Liver is involved in metabolic reactions, ammonia detoxification, and immunity. Multicellular liver tissue cultures are more desirable for drug screening, disease modeling, and researching transplantation therapy, than hepatocytes monocultures. Hepatocytes monocultures are not stable for long. Further, hepatocyte-like cells induced from pluripotent stem cells and in vivo hepatocytes are functionally dissimilar. Organoid technology circumvents these issues by generating functional ex vivo liver tissue from intrinsic liver progenitor cells and extrinsic stem cells, including pluripotent stem cells. To function as in vivo liver tissue, the liver organoid cells must be arranged precisely in the 3-dimensional space, closely mimicking in vivo liver tissue. Moreover, for long term functioning, liver organoids must be appropriately vascularized and in contact with neighboring epithelial tissues (e.g., bile canaliculi and intrahepatic bile duct, or intrahepatic and extrahepatic bile ducts). Recent discoveries in liver developmental biology allows one to successfully induce liver component cells and generate organoids. Thus, here, in this review, we summarize the current state of knowledge on liver development with a focus on its application in generating different liver organoids. We also cover the future prospects in creating (functionally and structurally) in vivo-like liver organoids using the current knowledge on liver development.

Progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC) are two rare autosomal recessive disorders, characterized by cholestasis. They are related to mutations in hepatocellular transport system genes involved in bile formation. The differentiation between PFIC and BRIC is based on phenotypic presentation: PFIC is a progressive disease, with evolution to end-stage liver disease. BRIC is characterized by intermittent recurrent cholestatic episodes, with irresistible pruritus, mostly without evident liver damage. Between symptomatic periods, patients are completely asymptomatic. In this article, a short overview of the aetiology, the clinical and diagnostic characteristics and the therapy of both PFIC and BRIC are given.

1. Whole-body sterol (cholesterol and xenosterol) balance is delicately regulated by the gastrointestinal tract and liver, which control sterol absorption and excretion, respectively, in addition to the contribution to the cholesterol pool by whole-body cholesterol synthesis. In the past ten years enormous strides have been made not only in establishing that specific transporters mediate the entry and exit of sterols and how these may regulate selective sterol access to the body pools, but also in how these pathways operate to integrate these physiological pathways. 2. The entry of sterols from the gastrointestinal and biliary canalicular lumen into the body is mediated by NPC1L1, which was discovered by a novel method, via a genomics-bioinformatics approach. 3. Identification of the genetic basis responsible for causing sitosterolaemia, characterized by plant sterol accumulation, led to the identification of two half-transporters (ABCG5 and ABCG8) that normally efflux plant sterols (and cholesterol) into the intestinal and biliary lumen for faecal excretion. 4. The objective of this review is to provide up-to-date knowledge on genomics, proteomics and function of these two transporter systems.

The transport processes responsible for bile flow are reviewed. Canalicular bile acid-dependent flow is the result of active transport of bile acids by the hepatocyte into bile canaliculi. Bile acids are taken up by at least two transport systems whose mRNA have been expressed in Xenopus oocytes: (i) a Na(+)-dependent system, named NTCP, and (ii) a Na(+)- independent system, named OATP. Bile acids are then secreted into bile by two other transport systems, an ATP-dependent system and an \'electrogenic\' voltage-dependent system. It is not known whether these two systems are mediated by the same protein or by two different proteins. Canalicular bile acid-independent flow is mainly the result of the secretion of glutathione into bile. The canalicular membrane also contains several proteins of the multi drug resistance (MDR) family. MDRI is responsible for biliary secretion of cationic drugs. MDR3 (mdr 2 in mice) plays a major role in the secretion of phospholipids. A third MDR-related protein has been shown recently to be the canalicular carrier of organic anions, such as bilirubin and dyes (the canalicular multiple organic anion transporter, or cMOAT). Biliary epithelial cells secrete a bicarbonate-rich solution, mostly in response to secretin. This secretion depends upon the presence, on the apical membrane of these cells of the CFTR, a chloride channel activated by cAMP and of a chloride/bicarbonate exchanger. Knowledge of these transport systems should allow a better understanding of the mechanisms involved in cholestasis.

Ultrastructural observations on 12 liver biopsies from 10 patients with arteriohepatic dysplasia syndrome (Alagille\'s syndrome) are reported. The electron microscopic changes in the liver in this condition are different from those seen in other forms of chronic intra- and extrahepatic cholestasis. In particular, the bile canalicular and pericanalicular changes classically observed in cholestasis are infrequently seen. When compared with other forms of intrahepatic cholestasis including syndromes associated with paucity of intrahepatic bile ducts, the ultrastructural changes in Alagille\'s syndrome appear to be distinctive. Bile pigment retention is found in the cytoplasm especially in lysosomes and in vesicles of the outer convex face of the Golgi apparatus (cis-Golgi), but rarely in bile canaliculi or the immediate pericanalicular region. These results suggest a block in the Golgi apparatus or in the pericanalicular cytoplasm.