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Liver Physiology

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					                                            Okamoto – CH34                                                1



 Liver Physiology
       1. Major Functions of the Liver – Introduction
               a. Metabolism of nutrients, vitamins, and drugs
                          i. These are up taken from our diet
                         ii. Stored in the liver
                        iii. Distribution/redistribution according to the metabolic demands of the body.
                             Some drugs are absorbed in the small intestine, and then go into portal
                             circulation to the liver where they are processed/stored..
               b. Regulation of blood sugar levels
               c. Regulation of circulating lipids, different types and levels
               d. Synthesis of plasma proteins:
Involved in
                          i. Transferrin – Binds to iron in the blood
iron transport           ii. Ferretin – binds inside epithelial cell (can’t be transported across
                               basolateral membrane so it is lost into the lumen when the epithelial cell is
                               sloughed off)
                        iii. Albumin
               e. Mechanism of drugs and Xenobiotics (naturally occurring toxins – drugs look a
                     lot like xenobiotics…that is why the liver metabolizes drugs.)
               f. Excretion of bile pigments, cholesterol, and drugs:
                          i. These are excreted as components of bile (main way of getting rid of
                               cholesterol).
                         ii. Drugs are secreted in their inactive form.
               g. Synthesis and secretion of bile
               h. The liver has endocrine functions:
   The liver handles       i. It not an endocrine gland, but it is important in the metabolism circulating
      pretty much              hormones and secretes hormones.
   anything that is in             1. It secretes hormones that modify the action of other hormones.
      the blood.


      2. The Anatomy of the Liver – Plays a Large Role in its Function
            a. Different cell types:
                    i. The arrangement of Hepatocytes facilitates the rapid exchange of
                       molecules.
                   ii. Have endothelial cells in Sinusoids.
                           1. Theses cells are functionally very porous to facilitate the exchange
                               of molecules in the plasma to the hepatocyte.
                           2. Do NOT have a basement membrane.
                           3. Have Fenestrations – Large pores in their capillaries
                           4. Have lots of cell membrane surface area, their arrangement of cells
                               is VERY important.
                  iii. Kupffer Cells – a name for macrophages in the liver.
                  iv. Fat Storage Cells – When a person starts to have liver disease,
                       hepatocytes are replaced by fat cells.
            b. Circulation
                    i. 25% of cardiac output goes to the liver
                   ii. 70 – 80% of blood is supplied by the Portal Vein
                                          Okamoto – CH34                                             2


                             1. All this is deoxygenated blood.
                    iii. 20 – 30 % (the remainder) of blood is supplied by the hepatic artery.
                             1. This blood is oxygenated.
              The Liver is the largest Gland in the body
      3. Biliary Secretion
              a. Anatomy
                      i. The production site of bile is the LIVER.
                     ii. The Storage site for bile is the GALLBLADDER.
              b. Composition of Bile
                      i. Bile Acid – Dependent Flow:
                             1. The flow depends of the nature of the meal eaten.
                     ii. Bile Acid Independent Flow
                             1. The amount of bile that is always being secreted – does not depend
                                  on what is eaten. Constituently being released.
                    iii. Canalicular Bile vs. Gallbladder Bile.
                             1. Gallbladder bile is much more concentrated than Canalicular (liver)
                                  bile.
                                      a. The epithelial cells of the gallbladder extract salt and water
                                          from the stored bile; this concentrates the bile acids 5 – 20
                                          Folds in comparison to the bile in the liver.
              c. The Regulation of Bile
                      i. The Feedback Loop of Bile:
                             1. The Rate of Return of the bile acids to the liver affects the rate of
                                  the synthesis and secretion of the bile acids
                             2. Bile acids in the portal blood stimulate the uptake and resecretion
                                  of bile acids by hepatocytes.
                     ii. The Hormonal Control of Bile Secretion:
Strongest stimulus           1. CCK – Stimulates bile secretion.
  for gallbladder
 secretion of bile                    a. The release of this hormone is stimulated by the presence
                                          of fatty acids in the small intestine.
                                      b. This causes the gallbladder to contract and release bile.
                             2. Gastrin – helps elicit gallbladder contractions during the cephalic
                                  and gastric phases of digestion.
                             3. Motilin – stimulates bile secretion
                             4. Steroid Hormones – INHIBITS bile secretion.
                             5. Secretin – Stimulated by HCO3- secretion by duct cells.
                    iii. Neural Control of Bile Secretion
                             1. The vagal nerve stimulates the secretion of gallbladder contraction.
                                       Okamoto – CH34                                              3




                    Composition of         Liver Bile       Gall Bladder Bile
                        Bile
                       Water                  98%                  92%

                        Bile Salt           1.1gm %              6 gm %

                       Billiruben            0.04%                0.30%

                      cholesterol            0.10%               .3-.9 %              Red font = the
                                                                                         higher
                       Fatty acid            0.12%               .3- 1.2%            concentration of
                                                                                    the component in
                        Lecthin              0.04%                0.30%
                                                                                           bile
                          Na+                 145                  130

                          K+                   5                    12
                             2+
                          Ca                   5                    23

                          Cl-                 100                   25

                        HCO3-                  28                   10


   4. Enterohepatic Circulation.
          a. This refers to the circulation of bile acids.
                 i. Venus blood leaving the ileum goes strait into the portal vein and returns
                     to the liver.
                         1. Hepatocytes are good at extracting bile acids from the sinusoidal
                              blood.
                         2. Bile acids are then transported across the hepatocytes to be
                              resecreted into canaliculi.
                ii. The entire bile acid pool is recirculated at least two times after a typical
                     meal.
   5. Bile Pigments:
          a. They are secreted by the liver
          b. Bile pigments are derived from hemoglobin degradation and then modified into
             water-soluble molecules.
                 i. The are filtered by the kidney and secreted as Urobilinogen
                ii. The feces excrete bile pigments as Sterocobilin.

The Metabolism of Drugs and Xenobiotics

          1. Mechanisms of Elimination - The more hydrophobic the molecule is, the longer it
             will stay in the body.
                 a. Drugs/Xenobiotic Molecules:
                          i. Tend to be hydrophobic molecules.
                         ii. If a drug is more hydrophilic, it is more likely to be reabsorbed by
                             the kidneys because it will be more soluble.
                                       Okamoto – CH34                                           4


                  b. Two Stages of Drug Metabolism:
                          i. Render the Drug More Soluble.
                                 1. Phase I – Add functional groups to make more soluble.
                                        a. Drug is oxidized – results in the addition of a
                                            hydroxyl group and/or carbonyl groups.
                     The basis for drug          i. There is a family of Cytochrome 450
                      metabolism is to              enzymes responsible for drug degradation
                      make the drug             ii. Many different polymorphisms of
                      more soluble –                Cytochrome 450, some of them change the
                     More Hydrophilic.              whole kinetics by which the enzyme works
                                               iii. There is not much incentive for drug
                                                    companies to invest in this type of research.
                                        b. Oxidation occurs in the cytoplasm of the smooth
                                            endoplasmic reticulum or the mitochondria
                                 2. Phase 2 –
                                        a. The drug is conjugated with {glucuronic acid, the
                                            amino acid glycine, taurine and glutathione - both
                                            amino acid derivatives, or sulfates}
                                                 i. The amino acid conjugate is both polar and
                                                    hydrophilic.
                                                ii. This occurs in the cytosol.
           2. Influences on Drug Metabolism
                  a. Age Dependent Drug Metabolism
                          i. Neonates have poor drug metabolism.
                         ii. Elderly – Have lower drug metabolism (capacity)
                  b. Nutritional factors – such as protein in diet
                          i. High-protein diets can enhance the rate of drug metabolism in part
                             by stimulating the induction of cytochrome P-450.
                  c. Induction affect
                          i. Cigarettes contain polycyclic aromatic heterocarbons
                         ii. This type of compound enhances the metabolism of drugs –
                             somehow turns on enzyme expression.

The Metabolism of Lipids – The liver is good at dealing with hydrophobic molecules.
         1. The Major Reaction: Oxidation of Free Fatty Acids
                a. β – Oxidation – occurs in the mitochondria
                        i. Involves the chopping of two carbons at a time – results in 8 acetyl
                           coenzyme A molecules.
                b. Formation/Uses of Acetyl-CoA
                        i. TCA (The Citric Acid Cycle) for ATP production
                       ii. Liver uses acetyl CoA to resynthesize Fatty acids – does this two
                           carbons at a time.
                      iii. Ketone bodies are formed when the body uses fat as a primary fuel
                           source.
         2. The Liver is the Major Organ for the Synthesis of Fatty Acids.
                              Okamoto – CH34                                             5


        a. Proteins, Carbohydrates contribute to the formation of acetyl CoA
            molecules, which enhances fatty acid synthesis.
        b. Palmitic Acid (16 Carbon Chain) – is the base for the synthesis of Fatty
            acids.
                  i. Β – oxidation – The shortening
                 ii. Elongation – by adding acetyl groups.
                iii. De-saturation – can add double bonds at specific sites to
                     unsaturated fatty acids.
3.   Synthesis of Lipoproteins:
        a. VLDL (Very Low density Lipoprotein) – 10 times higher in the liver than
            in the small intestine
                  i. The small intestine is the main site for chylomicron synthesis
                 ii. During a Fed State – Fatty acids are synthesized from
                     chylomicrons.
                iii. During a Fasting state – Fatty acids are synthesized from adipose
                     tissue.
        b. HDL (high density lipoprotein) and LDL (low density lipoprotein) are
            produced in small amounts.
                  i. HDL – “Good cholesterol” carries cholesterol from the peripheral
                     tissue to the liver.
                 ii. LDL – “Bad cholesterol”. Carries cholesterol ester from the liver
                     to peripheral tissues.
4.   Catabolism of Lipoproteins – The liver is the main site to break L.P down.
        a. This is for the deposition of cholesterol in hepatic tissue.
                  i. Have LDL uptake and catabolism (breaking down)
                 ii. Livers can uptake chylomicron remnants, and endothelial cells
                     then metabolize them.
                iii. Have the uptake of HDL cholesterol esters.
        b. There is receptor-mediated uptake for all Lipoproteins.
                  i. The lipoproteins are degraded intracellularly.
                 ii. Derangement of LDL leads to disease.
                         1. Families with mutated LDL receptor have severe
                             atherosclerosis – they can’t internalize the receptor and take
                             up the LDL.
5.   The Production of Ketone Bodies.
        a. This process is enhanced during periods of starvation (still is a normal
            process of the body)
        b. This is a lipid metabolism pathway.
        c. Ketones can be used for fuel by the body for all the cells in the body,
            EXCEPT the liver.
        d. This is a normal and efficient process.
6.   Cholesterol Metabolism:
        a. Two sources of Cholesterol: From new synthesis (by the liver) and
            Lipoprotein uptake (this is influenced by the diet).
        b. Liver is good at synthesizing cholesterol; a person would be just fine if
            they never ate any cholesterol again.
                                      Okamoto – CH34                                            6


                  c. The Functions of Cholesterol:
                         i. Bile Acid Formation – cholesterol is the backbone of bile acids.
                        ii. Biliary cholesterol secretion – forms an important component of
                            bile.
                       iii. Synthesis of VLDL’s – cholesterol for Steroidogenic Hormones
                            (such as gonads, adrenal medulla).
                       iv. Synthesis of Liver membranes – cholesterol is present in every
                            single plasma membrane.
                        v. Needed to synthesize vitamin D (precursor).

Metabolism of Carbohydrates – In Liver

   1. Uptake and Metabolism of Monosaccerides-
          a. Carbohydrates come from portal circulation after we absorbed them from our diet.
   2. Glycolysis or Glycogenesis: balance between these two pathways: primarily dictated by
      insulin and glucagons.
          a. Important biochemical pathways
          b. Glycolysis – Stimulates glycogen breakdown to glucose.
          c. Glycogenesis – glucose is converted to glycogen (anabolism).
                  i. Glycogen is stored in the liver and muscles.
   3. Glycosylation (sugar groups attached to proteins or lipids – glycosylation)
          a. This is responsible for the formation of glycolipids and glycoproteins.
   4. Gluconeogenesis
          a. Production of glucose from amino acids, fat, and lactate – molecules other that
              glycogen..
          b. Provides fuel for the brain during periods of starvation and fuel for itself (liver)
              because it doesn’t use ketone bodies.
   5. Glycogen Metabolism
   6. Regulation of Carbohydrate Metabolism
          a. Insulin – stimulates glycogenesis (glucose to glycogen) and inhibits
              glycogenolysis (glycogen catabolism) and gluconeogenesis.
          b. Epinephrine and Glucagon – Stimulates glycogenolysis (catabolism of glycogen
              (breakdown) into glucose.
                  i. Stimulates glycogen breakdown for fuel.

Metabolism of Proteins and Amino Acids
  1. Productions of Plasma Proteins –
         a. Albumin – major plasma protein.
                ii. Functions to Maintain Volume and Tissue Fluid Balance:
                        1. Maintains oncotic pressure of the plasma, it keeps fluid moving
                           toward the plasma because it is osmotically active.
                               a. Capillaries – blood pressure pushes fluid out (don’t want
                                  edema)
                                      i. Presence of albumin helps draw water back in on
                                          the venous side of capillaries.
         b. Complement System – immune system
                                       Okamoto – CH34                                            7


          c. Blood Clotting Factors.
          d. Iron Transport – Transferrin (Tf) – transports iron in the blood; haptoglobin and
              hemopexin (have intracellular antioxidant functions – mainly expressed in the
              liver. Binds to heme (b/c can be toxic) and acts as antioxidants..
                 iii. Liver synthesis ALL carrier proteins for iron.
                  iv. This is important because iron can be toxic in large amounts
                   v. The Fe-binding protein complex is metabolized in the liver by receptor-
                      mediated endocytosis.
   1. Urea Production – Ammonia Excretion: important because it is toxic.
   2. Inter-conversion of Amino Acids (must have in diet)
          a. Essential amino acids (body can’t make) are converted to non-essential amino
              acids: non-essential amino acids – can be made by the body so don’t need in the
              diet.

Liver as a Storage Organ:
   1. Storage of Fat soluble Vitamins (A,D,E, and K)
          a. Vitamin A is important of the synthesis of clotting factors
          b. Vitamin K is a major regulator of calcium and phosphate metabolism. Acts to
              sustain normal plasma concentrations of calcium and phosphate by increasing
              their inflow from the intestinal tract – required for normal bone growth.
   2. Iron storage and Homeostasis
          a. Cytoplasmic storage form
                  i. Ferritin – binds to iron inside epithelial cells (pretty much permanently)
                      and prevents them from being transported across the basolateral
                      membrane.
                 ii. Hemosiderin Granules – storage granules for ferric iron (in cytoplasm of
                      hepatocytes.
          b. Plasma circulating form is transferrin (binds to iron as it circulates in the blood.)
   3. Uptake Routes
          a. Hb – Haptoglobin – binds to iron and prevents iron loss in the urine.
          b. Hemopexin                        These are all bound to Fe
                  i. Binds to heme (very high affinity for) - transports heme and initiates
                      antioxidant activities (heme is very toxic b/c of free radical formation… so
                      hemopexin prevents oxidative stress)
          c. Transferin – TfR
                  i. Binds to iron in the blood.
   4. Glycogen Storage
          a. Regulate blood glucose levels.




Endocrine Functions of the Liver
                                     Okamoto – CH34                                         8


1. Modify Hormone Actions:
     a. Vitamin D        cholecalciferol         25-hydroxy-cholecalciferol        1,25-
           dihydroxycholecalcferol

                                             The conversion to
               The conversion to this       this form occurs in
                 form occurs in the
              kidney: Potent form that            the liver:
                regulates expression


                           Important in Ca2+ blood levels regulations

2. T3      T4 Conversion (This process is called deidination)
      a. Thyroid is converted form its inactive form to its active form (T3)to its active
         form (T4).
3. Somatomepin – is made in the liver.
      a. Liver converts growth hormone to somatomedin (IGF).
      b. It is insulin like growth hormone.
      c. It modulates the activity of growth hormone.
4. Removes Circulating Hormones, such as:
      a. Insulin
      b. Glucagon
      c. Growth hormone (GH)
5. Summary of Plasma Lipoproteins – Lipoproteins and source.
      a. Chylomicrons          Intestine
      b. VLDL                  Intestine and Liver
      c. LDL                   Chylomicron and VLDL
      d. HDL                   Chylomicron and VLDL
                                              Okamoto – CH34                                               9




 Lipid Metabolism in the Liver:                                                                      Plasma
      Citric Acid                                                                           Ketone
                                          Acetyl CoA                                        Bodies
         Cycle
                                                                    Synthesis
                                               Β-Oxidation

                                                                                                         Fatty Acid
      Cholesterol Ester                                              Free F.A                             Bound to
Hydrolysis         Esterifications                           Hydrolysis                                   Albumin
                                                                                Synthesis

                                                                          T.G
           Cholesterol

                                                VLDL
           Bile Acids
                                               Synthesis                                             LDL, VLDL
                                                                                                     Chylomicron
                                                                                                      Remnants
             Bile Salts




                                     Plasma                                 Bile
                                                                          Canaliculi




 LDL                binds to LDL receptor protein
             The vesicle is endocytosed and the uncoated
             It fuses with other vesicles in the endosome
                   o The LDL receptors are on the outside, and the LDL is on the inside of the
                      uncoated vesicle in the endosome.
             Receptors are recycled to the plasma membrane
             LDL contained vesicle fuses with the lysozome.
                   o Free cholesterol is released (it inhibits LDL receptor and cholesterol synthesis.
                                                         Okamoto – CH34                                                   10

                                                                                          Na+/H+ Exchanger
                                 Free Bile Acids or                                         Na+
                      Na+            Bile Salts                                                              CO2
Basolateral
Membrane
                                                                                                                          Basolateral
                                                                              Tight                                       Membrane
                      Na+              Free Bile
                                                                            Junctions
                                        Acids                                                      H+         CO2

                                                   Apical Membrane      Apical Membrane
        Conjugated
        Taurine of
       glycine: Now                                                                                          H2CO3
        have perm.                                                   BILE
                                 ATP                                               -                          Carbonic
       Charged bile                                                          HCO3
            salt                                                                                              anhydrase
                      ADP + Pi
                      Na+              K+
                                                                                                   HCO3-
                                                                              Tight
                         Na+                                                Junctions




                      Na+              K+
                                                               Portal Blood


                                       The Bile secreted by hepatocytes is bicarbonate and
                                        sodium rich.
      Unconjugated                    Cholesterol diffuses across the membrane while lecithin
       hydrophobic.                                                                                    Bile Acid
                                        needs to be transported across.
                                                                                                Is ionized, so cannot
     Both conjugated and
                                       Bile Acids have carboxyl groups attached to them and       passively diffuse
      unconjugated are                  Bile Salts have derivatives esterified to the molecule.  into the Enterocyte.
      reabsorbed in the                                                                                      Needs a Na+ – co
        distal ileum.                                                                                          transporter.
                                            Okamoto – CH34                                                      11


               Enterohepatic Circulation – The recycling of Bile salts and acids.




                  Liver
                                                            Portal
           Bile Acid Conjugation.                         Circulation
                                                                                                   Colon
1˚Bile Salts     2 ˚ Bile Salts   Bile
                                  Salts




                                  Gallbladder                     Bile
                                                                  Salts
                          Bile Storage

                                                                       Bile
                                          Active uptake
                                                                      Acids
                                                          1
                                                                 2          Diffuses

                            Small Intestine                                            Deoxycholic Acid




               Bile Salts                                 3      Bile          4
                                                                 Acids
                                                                                            Lithocholic acid.



                                            An example of a conjugated
                                            bile salt (conjugated with an
                                            amino acid)

				
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