Chapter 12: Liver Structure & Function Flashcards
What are the functions of the liver?
• Crucial for management of:
– Nutrients
• “First stop” of portal blood from intestines
– Travel from duodenum via portal vein
- Blood glucose regulation
- Lipid and protein metabolism
- Storage of vitamins and minerals
– Wastes
- Urea
- Billirubin (heme catabolite)
- Drug metabolism
– Plasma proteins
- Albumin
- Clotting factors
- Complement proteins
Liver Blood Supply
• Circulation is key to liver’s central role in the body
– Hepatic portal vein carries 75% of blood supply to liver
• Portal blood contains:
– Nutrients and toxins absorbed from intestine – Blood cells and their breakdown products from spleen
• Positions liver to be a “metabolic clearinghouse” for the body
– Hepatic artery carries remaining 25% of liver blood supply and provides oxygenated blood
– Hepatic vein carries all blood from liver to inferior vena cava
Hepatocyte Structure
• Major cell type of liver (~75% of liver mass)
– Large cells, 20-30 um in diameter
- Although they vary with location within the liver, hepatocytes typically have – Numerous mitochondria
- Many energy utilizing pathways
– Extensive ER and Golgi
- RER and golgi synthesis for plasma proteins
- SER for lipid and bile salt synthesis
– Glycogen storage granules
• Blood glucose control
– Microvilli
• Perform all major liver functions
Hepatocyte Plates
Hepatocytes are polarized epithelial cells organized in parallel rows (plates/cords) – Note structures characteristic of polarized epithelium
- Microvilli ( increase of absorption)
- Desmosomes (anchor neighboring cells together)
- Tight junctions surround bile canaliculus (prevent leakage) Hepatocyte plates are surrounded by Sinusoid endothelial cells (SECs) that are supported by ECM reticular fibers. Reticular fibers are produced by stellate cells.
Sinusoid
• The typical capillary has a continuous endothelial cell lining
– Sufficient for exchange in most situations but, in the liver, an increased level of exchange is necessary
• The SECs form a discontinuous endothelial wall or a Sinusoid to allow for efficient solute exchange between blood and cells which is key to lobule function
– Allows secreted proteins such as albumin, clotting factors, and complement proteins to enter into circulation without transporters
– Also facilitates absorption of material by hepatocytes
Hepatocytes and Sinusoids
• Space of Disse is a
– Narrow space separating hepatocyte microvilli and SECs
– Key for diffusion of metabolites into and products out of the hepatocyte
• Note intercellular space between endothelial cells characteristic of a discontinuous endothelium
Hepatocyte Function: Plasma Proteins
• The hepatocyte synthesizes most plasma proteins
– Albumin
– Clotting proteins
– Binding and transport proteins
- Steroid binding proteins
- Iron transport proteins
- Note that proteins exit hepatocyte by exocytosis but then travel freely (diffuse) through the space of Disse into the Sinusoid to enter circulation
Hepatocyte Function: Detoxification
• The hepatocyte is the major site for detoxification of:
– Wastes
—– Toxic ammonia produced in amino acid metabolism is converted to urea which is easily excreted
—— Bilirubin (heme waste product)
– Xenobiotics*
——Drugs
—— Toxins
- Detoxified substances excreted by kidneys or in bile
–—- Kidney is typical route for hydrophilic substances while bile is typical for more hydrophobic products
• Focus on the example of bilirubin
Example: Detoxification of Bilirubin
• Heme is excreted in the form of conjugated bilirubin (or Bile Pigment) in the bile. Process involves a two step reaction:
– Phase 1 reaction to convert heme to water-insoluble bilirubin occurs in macrophages in spleen and liver
– Bilirubin is absorbed by the hepatocyte, conjugated (Phase 2 reaction), and secreted into bile as conjugated bilirubin
- Conjugation occurs in hepatocyte SER by UDP-glucuronyltransferase (UGT)
- This conjugation increases the hydrophilicity of bilirubin so that it can be secreted into bile
Hepatocyte Function: Bile
Bile is composed of molecules that aid digestion & absorption of nutrients (particularly important for hydrophobic nutrients):
-Bicarbonate : synthesized by cholagiocytes to neutralize stomach acid so that digestive enzymes (with pH optima of ~7) are active
-Bile salts and acids: synthesized by hepatocytes to emulsify lipids. Synthesized from cholesterol and form the majority of bile (67%).
-Phospholipids: help form vesicles with bile salts and acids
-Cholesterol: only route out of the body for cholesterol -Bile pigments: or conjugated bilirubin: heme catabolite
• Hepatocytes secrete components of bile into the bile canaliculus and does not enter the sinusoid
– Detergent properties of bile acids are too “dangerous” for contact with “normal” cells
– Tight junctions surround canaliculi to prevent leakage
• Bile travels through the canaliculus to the bile duct and then to the gallbladder for eventual release into the intestine after meals
Bile Function
• Bile aids in digestion and absorption of fat and fat soluble vitamins
– Bicarbonate increas of pH of chyme so digestive enzymes are more effective
– Detergent properties of bile salts/acids –> micelles composed of dietary fats, fat soluble vitamins, and bile salts/acids) –> increased enzymatic digestion & absorption of micelle components
– Without bile salts/acids, absorption decreases –> steatorrhea and deficiencies in fat soluble vitamins
• Liver produces ~700 ml of bile per day but components of the bile are reused
– After secretion into the GI tract, they are re-absorbed into the portal blood and then imported into the hepatocyte for resecretion into the bile
Enterohepatic recirculation
• Example: 95% of bile salts are re-absorbed from the intestine
– Remaining 5% will be excreted in the feces
- Reabsorbed bile salts reach the liver via the hepatic portal vein and are taken up by the hepatocyte from the sinusoid for re-secretion into the bile canaliculus
- Thus, bile salts recirculate between the gut (entero) and liver (hepatic)
Bile recirculation
• Bile salt transport in hepatocytes
– Absorb bile salts from sinusoids
- NTCP: Na+ coupled symport
- OATP: Cl- coupled antiport (also used for bilirubin)
– Transport bile salts into canaliculus
- BSEP: primary active transport
- MRP2: primary active transport (also used for bilirubin)
Bile Formation
• Bilirubin transport in hepatocytes (0.3% of bile) to canaliculus
– Absorb bilirubin from sinusoids
• OATP: Cl- coupled antiport
– Transport conjugated bilirubin into canaliculus
• MRP2: primary active transport
Liver Lobule
• Cells in the liver are organized into lobules
– At the organ level, the liver is divided into lobes (left and right)
– Each lobe is subdivided into lobules
• The lobule is
– The fundamental unit of liver function
– A hexagonal column of liver tissue organized around a central vein
Portal Triad
- Set of three vessels found at each corner of lobule
– Portal arteriole
– Portal venule
– Bile duct
– Kupffer cells: name of macrophages that are in the liver
Regions of Lobule
• Hepatocytes located in different regions in liver lobule have varied functions
– Periportal region rich in O2 and energy that are depleted as blood flows to perivenous region
– Metabolism shifts along this O2 gradient
• As functions of hepatocytes differ, they will express different proteins
– These differences can be used diagnostically
Cell Types in Liver
Hepatic stellate cells (HSCs, Ito cells)
- Located in space of Disse
- Store vitamin A and fat
- Act like a type of fibroblast
– Produce extracellular matrix (ECM)
• Act as antigen presenting cells (APCs)
– Macrophages called Kupffer cells
– Pit cells are liver specific natural killer cells
– Oval cells (stem cells): sit in Hering’s canal
Phases of Detoxification (Hepatocyte Function)
– Phase I reactions inactivate compounds (cytochrome p450 system)
- Composed of heme containing CYP proteins which catalyze redox or electron transfer reactions
- Some pharmaceuticals are activated as a result of Phase I reactions
– Phase II reactions increase hydrophilicity of compounds so that they are water soluble and can be excreted
Bile formation: Choliagiocytes
Cholangiocytes
- Secrete HCO3- to help neutralize acid from stomach entering duodenum
- Absorbed from interstitial space or synthesized in the cholangiocyte
- Net HCO3- transport requires Cl-, H+, K+, and Na+ transport to maintain osmotic balance
Periportal region and pericentral region
