirubin diglucuronide (water-soluble) 2 UDP-glucuronic acid via bile duct to intestines Stercobilin excreted in feces Urobilinogen formed by bacteria KIDNEY Urobilin excreted in urine CO Biliverdin IX Heme oxygenase O2 Bilirubin (water-insoluble) NADP+ NADPH Biliverdin reductase Heme Globin Hemoglobin reabsorbed into blood Bilirubin (water-insoluble) via blood to the liver INTESTINE Catabolism of hemoglobin unconjugated 3/28/2023 ORGANS FUNCUTION TEST A 22 Detoxification(Conjugation and Excretion of Bilirubin)
  24. Liver Metabolism Detoxify Lactate Produced by Muscle and RBC through CORI CYCLE) Gluconeogenesis Glycolysis
  25. Glucose-Alanine Cycle Detoxify NH3 from Muscles Proteins Degradation Through UREA CYCLE During Starvation and Diabetes
  26. Liver Metabolism Only Liver blood glucose homeostasis through gluconeogenesis & glycogenolysis Only Liver clear glycerol produced by adipose tissue TAG lipolysis
  27. Liver Metabolism Only in the Liver Ketogenesis (Ketone Bodies Synthesis occur)
  28. Structure of Cholesterol & Regulation of Cholesterol Homeostasis by Promoting Bile Acids and Bile Salts Synthesis in the Liver  Bile acids are synthesized in the liver from cholesterol & stored in the gall bladder.  About 15-30 grams/day of bile acids is secreted into the GIT through common bile duct. CH3 CH3 HO H3C CH3 CH3 A B C D 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27
  29. Structure of Primary Bile Acids
  30. The Difference between Bile Acids Cholesterol :  The rings in bile salts contain more OH groups (2/3) than cholesterol The rings in bile salts contain less carbons (24-C) than cholesterol (27C) Bile salts have a polar side chain (carboxylic acid (COOH) function group Unlike cholesterol bile acids lack a C5–C6 double bond.
  31. Functions of Bile  The alkaline pH of the bile serves to neutralize the acidity of the gastric juice.  The bile salts are efficient surfactants and detergents.  Bile is the only route of excretion for bilirubin, the end product of heme catabolism.  It serves to excrete cholesterol, thus regulating the body cholesterol pool.  Bile serves as the medium of excretion for several drugs which are detoxified by liver  Bile acids are emulsifier of lipids  Bile acids promote absorption of fat and fat -soluble vitamins (A, D, E & K).  They also maintain cholesterol homeostasis by promoting excretion of cholesterol  i.e. extra cholesterol can be disposed as bile acids
  32. Bile Acids synthesis and secretion serves as a major route to get rid of Cholesterol
  33. Bile Acids synthesis and secretion serves as a major route to get rid of Cholesterol
  34. Clinical Significance of Bile Salts Metabolism (Cholestasis (Cholelithiasis))  Cholelithiasis (the presence of stone in the gallbladder or bile duct) is caused by: Decreased bile salts and phospholipid  Increased cholesterol in the bile (>15%) Cholecystitis (Infections of the gallbladder) Dehydration  Those type of bile is called Lithogenic bile (promoting the formation of calculi). 34
  36. LIVER FUNCTION TESTS  Liver function tests are a group of tests done to assess the functional capacity of the liver as well as any cellular damage to the liver cells such as: 1.Its Synthetic ability: By measuring the various plasma proteins such as albumin and prothrombin that are synthesized by the liver and PT  The half-life of prothrombin is 6 hours only; therefore, PT indicates the present function of the liver.  PT is prolonged only when liver loses more than 80% of its reserve capacity. 2. Liver Enzyme Panel: two types 1.Those indicating hepatocellular damage and ALT, AST, GGT, LDH; AST may be more than ALT in alcoholic liver disease. 2. Those indicating cholestasis (obstruction): GGT used as major discriminate the source of elevated ALP  If ALP is elevated parallel with GGT source of the elevated ALP is most likely biliary tract 3. Its secretory/excretory abilities: By measuring the serum bilirubin level
  37. Liver Function Tests Bilirubin (Total and direct bilirubin)-should be low in serum Total protein (high) Albumin (serum level should be high if it is normal), Prothrombin time (shorter)  Lipids profile (LDL, HDL, VLDL and TAG) Ammonia and Urea: NH4 ----------> Urea Liver Inflammatory enzymes: ALT, AST, ALP, GGT
  38. PANCREATIC FUNCTION TESTS Endocrine function (glucagon Insulin) Exocrine function
  39. PANCREATIC FUNCTION TESTS  Disease of the pancreas Diabetes Mellitus: hyperglycemia and glycosuria Pancreatitis: Inflammation of pancreas Malabsorption syndrome : Decreased acinar cell activity leading to reduce digestive enzymes Pancreatic carcinoma:
  40. PANCREATIC FUNCTION TESTS  Acute Pancreatitis serum amylase  Derived from pancreatic acinar cells  amylase level rises over the first 2-12 hours, peaks at 48 hours, returns to normal within 3-5 days  Serum: 70 - 340 IU/L, Urine: up to 300 IU/L per hour  Serum lipase is derived from pancreatic acinar cells, it rises slightly earlier than amylase, 1-8 hours peaks earlier, at 24 hours The serum lipase also lasts longer in the serum, 8-14 days Serum lipase is more sensitive and specific than the serum amylase 159 Reference : 0 - 62 U/L
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Notas del editor

  1. The liver is the essential site of carbohydrate metabolism. It produces, stores, and breaks down glycogen - glycogenesis and glycogenolysis. The liver is an essentil site of protein metabolism. It is involved in: the synthesis of urea from ammonia NH4 ----------> Urea This is the last function of the liver to fail. Once this function fails, then the body gets a buildup of toxic ammonia. The liver is involved in the synthesis of plasma proteins and coagulation factors. The liver also is involved in the deamination and transamination of amino acids The liver is an important site of synthesis of cholesterol and cholesterol esters, lipoproteins, and fatty acids, bile acids, and ketone bodies. It is involved in the complex transportation of lipid materials from digestion to excretion. The liver converts compounds and foreign substances to soluble metabolites so excretion may occur: e.g., drugs (active --------> inactive); bilirubin ---------> conjugated bilirubin. This makes the substances more water soluble so the kidney can excrete them. Lipid soluble vitamins which are important for coagulation are stored in the liver. What are these vitamins: Vitamin K Bile is formed in the liver, stored in the gallbladder, and excreted via the common bile duct into the small intestine to aid in digestion.
  2. Tests for liver function include bilirubin, albumin, prothrombin time and others. Bilirubin is an excretory product of the liver so should normally have a low concentration in serum when the liver functions properly. Albumin and blood clotting factors are normally produced by the liver so can be used to test liver function. Serum albumin concentration is low and prothrombin time is prolonged when the liver is not functioning properly. The two tests historically used to assess hepatic handling of exogeneously-administered compounds are: 1. The Bromsulfophthalein (BSP) excretion Test 2. The Hippuric acid Test