Polycystic Liver Disease: Advances in Understanding and Treatment

Abstract

Polycystic liver disease (PLD) is a group of genetic disorders characterized by progressive development of cholangiocyte-derived fluid-filled hepatic cysts. PLD is the most common manifestation of autosomal dominant and autosomal recessive polycystic kidney diseases and rarely occurs as autosomal dominant PLD. The mechanisms of PLD are a sequence of the primary (mutations in PLD-causative genes), secondary (initiation of cyst formation), and tertiary (progression of hepatic cystogenesis) interconnected molecular and cellular events in cholangiocytes. Nonsurgical, surgical, and limited pharmacological treatment options are currently available for clinical management of PLD. Substantial evidence suggests that pharmacological targeting of the signaling pathways and intracellular processes involved in the progression of hepatic cystogenesis is beneficial for PLD. Many of these targets have been evaluated in preclinical and clinical trials. In this review, we discuss the genetic, molecular, and cellular mechanisms of PLD and clinical and preclinical treatment strategies. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Autophagy promotes hepatic cystogenesis in polycystic liver disease by depletion of cholangiocyte ciliogenic proteins

“…Limited data generated primarily by us show that these mechanisms are mostly linked to 30 dysregulated pathways in PLDCs, including alterations in autophagy that result from overexpression of autophagy‐related genes, cilia‐mediated intracellular cAMP signaling, and cholangiocyte proliferation that are considered current targets for therapeutic interventions in PLD. [ 7,39 ]…”

“…[2,3,7,37,38] To date, 12 PLD-causative genes have been discovered; nevertheless, despite many advances in genetics, studies on how mutations in PLD-causative genes initiate HC formation are still needed. [7,37] In contrast, the mechanisms of the progression of HCG are partially clarified. Limited data generated primarily by us show that these mechanisms are mostly linked to 30 dysregulated pathways in PLDCs, including alterations in autophagy that result from overexpression of autophagy-related genes, cilia-mediated intracellular cAMP signaling, and cholangiocyte proliferation that are considered current targets for therapeutic interventions in PLD.…”

A missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

“…Clinical trials testing the efficacy of mTOR inhibitor treatment in PKD yielded conflicting results. [ 11 ] Our results shed light on the mechanisms underlying rapamycin's action on cystogenesis and reveal additional therapeutic targets to improve treatment.…”

“…[8,9] Mutations in PKHD1, which encodes a primary cilium protein fibrocystin, are associated with autosomal recessive polycystic kidney disease (ARPKD). [10] Isolated polycystic liver diseases have been linked to mutations in genes including Protein kinase C substrate 80K-H (PRKCSH), SEC63 homolog, protein translocation regulator (SEC63), LDL receptor related protein 5 (LRP5), SEC61 translocon subunit beta (SEC61B), ALG8 α-1,3-glucosyltransferase (ALG8), Glucosidase II α subunit (GANAB), and ALG9 α-1,2-mannosyltransferase (ALG9) (reviewed by Masyuk et al [11] ). Except for LRP5, all of these genes encode proteins located in the endoplasmic reticulum (ER).…”

A novel missense mutation in the proprotein convertase gene furinb causes hepatic cystogenesis during liver development in zebrafish

“…In humans, PLDs have been linked to defects in the structure or function of primary cilia in cholangiocytes (Masyuk et al, 2021). Our study suggests that ciliopathy may not cause hepatic cystogenesis in zebrafish during development.…”