Secondary, Somatic Mutations Might Promote Cyst Formation in Patients With Autosomal Dominant Polycystic Liver Disease

BackgroundA major difference between autosomal recessive polycystic kidney disease (ARPKD) and autosomal dominant polycystic kidney disease (ADPKD) lies in the pattern of inheritance, and the resultant timing and focality of cyst formation. In both diseases, cysts form in the kidney and liver as a consequence of the cellular recessive genotype of the respective disease gene, but this occurs by germline inheritance in ARPKD and somatic second hit mutations to the one normal allele in ADPKD. The fibrocystic liver phenotype in ARPKD is attributed to abnormal ductal plate formation because of the absence of PKHD1 expression during embryogenesis and organ development. The finding of polycystic liver disease in a subset of adult PKHD1 heterozygous carriers raises the question of whether somatic second hit mutations in PKHD1 in adults may also result in bile duct-derived cyst formation.MethodsWe used an adult-inducible Pkhd1 mouse model to examine whether Pkhd1 has a functional role in maintaining bile duct homeostasis after normal liver development.ResultsInactivation of Pkhd1 beginning at 4 weeks of age resulted in a polycystic liver phenotype with minimal fibrosis at 17 weeks. Increased biliary epithelium, which lines these liver cysts, was most pronounced in female mice. We assessed genetic interaction of this phenotype with either reduced or increased copies of Pkd1, and found no significant effects on the Pkhd1 phenotype in the liver or kidney from altered Pkd1 expression.ConclusionsSomatic adult inactivation of Pkhd1 results in a polycystic liver phenotype. Pkhd1 is a required gene in adulthood for biliary structural homeostasis independent of Pkd1. This suggests that PKHD1 heterozygous carrier patients can develop liver cysts after somatic mutations in their normal copy of PKHD1.

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Metformin slows liver cyst formation and fibrosis in experimental model of polycystic liver disease.

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00120.2020 ◽

2021 ◽

Author(s):

Yoichi Sato ◽

Jiahe Qiu ◽

Takuo Hirose ◽

Takahiro Miura ◽

Yasunori Sato ◽

...

Keyword(s):

Liver Disease ◽

Cellular Proliferation ◽

Transforming Growth Factor ◽

Cyst Formation ◽

Liver Cyst ◽

Signaling Cascades ◽

Polycystic Liver Disease ◽

Ki 67 ◽

Abdominal Symptoms ◽

Polycystic Liver

Background Polycystic liver disease (PLD) is hereditary liver disease in which the number of cysts increases over time, causing various abdominal symptoms and a poor quality of life. Although effective treatment for PLD has not been established, we recently reported that long-term exercise ameliorated liver cyst formation and fibrosis with activation of AMP-activated protein kinase (AMPK) in polycystic kidney (PCK) rats, a PLD model. Therefore, the aim of this study was to investigate whether metformin, an indirect AMPK activator, was effective in PCK rats. Methods PCK rats were randomly divided into a control (Con) group and a metformin group (Met group). The Met group was treated orally with metformin in drinking water. After 12 weeks, liver function, histology and signaling cascades of PLD were examined in the groups. Results Metformin did not affect body weight or liver weight, but it reduced liver cyst formation, fibrosis and Ki-67-positive cells around the cyst. Metformin increased the phosphorylation of AMPK and decreased the phosphorylation of mammalian target of rapamycin and extracellular signal-regulated kinase and the expression of cystic fibrosis transmembrane conductance regulator, aquaporin I, transforming growth factor-β and type 1 collagen in the liver. Conclusions Metformin slows the development of cyst formation and fibrosis with activation of AMPK and inhibition of signaling cascades responsible for cellular proliferation and fibrosis in the liver of PCK rats.

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