Liver physiology

From Iusmphysiology

• started here on 02/24/11 at 11AM.

Contents 1 Liver physiology 1.1 Hepatic circulation 1.2 Classic hepatic lobule 1.3 Metabolic zonation 1.4 CArbohydrate metabolism 1.5 Protein metabolism 1.6 Lipid metabolism 1.6.1 Cholesterol homeostasis 1.7 Bile 1.7.1 Formation 1.7.2 Bile stalts 1.7.3 Transporters 1.7.4 Formation 1.7.5 Isotonic fluid reabsorption by the gallbladder epith 1.7.6 Gallbladder tone 1.7.7 Enterohepatic circulation 1.8 Bilirubin metabolism and excretion 1.9 Drug metabolism 1.10 Fat-soluble vitamins 1.11 Copper and wilson disease 1.12 Iron and hemochromatosis

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.