Dataset Information

Therapeutic Targets in Polycystic Liver Disease.

ABSTRACT: Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as cholangiociliopathies since many disease-causative and disease-related proteins are expressed in primary cilia of cholangiocytes. Aberrant expression of these proteins in primary cilia affects their structures and functions promoting cystogenesis. Current medical therapies for PLD include symptomatic management and surgical interventions. To date, the only available drug treatment for PLD patients that halt disease progression and improve quality of life are somatostatin analogs. However, the modest clinical benefits, need for long-term maintenance therapy, and the high cost of treatment justify the necessity for more effective treatment options. Substantial evidence suggests that experimental manipulations with components of the signaling pathways that influence cyst development (e.g., cAMP, intracellular calcium, receptor tyrosine kinase, transient receptor potential cation channel subfamily V member 4 (TRPV4) channel, mechanistic target of rapamycin (mTOR), histone deacetylase (HDAC6), Cdc25A phosphatase, miRNAs and metalloproteinases) attenuate growth of hepatic cysts. Many of these targets have been evaluated in pre-clinical trials suggesting their value as potential new therapies. This review outlines the current clinical and preclinical treatment strategies for PLD.

SUBMITTER: Masyuk TV

PROVIDER: S-EPMC5777530 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Therapeutic Targets in Polycystic Liver Disease.

Masyuk Tatyana V TV Masyuk Anatoliy I AI LaRusso Nicholas F NF

Current drug targets 20170101 8

Polycystic liver diseases (PLD) are a group of genetic disorders initiated by mutations in several PLD-related genes and characterized by the presence of multiple cholangiocyte-derived hepatic cysts that progressively replace liver tissue. PLD co-exists with Autosomal Dominant Polycystic Kidney Disease (ADPKD) and Autosomal Recessive PKD as well as occurs alone (i.e., Autosomal Dominant Polycystic Liver Disease [ADPLD]). PLD associated with ADPKD and ARPKD belong to a group of disorders known as ...[more]

PMID: 25915482

Similar Datasets

Project description:Polycystic liver disease (PLD) is a group of genetic disorders characterized by bile duct dilatation and/or progressive development of multiple intrahepatic fluid-filled biliary cysts (>10), which are the main cause of morbidity. Current surgical and/or pharmacological therapies exert short-term and modest benefits, and thus liver transplantation represents the only curative option. Recently, novel PLD-causative genes, encoding for endoplasmic reticulum (ER)-resident proteins involved in protein biogenesis and transport, were identified. Here, we hypothesized that aberrant proteostasis contributes to PLD pathogenesis, representing a potential therapeutic target. In this regard, ER stress was assessed at transcriptional (qPCR), proteomic (mass spectrometry), morphological (transmission electron microscopy; TEM) and functional (20S proteasome activity) levels in different models of PLD (i.e., human and rat). Moreover, PCK rat (animal model of PLD) was employed to determine the effects of ER stress inhibitors [4-phenylbutyric acid (4-PBA)] and/or inducers [tunicamycin (TM)] in hepatic cytogenesis and, consequently, in the progression of the disease. Likewise, the impact of the aforementioned ER stress modulators was also analyzed on the expression of unfolded protein response (UPR) factors, the 20S proteasome activity, the mechanisms involved in the maintenance of ER proteostasis and the cell fate decisions (i.e., survival/apoptosis). Interestingly, the expression levels of the UPR factors were markedly upregulated in liver tissue from PLD patients and PCK rats, as well as in primary cultures of human and rat cystic cholangiocytes, compared to normal controls. Additionally, cystic cholangiocytes showed altered proteomic profiles, mainly related to proteostasis (i.e., synthesis, folding, trafficking and degradation of nascent proteins), marked enlargement of the ER lumen (by TEM), and hyperactivation of the 20S proteasome. Notably, chronic treatment of PCK rats with 4-PBA decreased liver weight, as well as both liver and cystic volumes, of animals under baseline or TM administration compared to control groups. In vitro, 4-PBA downregulated the expression (mRNA) of UPR effectors, normalized, at least in part, proteomic profiles related to protein synthesis, folding, trafficking and degradation, and reduced the proteasome hyperactivity in cystic cholangiocytes, reducing their hyperproliferation and apoptosis. Conclusion: Restoration of proteostasis in cystic cholangiocytes with 4-PBA halts hepatic cystogenesis, emerging as a novel and promising therapeutic strategy.

Dataset Information

Therapeutic Targets in Polycystic Liver Disease.

Publications

Therapeutic Targets in Polycystic Liver Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets