These mutations, together with the newly identified ones in SEC61B and Alpha-1,3-Glucosyltransferase (ALG8), can be found in ∼50% of patients with isolated polycystic liver disease.
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]).
Genetic defects in polycystin-1 or -2 (PC1 or PC2) cause polycystic liver disease associated with autosomal dominant polycystic kidney disease (PLD-ADPKD).
Cdc25A expression was analyzed in livers of control and polycystic kidney (PCK) rats, control and polycystic kidney 2 (Pkd2(ws25/-)) mice, healthy individuals, and patients with PLD.
In polycystic kidney disease and polycystic liver disease (PLD), the normally nonproliferative hepato-renal epithelia acquire a proliferative, cystic phenotype that is linked to overexpression of cell division cycle 25 (Cdc25)A phosphatase and cell-cycle deregulation.
In polycystic kidney disease and polycystic liver disease (PLD), the normally nonproliferative hepato-renal epithelia acquire a proliferative, cystic phenotype that is linked to overexpression of cell division cycle 25 (Cdc25)A phosphatase and cell-cycle deregulation.
Interestingly, recent genetic work has linked mutations in the human and murine SIL1 genes to neurodegeneration, and mutations in the human SEC63 gene to autosomal dominant polycystic liver disease.
Nevertheless, TGR5 overexpression or constant stimulation of the receptor can promote cholangiocyte proliferation leading to cyst growth in polycystic liver disease or even progression of cholangiocarcinoma.
While TGR5 agonists may improve various aspects of metabolic, inflammatory, and cholestatic liver diseases, TGR5 inhibitors may attenuate disease progression in polycystic liver disease and cholangiocarcinoma.
However, the activation of TGR5-dependent signalling may also trigger proliferation and apoptosis resistance of cystic cholangiocytes and malignantly transformed cholangiocytes, thus promoting cyst growth in polycystic liver disease or progression of cholangiocarcinoma.
TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease.(Hepatology 2017;66:1197-1218).
Combination of a Histone Deacetylase 6 Inhibitor and a Somatostatin Receptor Agonist Synergistically Reduces Hepatorenal Cystogenesis in an Animal Model of Polycystic Liver Disease.
Tolvaptan therapy significantly improved cyst burden and slowed disease progression among patients with early-stage ADPKD in a large-scale trial, while somatostatin therapies may also be useful in halting disease progression and managing comorbid polycystic liver disease.
TGR5 contributes to hepatic cystogenesis by increasing cAMP and enhancing cholangiocyte proliferation; our data suggest that a TGR5 antagonist alone or concurrently with somatostatin receptor agonists represents a potential therapeutic approach in polycystic liver disease.(Hepatology 2017;66:1197-1218).