Liver physiology

From Iusmphysiology

  • started here on 02/24/11 at 11AM.


Contents

Liver physiology

  • Has one direct role in the digestion process: lipid metabolism.
  • But it also processes all the stuff we absorb.

Hepatic circulation

  • Portal vein brings blood into the liver along with hepatic artery.
  • Vein provides 2/3 of the blood supply and carries stuff from the gi tract.
  • Blood exits through the central hepatic vein to the IVC.
  • Liver lobules:
    • Hexagon in shaped
    • Filled with hepatocytes
    • Branches of hepatic artery and portal vein at each along with bile duct = portal triad.
    • At the center is the central vein which run to hepatic vein to the IVC.
  • Blood runs through sinusoids within the lobule.
    • Stuff goes into and out of the blood.
  • Bile canaliculi
    • Every hepatocyte can add to the biliary tree

Classic hepatic lobule

  • Each lobule is a mass of cells.
  • There is an epithelium that facilitates exchange of material.
  • Hepatocytes have a "canicular domain" that is surrounded by tight junctions.
    • It is here that hepatocytes dump stuff to go to the bile.
  • These hepatocytes are flooded with blood except in this area where tight junctions keep blood out and bile in.


  • Endothelial cells:
    • Sinusoid is fenestrated (a unique type of blood vessel).
    • Allows many proteins and molecules through.
    • Some large proteins don't get through and certainly not RBCs.
    • But chylomicrons can get through


  • Kupffer cell
    • Macrphages of the liver
    • Very important in removing unwanted material.
    • Make TNF-alpha and other inflammatory mediators
      • This can harm or protect


  • Stellate cells = Ito cells
    • Have a large fat droplet
    • Important in VitA metabolism
    • And it makes sense that liver handles metabolism of fat solbule vitamens like A, DEK
    • Can get transformed to fibroblasts which can produce a collagen-based scar matrix; associated with fibration of the liver and cirrhosis and such.


  • Scarring
    • Activation of kupffer cells, increase of TNFalpha and inflamasome
    • Convert stalatte cells to fibrotic cells
    • Hepatic cells are disappearing


  • Cholangiocyte
    • Line bile ducts
    • Many transporters (like the ducts of pancreas): HCO3 secretion, CFTR, etc.
    • Many hormones can regulate these cells

Metabolic zonation

  • Blood runs from triad to central vein.
  • Bile strats being formed near central vein and runs to the bile duct in the portal triad.
  • Oxygen concentration gradient runs from portal triad (high) to central vein (low).
    • Nearest the triad is zone 1, then zone 2, then zone 3 near the central vein.
    • Zone 3 is around the vein so we call it the pervenous zone = perivenous hepatocytes.
      • Does non-energy stuff like: See slide.
    • Zone 1 has the periarterial hepatocytes where all the high-oxygen demand stuff is occurring: synthesis, and detox (see slide).

CArbohydrate metabolism

  • Liver is super important for glucose control.
  • Liver is a storage for glucose in the form of glycogen.
  • GLUT2 is the hapatocyte glucose transporter
HOw is glut2 regulated?
  • Liver controls glucose when fasting (initially) by way of glycogen breakdown.
  • We have enough glycogen in our body for 1.5 days of not eating (liver and skeletal muscle).

Protein metabolism

  • AA taken up by hepatocytes
    • Used for making proteins
    • Or degraded
      • Produces amonnia, converted to urea via urea cycle
  • Secretion of protein is important:
    • Albumin
    • fibriongen, etc
  • Interconversion is important, too:
    • Convert essential aa into non essential aa.

Lipid metabolism

  • Lipids get int othe enterocyte of the gut, put in chylomicron, put in lymphatics, get into blood.
  • Lipoprotein lipase from vascular epithelijm cut up the chylomicrons to chylomicron remnants.
    • Now have few TAGs but lots of cholest
  • The few TAGs that get back to the liver get into hepatocytes and get beta oxidaized for energy or production of ketone bodies.
  • The choles that gets back can get esterified, get packaged into VLDLs (to be delivered to the rest of the body) or can be used to make bile salts.
    • Chol for bile stalts is dumped into the canaliculi.

Cholesterol homeostasis

  • We make 4-5 times as much chol as we take in diet.
  • Chol gets released as VLDL or as bile stalts.
  • VLDL:
    • Into blood
    • Lipoprotein lipase removes fatty acids and glycerol
    • VLDL becomes LDL which has lots of cholesterol (hence it is bad cholesterol)
    • ...
    • HDL
      • IMpt becuse all cells must regulate their cholesterol careful to maintin membrane integrity.
      • LCAT = lecithin cholesterol aminotransferase
      • CETP transfers chol from HDL to VLDL but mostly LDL
        • "Reverse cholesterol transfer system" because chol is removed from periphery.

Bile

  • 600 to 1200 ml of bile / day.
  • Don't memorize the numbers of this table.
  • Composition of bile:
    • Impt for boards, probably.
    • Bile acids, pigments, chol, phospholipids, electrolytes (HCO3 rich, thus pH is higher), water, proteins, toxins / metabolites.
  • Gallbladder concentrates the bile for storage by extracting the HCO3- and thus it becomes more acidic (ph ~6).

Formation

  • Primary bile acids are cholic acid, chenodeoxycholic acids.
    • These are usually connected to glycine and taurine before secretion.
Why?
  • Secondary bile acids occur in the GI tract because of the presence of bacteria.

Bile stalts

  • At neutral pH they are ionized so we call them salts.
  • Salts are more polar than the acids.
  • So emulsification is achieved primarily by salts (because they are more polar).
  • Function:
    • Polarity is import to emulsify and absorb lipids.
    • Allows lipases to cut up the lipids

Transporters

  • Four steps.
  • Molecules from blood leave through fenestrated vessels, enter hepatocytes, get modified or processed, then put into bile canaliculi.
    • Each stemp, especially steps 1 and 4 require transporters.
  • Housekeeping transporters maintain Na and K and such are regulated.
  • NOte that BA- = unconjugated bile salt.
  • Z indicates conjugation to glycine or taurine
    • Occurs in the hepatocyte
    • Makes primary bile acid
  • Y indicates conjugation to sulfate or glucoronate
Cover transporters on your own.
  • There are transporters for moving bile out into the cancaliculus but also back into the hepatocyte from the blood (because they get recycled).
  • MRPs transports bile and bilirubin, drugs, and lecithins.

Formation

  • Hepatocytes actively secrete bile in canaliclus to generate canalicular flow
    • 75% of bile
  • Hepatocytes that line the duct provide ductular secretion = 25% = mostly HCO3.
  • Between meals about half the bile is divered to the gallbladder.
  • Two parts of the flow:
    • ORganic: generates an osmotic driving force for biel acid independent flow
      • 50% of flow
    • Postiively charged ions: generates bile-dependent flow
What?

Isotonic fluid reabsorption by the gallbladder epith

  • In the gallbladder, Na / H are exchanged and Cl / HCO3 is exchanged.
    • Na / H is far greater in exchange than cl / HCO3
**So water moves ...
    • And pH drops
      • Prevents gallstone formation

Gallbladder tone

  • CCK causes sphincter of oddi to relax so bile can come out.

Enterohepatic circulation

  • Once bile enters the GI, it gets reabsorbed to get back to the liver.
  • Bacteria generate secondary bile salts in the proximal ileum.
  • ASPT absorbs bile and puts it in the blood to go back to the liver
    • Recirculates 5-15 times per day with 95% reabsorption.

Bilirubin metabolism and excretion

  • Livers convers many things and puts them into the bile.
  • Hb -> bilirumin which is useless and toxic.
  • 20 million RBC die each sentence meaning 5 quintillion Hb need to be broken down.
  • Free bilirum conjugated with glucaronic acid to be secreted.
  • Hepatocytes takes up bilirubin (via OATP1, bilitranslocase, and electroneutral mechanism)
  • Complexed with glucaronic acid
  • Put in bile
  • Broken dwon into bilirubin
  • Then to urobilogen (some goes to urine - yellow and some to feces - brown).

Drug metabolism

  • Phase 1:
    • Polar groups introduced to make the drug more polar so it can get out fo the body; adds an oxygen to the drug.
      • This is done via P450 reductase, which allows complex to add it's oxygen.
  • Phase 2:
    • Glucaronic acid, taurine, or glycine are conjugated to amke the compound hydrophillic so it can be secreted as urine.

Fat-soluble vitamins

  • VitA:
    • Impt for vision
    • Delivered in chylomicrons
    • Recall the cell of the liver impt for emtabolism
    • Can be stored or released
    • Retinol can be made
    • Retinol binding protein helps deliver retinol to the blood.
  • Vit D:
    • Liver converts to 25-hydroxyvitamin D
  • Vit E:
    • Absorbed as alpha or gram tocopherol
    • Alpha is good and secreted into VLDL
    • Gamma is bad and secreted
  • Vit K:
    • Impt for production of prothrombin (coagulation); a cofactor

Copper and wilson disease

  • Copper associated with wilson's disease
  • Hepatocytes absorb most of the copper.
  • LIver secretes most of it, too via bile.
  • Cu important for making our Cu carrying proteins.
  • Wilson's disease
    • Defect in atpase p-type cu transporter
    • Treat with penecillin which chelates the copper.

Iron and hemochromatosis

  • Hb turnover releases lots of iron.
  • Spaced out.
  • Hemochromatosis:
    • Bad


  • stopped here on 02/24/11 at 12PM.
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