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Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
The cause of posthepatic jaundice is a mechanical blockade in the bile canaliculi or bile duct (Figure 28). Due to this obstacle, bile canaliculi are distended, and the bile usually regurgitates into the blood stream. Obstruction of the main routes most frequently is caused by gallstones, tumors, or local metastic invasion.
Structural Organization of the Liver
Published in Robert G. Meeks, Steadman D. Harrison, Richard J. Bull, Hepatotoxicology, 2020
Bile ductules (terminal ductules, cholangioles, canals of Hering) form short channels that convey bile from bile canaliculi to the interlobular bile ducts in the portal tract. They are lined by cuboidal cells and are often difficult to identify in the normal liver. At the junction with the bile canaliculus, bile ductular cells share a canalicular lumen with hepatocytes (Figure 31). The bile ductules are smaller than the interlobular bile ducts, usually measuring 15–20 μm in diameter. Their lumenal surface has short microvilli. The nuclei and mitochondria of the ductular cells are smaller than those of adjacent hepatocytes. The endoplasmic reticulum is poorly developed, but the Golgi complex and pinocytotic vesicles are well developed, suggesting that ductular cells are active, presumably in absorption and secretion (Jones and Spring-Mills, 1984; Steinlieb, 1972; Steiner and Carruthers, 1961).
Liver, Gallbladder, and Exocrine Pancreas
Published in Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard, Toxicologic Pathology, 2018
Russell C. Cattley, James A. Popp, Steven L. Vonderfecht
The parenchymal cell of the liver, the hepatocyte, is responsible for the key metabolic and exocrine functions of the liver and is most often the target cell of hepatotoxicity. Hepatocytes are structurally arranged in cords that are lined by a specialized sinusoidal endothelium that is fenestrated and lacks basement membrane (Braet and Wisse 2002). This facilitates free exchange of blood solutes with the subendothelial membrane of the hepatocytes. Hepatocytes are connected to each other by gap junctions and tight junctions, the latter forming bile canaliculi, which are lined by the plasma membrane at the excretory pole of adjacent hepatocytes. The canaliculi form the channels for bile flow from the hepatocytes through the canals of Herring into the portal bile ducts that ultimately merge and conduct the bile out of the liver.
ZO-2 favors Hippo signaling, and its re-expression in the steatotic liver by AMPK restores junctional sealing
Published in Tissue Barriers, 2022
Laura González-González, Helios Gallego-Gutiérrez, Dolores Martin-Tapia, José Everardo Avelino-Cruz, Christian Hernández-Guzmán, Sergio Israel Rangel-Guerrero, Luis Marat Alvarez-Salas, Erika Garay, Bibiana Chávez-Munguía, María Concepción Gutiérrez-Ruiz, Dinorah Hernández-Melchor, Esther López-Bayghen, Lorenza González-Mariscal
The formation of bile acids is one of the main functions of the liver. Bile acids are transported across the hepatocytes apical membrane into the lumen of bile canaliculi. Then, via extrahepatic bile ducts reach the intestinal tract, having a fundamental role in the solubilization of dietary lipids. Bile acids are powerful detergents, and TJs prevent their leakage to the basolateral surface and the underlying parenchyma of hepatocytes and cholangiocytes. In the liver claudins −1, −2 and −3 have been observed in hepatocyte TJs.78,79,80 Claudin-2 has been more thoroughly studied, demonstrating its importance for the paracellular water flow required for proper bile composition, as a claudin-2 deficiency in mice increased bile concentration and promoted cholesterol gallstone formation.81 In humans, the role of ZO-2 in liver TJs appears to be critical and non-redundant since homozygote20,22 and compound heterozygote23,61 mutations in TJP2 cause PFIC-4. This disease, characterized by fluctuating jaundice, persistent cholestasis, pruritus, and malabsorption, affects young children and is an end-stage liver disease that leads to cirrhosis and hepatocellular carcinoma.22,23 In PFIC-4, the mutations of TJP2 that ablate ZO-2 expression induce a severe disease only in the liver, even though ZO-2 is a protein normally expressed in all epithelial cells. These observations suggest that in the human liver, ZO-2 plays a non-redundant role at TJs that cannot be compensated by other TJ proteins like, for example, ZO-1 or ZO-3.
Histological and Biochemical Changes in Adult Male Rat Liver after Spinal Cord Injury with Evaluation of the Role of Granulocyte-Colony Stimulating Factor
Published in Ultrastructural Pathology, 2020
Dalia A. Mohamed, Noura Mostafa Mohamed, Shaimaa Abdelrahaman
Electron micrographs of the control group showed a hepatocyte with a euchromatic nucleus and a prominent nucleus. The cytoplasm showed many mitochondria, parallel cisternae of rough endoplasmic reticulum and many glycogen globules. The same group showed a tight junction between adjacent cells, normal-shaped bile canaliculus lined by microvilli, and prominent microvilli projecting in the blood sinusoid (Figure 4a,b). SCI group (II) showed heterochromatic nuclei with the irregular nuclear envelope. The cytoplasm showed many lipid droplets and areas of the rarified cytoplasm. Multiple adjacent hepatocytes appeared with degenerated rarified cytoplasm, few mitochondria and dilated rER cisternae. Kupffer cell with characteristic heterochromatic nucleus could be seen (Figure 4c,d). Treated group (III) showed normal-shaped hepatocyte with the euchromatic nucleus and prominent nucleolus. The cytoplasm showed many mitochondria, rER cisternae and many glycogen globules. Some cells of group III were binucleated with heterochromatic nuclei and prominent nuclei. Tight junction between adjacent cells and normal-shaped bile canaliculi lined by microvilli was evident (Figure 4e,f).
Non-alcoholic fatty liver disease (NAFLD) models in drug discovery
Published in Expert Opinion on Drug Discovery, 2018
Banumathi K. Cole, Ryan E. Feaver, Brian R. Wamhoff, Ajit Dash
In order to build confidence on the use of in vitro models and systems in target identification, validation, or assessment of new therapies for NAFLD, a critical validation step required is to provide evidence of clinical translation using drugs that have already demonstrated proof of disease-modifying activity in the clinic. This is challenging because as of today there are no approved therapies for NASH, and the data available for most drugs are relatively limited. The previously described microfluidic NAFLD model by Kostrzewksi et al. [62] demonstrated direct anti-steatotic effects of pioglitazone, a drug that has been evaluated in the clinic for NAFLD, on hepatocytes within the system. The choice of pioglitazone was interesting since its effect is believed to include a significant non-hepatic peripheral component given that its target, PPARγ [91], is strongly expressed in extrahepatic tissues such as adipose tissue. In the study by Ijssennagger et al. using HPCLS [58], the phase III candidate, OCA was assessed in the system to understand mechanisms of FXR activation as it relates to known clinical outcomes with the drug. Davidson et al. [61] used micropatterned tri-cultures (MPTC) of primary human hepatocytes, 3T3-J2 murine embryonic fibroblasts and activated hepatic stellate cells to demonstrate that the latter caused a significant loss of canalicular structures and steatosis in the hepatocytes. Treatment with OCA in their system caused a partial recovery of bile canaliculi and reduced steatosis.