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Chapter 20 Liver Biochemistry

Chapter 20 Liver Biochemistry. The function of liver. Liver is the largest and metabolically the most complex organ in our body. It performs the following functions: It decomposes and cleanses all the toxic substances of the body; It generates the bile-juice to help digestion;

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Chapter 20 Liver Biochemistry

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  1. Chapter 20 Liver Biochemistry

  2. The function of liver Liver is the largest and metabolically the most complex organ in our body. It performs the following functions: • It decomposes and cleanses all the toxic substances of the body; • It generates the bile-juice to help digestion; • It regulates the glucose,lipidand protein metabolism;

  3. The function of liver • It manufactures numbers of protein e.g. serum albumin; • It stores fat soluble vitamins, minerals; • It is a major energy consuming organ, hence to maintain the body temperature and the weight of the body,etc.

  4. We will learn: -The Role of liver in metabolism -HepaticBiotransformation -Metabolism of bile acid -Bile pigmentMetabolism and jaundice

  5. the role of liver in metabolism • Carbohydrate metabolism • Lipid metabolism • Protein metabolism

  6. The role in carbohydrate metabolism Keep normal blood sugar • Glycogenesis: after a meal, liver take up excess • glucose in blood and synthesize glycogen • Glycogenolysis: when level of blood sugar begin to • decline, liver activate glycogenolysis to export glucose • back into the blood

  7. The role in carbohydrate metabolism Keep normal blood sugar • Glyconeogenesis: when hepatic glycogen reserves • become exhausted, liver begin synthesizing glucose • out of such things as amino acids and non-hexose • carbohydrates

  8. The role in lipid metabolism • oxidizes triglycerides to produce energy or ketone bodies. • synthesizes lipoproteins • converts excess carbohydrates and proteins into fatty acids and triglyceride, which are then exported and stored in adipose tissue • synthesizes large quantities of cholesterol and phospholipids. Some of them is packaged with lipoproteins, the remainder is excreted in bile as cholesterol or after conversion to bile acids.

  9. The role in protein metabolism • Deamination and transamination of amino acids, followed by conversion of the non-nitrogenous part of those molecules to glucose or lipids. • Removal of ammonia from the body by synthesis of urea. • Synthesis of non-essential amino acids. • Synthesis of most of the plasma proteins.

  10. Section 2 hepatic biotransformation

  11. What is biotransformation? Poorly soluble, biologically active, some toxic • Nonnutritive compounds -endogenous: ammonia, amine, hormones -exogenous: drugs, food additives, pollutants • The liver has the function by which various nonnutritive compounds can be metabolized to form lower toxic or more water-soluble before being excreted from the body, these processes are named biotransformation.

  12. What is biotransformation? • a series of enzyme-catalyzed process in which nonnutritive compounds are added polar group and become more water-soluble and easily to be excreted from kidneys. • Inactivate or detoxicate the nonnutritive compounds, make it easy tobe excreted. • Liver is the main site of biotransformation

  13. The basic reactions of biotransformation • Biotransformation processes often have two major phases -Phase I: oxidation, reduction, hydrolysis -Phase II: conjugation compounds + donor substrate polar metabolites

  14. The basic processes of biotransformation

  15. Phase I reaction • Expose a polar group (-OH, -COOH, -NH2) on the substrate to prepare a lipophilic compound to be hydrophilic • Enzymes are mainly located in liver ER membrane, others in the cytoplasm or mitochondria

  16. Phase I reaction • oxidation - Microsomal monooxygenase - Mitochondrial monoamine oxidase (MAO) - alcohol dehydrogenase(ADH) and aldehyde dehydrogenase(ALDH)

  17. Phase I reaction alcohol dehydrogenase(ADH) and aldehyde dehydrogenase(ALDH) Toxic and highly reactive

  18. Ethanol metabolism • Alcohol is rapidly distributed throughout the organism (a large amount is taken up by muscles and the brain) • The lethal blood alcohol level is 0.3- 0.4% The alcohol content of alcoholic beverages • Ethanol is rapidly taken up from • the digestive tract by diffusion • The maximum blood alcohol level • is reached within 60-90 minutes

  19. Ethanol degradation (in the liver) • Alcohol dehydrogenase oxidizes ethanol to ethanal (aldehyde) • It is futher oxidized to acetate (acetic acid) by aldehyde dehydrogenase • Acetate is then converted to acetyl-CoA by acetate-CoA ligase in an ATP-dependent reaction • Other enzymes are also involved in ethanol degradation (catalase, Cyt P450)

  20. Liver damage • Elevated consumption of ethanol over many years may lead to liver damage (the limit for a man is about 60g daily, and for a woman about 50g); these values are strongly dependent on body weight, health and the use of medication • The high levels of NADH and acetyl-CoA inhibit TAC activity and ketogenesis, whereas they exert a stimulatory effect on the synthesis of neutral fats and cholesterol (an increase in the storage of lipids leads to a fatty liver- it is reversible)--- Alcoholism is the leading cause of fatty liver in India. • In chronic alcoholism- liver cell death (cirrhosis of the liver, an irreversible, progressive loss of liver function)

  21. Phase II reaction • The function of Phase II reaction: inactivate biologically active substances of form more polar (more easily excretable) derivatives. • Conjugate compound to a water soluble adduct using the polar handle from Phase I (containing -OH, -COOH, -NH2 ) • Donor substrate: Glucuronic acid, Sulfate, acetate, • Glutathione, Glycine

  22. Phase II reaction • Conjugation with Glucuronic Acid This is the most common conjugation reaction. • The glucuronic acid group is donated by • UDPGA. (Water soluble)

  23. Characteristics of biotransformation • Continuity of the reactions • Variety of the types of reactions • Duality of deintoxication and causing toxin

  24. Influence factors of biotransformation • Many factors can influence the effectiveness of biotransformation. • Such as age, gender, genetic variability, nutrition, disease, exposure to other chemicals, dose level, etc. • Biotransformation capabilities are decreased in the new-borns and the aged.

  25. Section 3 The metabolism of bile acids

  26. bile • Produce: from liver • Store: in gallbladder • Function: digest fatty food

  27. bile • During interdigestive period (between meal) Bile is stored in the gallbladder, and concentrated. • In the fed state (after meal) The gallbladder contracts, forcing bile into the duodenum to digest fatty food.

  28. bile • Hepatic bile: just secreted from liver. it is pellucid • Gallbladder bile: hepatic bile passed into the gallbladder, the gallbladder concentrates this bile, and secret some mucus into it, make the bile more potent, then the bile is named as gallbladder bile • Solids: bile acid(50%-70%), lecithin, cholesterol, bilirubin

  29. Bile acid According to its structure • free bile acids: cholic acid, chenodeoxycholic • acid, deoxycholic acid, lithocholic acid • conjugated bile acids: free bile acids • conjugate with glycine or taurine to form • conjugated bile acids.

  30. Bile acid Glycocholic acids Taurocholic acids Glycochenodeoxycholic acids Taurochenodeoxycholic acids conjugated bile acids Glycodeoxycholic acids Taurodeoxycholic acids Glycolithocholic acids Taurolithocholic acids

  31. Cholic acid deoxycholic acid free bile acids

  32. COOH chenodeoxycholic acid lithocholic acid free bile acids

  33. Cholic acid Bile acid Structure of the conjugated cholic acids Conjugated bile acids are the major bile acids in bile.

  34. Bile acid According to its origin • primary bile acids: synthesized in hepatic • cells, including cholic acid, chenodeoxycholic acid • and their conjugated form. • secondary bile acids: produced in small intestine from • primary bile, including deoxycholic acid, lithocholic • acid and their conjugated form.

  35. Metabolism of bile acid Key enzyme

  36. Metabolism of bile acid • The further transformation of cholyl-CoA and chenodeoxycholyl-CoAis to form cholic acid, chenodeoxycholic acid • Primary bile acids are mainly conjugated form. • primary bile acids pass into small intestine, part of • them turn into secondary bile acids by 7α- • dehydroxylation. • Bile salts: bile acids always exist in a salt form.

  37. Cholic acid deoxycholic acid primary bile acids 7α-dehydroxylation secondary bile acids

  38. COOH chenodeoxycholic acid lithocholic acid primary bile acids 7α-dehydroxylation secondary bile acids

  39. The enterohepatic circulation 1. The bile acids secreted into the gut can be absorbed , returning to the liver by way of the portal circulation. 2. After hepatic extraction, bile acids are recirculated into gut, complete the circuit. This process is known as the enterohepatic circulation. 3. Except lithocholic acid, about 99% of the bile acids secreted into the gut are reabsorbed.

  40. Significance of the enterohepatic circulation Limited bile acids can be fully utilized. The enterohepatic circulation of the bile salts is so efficient that each day the relatively small pool of bile acids (about 3~5 g) can be cycled through the intestine 6~10 times with only a small amount lost, which can meet the needs of fat digestion.

  41. Functions of Bile Bile acids perform four physiologically significant functions: • eliminate of excess cholesterol. • prevent the precipitation of cholesterol in the gallbladder. • facilitate the digestion of dietary triacylglycerols by acting as emulsifying agents that render fats accessible to pancreatic lipases. • facilitate the intestinal absorption of fat-soluble vitamins. Gallstones ??

  42. Gallstones

  43. Functions of Bile The formation of gallstones • The solubility of cholesterol in bile depends on the relative proportion of bile salt, lecithin and cholesterol. • When bile is supersaturated with cholesterol, the excess cholesterol is precipitated to form crystals. • The crystals may grow to form stones.

  44. Section 4 Bile pigment metabolism and jaundice

  45. What is Bile pigment • It is the main catabolic product of iron porphyrincompounds in the body. • Including bilirubin, biliverdin, bilinogen and bilin. All except bilinogen present certain color, so collectively call them bile pigment. • Bilirubin is the major pigment in bile which is yellow, and its metabolism is the center of metabolism of bile pigment. • Liver has a central role in metabolism of the bile pigment.

  46. Formation of bilirubin The source of bilirubin • The compounds involving iron porphyrin in • the body are hemoglobin, myoglobin, • cytochrome, catalase, and peroxidase, etc. • Hemoglobin is the main source of bile • pigment.

  47. Formation of bilirubin

  48. Metabolism of Bilirubin • Transportation of bilirubin in blood • Bilirubin metabolism in liver • Bilirubin metabolism in intestine

  49. Transportation of bilirubin in blood Unconjugated bilirubin(UCB) liberated into the plasma is bound to albumin then presented to the liver.

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