UW Division of Gastroenterology - Gut Course Syllabus (HuBio 551)

	Updated: 03/13/08 01:44 PM

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Authors: W. Volwiler, R.A. Willson, A.M. Larson, and J.D. Ostrow
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F. Function of Components of the Liver
		There are three main cell types within the liver, each performing specific functions. The largest cell mass is that of the hepatocytes. The other cell types include the sinusoidal lining cells (Kupffer cells, endothelial cells, and stellate cells [lipocytes or Ito cells]), and the bile duct epithelial cells (cholangiocytes). All have metabolic interactions with each other and the hepatobiliary system also has extensive metabolic interrelationships with the intestine and the bacterial flora contained therein (Figure 8). Thus, products of hepatic metabolism reach the intestine through the bile, and products of intestinal/bacterial metabolism reach the liver through the portal venous circulation.
1. Hepatocytes
		The hepatocytes make up approximately 60-80% of the cytoplasmic mass within human liver tissue. They perform essential functions: synthesis of proteins; storage and transformation of carbohydrates; synthesis of cholesterol, bile salts and phospholipids; and detoxification, modification and excretion of exogenous and endogenous substances (many of which have important biologic activities). In addition, the hepatocyte initiates the formation and secretion of bile. Reflecting these multiple metabolic and secretory functions, the liver cells contain an extraordinarily well-developed system of organelles (e.g., mitochondria, lysosomes, peroxisomes, rough and smooth endoplasmic reticulum).
		a. Protein synthesis.
Sole site of synthesis of many proteins.		The hepatocyte is the only cell in the body that manufactures albumin, fibrinogen, and the prothrombin group of clotting factors. It is the main site for the synthesis of lipoproteins, ceruloplasmin, transferrin, and glycoproteins. In addition, the hepatocyte manufactures its own structural proteins and intracellular enzymes. Synthesis of proteins, and of complexes of proteins, lipids, and carbohydrates, occurs in the rough endoplasmic reticulum. Both smooth endoplasmic reticulum and the Golgi are involved in post-translational modification and secretion of the proteins formed.
		b. Carbohydrate metabolism.
Glucose homeostasis		The liver accommodates our intermittent food intake by storing carbohydrate and releasing it upon demand. Following absorption by the small intestine, galactose, mannose, fructose, and glucose are transported to the liver by the portal system. There, they are converted by enzymes in the cytosol of the hepatocyte to glucose or fructose phosphate, which may then be polymerized into glycogen, a large storage polysaccharide. Upon physiological demand mediated by various hormones, this is depolymerized and released into the blood stream as glucose. The liver is about the only tissue source of blood glucose and has the major responsibility for supporting and maintaining a consistent plasma glucose concentration. It does this by balancing the uptake of glucose and its conversion to glycogen (glycogenesis, stimulated by insulin) with the breakdown of glycogen to produce glucose (glycogenolysis, stimulated by glucagon and epinephrine). The hepatocytes may also convert amino acids and glycerol to glucose (gluconeogenesis)..
		c. Lipid metabolism and secretion.
Liver synthesizes VLDL and HDL, takes up LDL from peripheral tissues. Bile salts synthesized only in hepatocytes ATP-dependent canalicular transporters for bile salts and lecithin Bile is a major route of cholesterol excretion		The liver forms fatty acids from carbohydrates and synthesizes triglycerides and phospholipids from fatty acids and glycerol. The hepatocytes also synthesize apoproteins, which they then assemble with lipids for export as lipoproteins (VLDL, HDL). The liver receives LDL from the systemic circulation and metabolizes remnants of chylomicrons. The liver synthesizes cholesterol from acetate and then converts it to bile salts. Bile salts, synthesized only by the liver, are the major pathway for removal of cholesterol. Secretion of bile salts, phospholipids and cholesterol into bile is mediated by several ATP-dependent, canalicular transporters. Bile salts are secreted into bile by the bile salt export pump (BSEP). Phospholipids (mainly phosphatidylcholine = lecithin) are secreted into bile independently by the phospholipid flippase MDR3. Secreted bile salts + lecithin form mixed micelles which strip cholesterol into bile from the outer leaflet of the canalicular plasma membrane. Bile salts, returning in the portal venous blood after reabsorption from the intestine, are taken up into the hepatocytes by the basolateral Na+-bile salt cotransporter (NTCP). This biliary secretion of lipids is intimately related to the metabolism of these components and lipoproteins in the liver, and to the alterations in bile composition associated with gallstone disease.
		d. Organic anion and cation transport in the hepatocyte (Fig. 9).
Transporters in the plasma membranes of the hepatocytes mediate basolateral uptake (OCTs, OATPs) or export (MRPs), and canalicular secretion (MRP2 and MDRs)		Organic anions are taken up into the hepatocyte, across the basolateral membrane, by groups of transport proteins (OATPs and OATs) with overlapping specificity. The organic anions (including bilirubin and glutathione) are then bound to cytosolic ligandins and diffuse across the hepatocyte, usually being modified by conjugation in the microsomes. These conjugates can then be secreted into bile by the ATP-dependent canalicular multispecific organic anion transporter, MRP2 (formerly designated cMOAT). Organic cations are taken up into the hepatocyte by basolateral OCT transporters and secreted into bile by MDR1. After uptake, some compounds may, in part, reflux back into the plasma due to ATP-dependent export mediated by several Multidrug Resistance Associated Proteins (MRPs). These transporters are expressed at the basolateral membrane of the hepatocyte and show considerable overlap of substrate specificity. MRP1 exports both unconjugated and conjugated bilirubins, whereas MRP3&4 and OSTa,ß best export conjugated bile salts. All of them have low expression in the normal liver, but are upregulated in cholestasis, protecting the hepatocytes against excessive accumulation of toxic bile pigments and bile salts.
Figure 8 An overview of metabolic relationships between gut and liver. Please note some arrows have been omitted to avoid clutter. For example, xenobiotics are absorbed from the upper small intestine, and from the colon; glucose and amino acids can be absorbed from the ileum.
Figure 9 Transporters in Basolateral and Canalicular Membranes of Hepatocytes A schematic of two hepatocytes and their shared bile canaliculus, showing the major transporters in the basolateral and canalicular (apical) membranes. The apical transporters are all ABC (ATP-Binding Cassette) proteins that actively export their substrates into bile using energy derived from hydrolysis of ATP. As illustrated in the right-hand hepatocyte, Na⁺-coupled uptake of bile salts from the space of Disse is mediated by the basal Na⁺-Taurocholate Co-transporting Polypeptide (NTCP), driven by the plasma-to-cytosol gradient of Na⁺, created by the basal Na⁺/K⁺-ATPase. The conjugated bile salts are then secreted into bile by the canalicular Bile Salt Export Pump (BSEP). Phosphatidylcholine (lecithin) is transported to the outer leaflet of the canalicular membrane by the phospholipid flippase, MDR3, from where it is stripped into bile by secreted bile salts. As illustrated in the left-hand hepatocyte, organic anions and cations are taken up across the basal membrane by Na⁺-independent processes. Uptake of organic cations is mediated by a family of Organic Cation Transporters (OCTs). Uptake or organic anions is mediated by families of Organic Anion Transporting Polypeptides (OATPs) and Organic Anion Transporters (OATs). After conjugation, the organic anions, as well as glutathione, are then secreted into bile by MRP2, a polyspecific apical transporter at the canalicular membrane. A wide variety of amphipathic compounds (including many drugs and organic cations) are exported from the hepatocytes into bile by apical MDR1. MRPs 1,3 & 4 and OST α,β are basolaterally located, ATP-dependent, transporters. The shading of these transporters, and the white arrows in the pathways leading to and through them, symbolize their low activity in the normal hepatocyte. With hepatocellular disease or cholestasis, they are greatly upregulated, increasing the export of organic anions back into plasma, thus limiting accumulation of toxic organic anions (e.g. bilirubin, bile salts) within the hepatocyte.
Figure 10 Hepatic Metabolism and Entero-Hepatic Cycling (EHC) of Xenobiotics Hepatic metabolism is the other mechanism that protects the body against toxic exogenous compounds (xenobiotics), including drugs. Lipophilic xenobiotics reach the liver by passive intestinal absorption into the portal venous system after oral intake (ingestion), and also via the hepatic artery and portal vein after systemic administration (not shown). After uptake into the hepatocyte, these compounds usually undergo a two-step biotransformation that detoxifies them and allows them to be secreted into the bile. In Step I, most lipophilic compounds (white symboles) initially undergo modification by a wide variety of reactions, mainly oxidation or hydroxylation, to yield weakly polar derivatives (stippled symbols). The weakly polar groups thus introduced can then be covalently coupled to highly polar molecules (e.g. glucuronic acid, sulfate, glutathione) by Step II conjugation reactions. The resultant water-soluble conjugates (striped symbols) are readily secreted into bile and urine by MRP2 and other transporters. Being more weakly bound to plasma proteins, the conjugates can also appear in the urine by glomerular filtration. The highly polar conjugates cannot be passively reabsorbed from the intestine. In the lower intestine and colon, however, the enteric bacteria produce enzymes that can deconjugate and reduce the excreted conjugates back to the Phase I derivative and original xenobiotic. These relatively non-polar compounds can then be passively reabsorbed into the portal circulation and return to the liver, constituting entero-hepatic cycling (EHC).
		e. Detoxification (Figure 10).
Liver metabolizes absorbed solutes carried in portal blood = “first pass metabolism” Biotransformation of compounds by the hepatocytes involves two stages.		Hepatocytes also have the ability to metabolize and excrete a wide variety of exogenous compounds such as drugs and insecticides and endogenous compounds such as steroids and UCB. Such metabolism and excretion of miscellaneous substances is required to protect the body against ingested toxins that are absorbed from the intestine and reach the liver via the portal venous blood. This process is mediated by two types of reactions that usually occur sequentially. Most stage I reactions involve oxidation or hydroxylation, mediated by microsomal monoxygenases (cytochromes P450 & P448, CYPs). Stage I reactions change compounds (e.g. vitamin D and some procarcinogens) into a biologically more active form. Stage II reactions prepare the Stage I metabolites for biliary excretion by covalently conjugating them with highly polar ligands (e.g., glucuronic acid, or glutathione), rendering them inactive, membrane-impermeable, water-soluble and more readily excreted in bile. Some compounds may undergo only Stage I or Stage II reactions.
Intestinal metabolism of secreted conjugates may regenerate toxic intermediate. Enterohepatic circulation of deconjugated intermediates		As shown in (Figure 10), once xenobiotics or their inactive conjugates are secreted into bile, they may be deconjugated and/or reduced by intestinal bacteria. Deconjugation regenerates the oxidized, often toxic metabolites from the phase I reactions, which may be partially reabsorbed in the intestine. These undergo an enterohepatic circulation to reach the liver, where they may contribute to hepatocellular necrosis or carcinoma. The unabsorbed metabolites that reach the colon may have oncogenic effects on the colonic epithelium, contributing to colon cancer, or on the hepatocytes, contributing to hepatocellular necrosis or carcinoma. The deconjugated metabolites may also be reduced by gut flora to the original xenobiotics, which may likewise undergo enterohepatic circulation, prolonging their half-life in the body
Impaired drug metabolism in liver diseases The liver converts ammonia to urea via amino acid intermediates.		The liver is the primary site for the metabolic inactivation of drugs, including ethanol, opiates, and many sedatives, steroids, and antibiotics. Patients with decreased hepatic function (i.e. cirrhosis) may thus suffer excessive effects from standard doses of drugs, due to poor hepatocyte function and shunting of portal venous blood past the liver. The hepatocyte plays a major role in the detoxification of ammonia, a noxious product of protein and amino acid catabolism. This process involves a complex of interrelated enzyme systems in the hepatocyte (the Krebs-Henseleit urea cycle), through which ammonia + citrulline eventually yield arginine, which is then hydrolyzed to form urea + ornithine. Urea is then delivered into the plasma for urinary and gastrointestinal excretion. Decreased urea synthesis, due to (a) liver disease or (b) congenital absence of one or more of the enzymes in the urea cycle, can result in toxic hyperammonemia with encephalopathy.
		f. Storage
		Hepatocytes are important depots for storage of iron, vitamin B₁₂, and the fat-soluble vitamins D, E and K. Vitamin A is stored in the stellate cells (see below).
2. The Sinusoidal Lining Cells (Kupffer Cells, Endothelial Cells and Stellate Cells)
		a. Endothelial cells
Sinusoidal endothelial cells have large pores that permit access of plasma albumin to the Space of Disse		The endothelial cells that line the sinusoids have large fenestrae, (pores) which provide a graded barrier between the sinusoid and space of Disse. The size of the fenestrae determines the exchange of fluids and size of molecules that can pass from the plasma into the space of Disse and the basolateral surface of the hepatocyte.
		b. Kupffer cells
Kupffer cells are part of the reticulo-endothelial (RE) system		The Kupffer cells line the sinusoids of the liver and are attached to the endothelial cells. They are derived from blood monocytes and are the largest group of fixed macrophages in the body. They actively remove macromolecules and particulate matter from the bloodstream (phagocytosis), including old cells, foreign particles, tumor cells, bacteria, yeast, viruses, and parasites. The large size of the liver and tremendous numbers of Kupffer cells makes the sinusoids a very important location for clearance of particulate matter and pathogens from the plasma. The liver’s function as a filter can be appreciated when you remember that about one-third of the cardiac output flows though the liver.
		c. Stellate (Ito) cells
Stellate cells are myofibroblasts that store Vitamin A.		The stellate cells, also called lipocytes or Ito cells, are smaller, and lie within the Space of Disse, encircling the sinusoidal endothelium. In the resting state, they resemble fibroblasts but their cytoplasm contains numerous droplets in which vitamin A is stored. Upon activation, stellate cells elongate to resemble myocytes and exhibit contractile function that plays a role in regulation of sinusoidal tone and resistance.
Activated stellate cells synthesize collagen.		In chronic liver disease, the stellate cells synthesize and secrete collagen into the Space of Disse, leading to “capillarization” (fibrosis) of the sinusoids. The final stage of this fibrosis is cirrhosis.
3. The Bile Duct Epithelial Cells (Cholangiocytes)
		The bile duct cells form a tubular passage for the excretion of bile from the liver to the gut. It is known that, secondary to neurohumoral stimulation, these cells make significant changes in the composition of bile as it flows past, particularly in its water and electrolyte components.
Next Section (G): Bile Secretion and Its Control »