Biochemistry of Specialized Tissues



Biochemistry of Specialized Tissues

Aim: Adaptation of tissue cells to suit their function.

The Liver: (The greatest organ in its functional capacity).

Structure: 2 major cell types.

1. Parenchymal cells: 60-80% of liver mass.

Part of liver functional units termed: acini (see diagram)

2. Kupffer cells: ~30% (phagocytic role)

Blood Supply: -Portal vein: 1.51 l/min - carries out “Nutrients”.

- Hepatic artery: 0.4 l/min – oxygen supply.

The portal tract consists of: (1) biliary canaliculus (2) portal vein (3) hepatic artery. Blood flows from portal veins and hepatic arteries through sinusoids towards hepatic veins.

• Blood in the sinusoids is separated from hepatocytes by kupffer cells and space of Disse.

• Bile canaliculi: grooves in hepatocytes lined by microvilli, into which bile is secreted bile ducts (direction of flow opposite blood flow.)

Metabolic Roles of the Liver (Normal Hepatic Function):

1. Carbohydrate Metabolism:

a- Interconversion of monosaccharides: Glucose Fructose,

Gal Glucose.

b- Conversion of glucose to pentoses (used in nucleic acids synthesis): The Pentose Phosphate pathway.

c- Glycosis

d- Gluconeogenesis: hepatic glucose output (maintenance of blood glucose level between meals) along with:

e- Glycogenolysis: the above two functions can be assessed by measuring blood glucose level.

f- Lactate Utilization: assessed by measuring blood lactate level.

g- Galactose Metabolism: assessed by galactose elimination capacity.

h- Glycogen synthesis: reducing blood sugar level after a rich CHO meal.

2. Lipid Metabolism:

a. TAG synthesis from glucose, fructose, and certain a.a.s. (esp. low-fat diet/high intakes of CHO/proteins).

b. Endogenous synthesis of TAG: Excess f. as. in. relation to protein will lead to fatty liver.

c. Fatty acid synthesis.

d. Cholesterol synthesis and excretion.

e. Lipoprotein metabolism: assessed by serum lipid and lipoprotein levels.

f. Synthesis of ketone bodies: during starvation/uncontrolled D.M.

g. Bile acid synthesis: assessed by serum b.acids, tests for fat malabsorption.

h. 25 – Hydroxylation of Vit. D.: assessed by 25-OH cholecalciferol levels.

3. Protein Metabolism:

a. Plasma protein synthesis (including some coagulation factors but not immunoglobulins): Albumin, α-/β globulins, fibrinogen and blood clotting factors: II, VII, IX and X. Assessed by plasma protein concentrations.

b. Special transport proteins: transferrin, ceruloplasmia and transcobalamins.

Protein Clinical Utility

Albumin Decreased in chronic liver disease

α1–Antitrypsin Decrease in α1–antitrypsin deficiency

Ceruloplasmin Decrease in Wilson’s disease

Coagulation factors Decrease in chronic liver disease

α –Fetoprotein Decrease in hepatocellular carcinoma

Haptoglobins Decrease in hemolysis

Transferrin Saturated with “iron” in hemochromatosis

c. Urea and Ammonia: Assessed by serum and blood urea and NH4+.

4. Amino Acid Metabolism: (see diagram below)

Amino Acids

5. Storage: a. Glycogen 0.3% of liver wt. in fasting conditions.

10% of liver wt. after CHO-Rich meal.

Glycogen provides glucose up to 12 hrs. after a meal.

b. b. General store of protein.

c. Store of blood-clotting factors. e.g. Prothrombin.

d. Vitamins store: A, B12.

c. e. Iron state: as ferritin in parenchymal cells.

d. In hemochromatosis excess Fe stored in kuppfer cells as: hemosiderin. These stores provide supply during nutritional inadequacy and pregnancy.

e.

6. Detoxification and Excretion:

a. Bilirubin metabolism: assessed by serum bilirubin levels, urinary bilirubin and urabilinogen.

b. Excretion of foreign compounds (xenobiotics): Assessed by: Bromosulpthalein, indocyanine green, aminopyrine excretion.

7. Hormone Metabolism:

a. Metabolism and excretion of steroid hormones.

b. Metabolism of polypeptide hormones.

In clinical practice, assessment of “Liver Function”: the following tests are performed: Serum levels of bilirubin, hepatic enzymes and proteins. Other tests are done occasionally.

* Damage to liver may not affect its activity since the liver has considerable functional reserve. Therefore, the above tests are insensitive indicators.

8. Digestive Secretions:

- Bile: bile salts aid fat digestion.

- Phosphalipids: aid fat emulsification, HCO3- neutralizes gastric activity.

Types of Bile Acids:

Primary: cholic acid/chenodeoxyxholic acid.

Glyco/Tauro cholic acid/ Glyco/tauro cheno- “Conjugates” deoxycholic acid.

Secondary: Deoxycholic acid (formed by bacterial reduction of cholic acid in the gut).

Glyco/Tauro deoxycholic acid “conjugates”

Enterohepatic Circulation of Bile Acids: (see diagram).

Control of bile acids synthesis: 1. Feedback of bile acids into liver dampens down their synthesis. 2. Cholesterol synthesis control.

350 mg cholesterol/day Bile acids

650 mg cholesterol/day lost in feces

Cholesterol in bile is maintained soluble by bile acids precipitation of cholesterol causes “gall stone.”

- Detoxification (Metabolites synthesis, processing) and Excretion:

- This occurs via two routes:

1) Water-soluble compounds are passed out to the blood for excretion by the kidney.

2) Lipid-soluble/insoluble compounds are excreted through the bile, to the feces.

Formation of Water -Soluble Metabolites:

a. Urea formation

b. Xenobiotics metabolism (detoxification processes):

- Converting a toxic, lipophilic molecules into relatively non-toxic, hydrophilic, more acidic molecules that can easily be excreted by the kidney. (This determines the life span and activity of the drug introduced).

* Types of reactions involved in xenobiotics metabolism:

- phase (I) reactions: oxidation, reduction, hydrolysis and methylation.

- phase (II) reaction: Conjugation

followed by: Excretion see detail of these reactions.

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“A.A Pool”

portal venous

blood

Extrahepatic tissues: via

hepatic arterial blood

Interconversion

(TCA cycle / Transamination)

Glu

oxoacids

CO2

plasma

O2

Heme,

purines,pyrs.,

etc.

plasma

protein

plasma

a.as.

ASP

NH3

urea

Glucose

Gly/Taurine

urea

Gly/Taurine

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