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PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer [Western Diet + CCl4]

ABSTRACT: Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.

ORGANISM(S): Mus musculus

PROVIDER: GSE264521 | GEO | 2024/05/15

REPOSITORIES: GEO

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PKD1 mutant clones within cirrhotic livers inhibit steatohepatitis without promoting cancer [Normal Chow diet]

Project description:Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness, however, it is uncertain if these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency accelerated regeneration after partial hepatectomy. We tested Pkd1 in fatty liver disease, showing that Pkd1 loss was protective against steatosis and glucose intolerance. Mechanistically, Pkd1 loss selectively increased mTOR signaling without SREBP activation. In summary, PKD1 mutations in cirrhotic livers exert adaptive functionality without increasing transformation risk.

2024-05-15 | GSE264520 | GEO

Dehydration facilitates cyst formation and growth in Pkd1-/- mice via macrophage

Project description:The Pkd1 gene was inactivated by tamoxifen at postnatal day 30 (P30) to generate a chronic-onset conditional Pkd1 gene knockout mouse model. Without any intervention, micro cysts could be detected adjacent to renal medulla-corticomedullary junction in Pkd1-/- mice until P180 and cystic phenotype is severe at P300. However, under dehydration situation, the cyst growth was more accelerated and progressive. The dehydration protocol resulted in Pkd1-/- mice varying degrees of sweating and weight loss. Mice that were not provided water during the day (water at night (D-WAN)) and mice that had access to water during the day (water all time (D-WAT)) showed significantly more weight loss compared with the control Pkd1-/- mice, although they drank more water at night. Interestingly, although D-WAN Pkd1-/- mice and D-WAT Pkd1-/- mice lost approximately body weights after one-day dehydration, while cyst enlargement and renal dysfunction was much more severe in the D-WAN Pkd1-/- mice after two-month intervention.

2021-04-27 | E-MTAB-10449 | biostudies-arrayexpress

Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

Project description:Autosomal dominant polycystic liver disease (ADPLD) is caused by mutations in PRKCSH, SEC63, and LRP5, while autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, and PKD2. Liver cyst development in these disorders is explained by somatic loss-of-heterozygosity (LOH) of the wild type allele in the developing cyst. We hypothesize that we can use this mechanism to identify novel disease genes that reside in LOH regions. In this study, we aim to map abnormal genomic regions using high-density SNP microarrays to find novel polycystic liver disease genes. We collected 46 cysts from 23 patients with polycystic or sporadic hepatic cysts, and analyzed DNA from those cysts using high-resolution microarray (n=24) or Sanger sequencing (n=22). We here focused on regions of homozygosity on the autosomes (>3.0Mb), and large CNVs (>1.0Mb). We found frequent LOH in PRKCSH (22/29), and PKD1/PKD2 (2/3) cysts of patients with known heterozygous germline variants in the respective genes. In the total cohort, 12/23 patients harbored abnormalities outside of familiar areas. In individual ADPLD cases, we identified germline events: a 2q13 complex rearrangement resulting in BUB1 haploinsufficiency, a 47XXX karyotype, chromosome 9q copy number loss, and LOH on chromosome 3p. The latter region was overlapping with an LOH region identified in two other cysts. Unique germline and somatic abnormalities occur frequently in and outside of known genes underlying cysts. Each liver cyst has a unique genetic makeup. LOH driver gene BUB1 may imply germline causes of genetic instability in PLD. 24 liver cysts from 23 patients

2016-06-30 | E-GEOD-78808 | biostudies-arrayexpress

PKD1

Project description:PKD1 gene and protein study

| PRJEB28230 | ENA

Epigenetic silencing of PKD1 in autosomal dominant polycystic kidney disease

2012-02-16 | GSE35831 | GEO

Pkd1 and Pkd2 mRNA cis-inhibition drives polycystic kidney disease progression [Pkd1]

Project description:We report the findings of deletion of the miR17 binding motif from Pkd1 mRNA

2022-02-11 | GSE196588 | GEO

Chromosomal abnormalities in hepatic cysts point to novel polycystic liver disease genes

2016-06-30 | GSE78808 | GEO

Effects of Pkd1 inactivation defined by important developmental switch in post-natal kidney maturation

Project description:Autosomal dominant polycystic kidney disease (ADPKD) is an important cause of end stage renal disease for which there is no proven therapy 1. Mutations at PKD1 are the principal cause of disease. The disease begins in utero2 and is slowly progressive but it is not known whether cystogenesis is an ongoing process during adult life. We now show that inactivation of Pkd1 in mice prior to post-natal day 13 results in severely cystic kidneys within three weeks, whereas inactivation at day 14 and later results in cysts only after five months. We found that cellular proliferation was not appreciably higher in cystic specimens than in age-matched controls but that the abrupt change in response to Pkd1 inactivation corresponded with a previously unrecognized brake point during renal growth and significant changes in gene expression. These findings suggest that the effects of Pkd1 inactivation are defined by a developmental switch that signals the end of the terminal renal maturation process. These studies show that Pkd1 regulates tubular morphology in both developing and adult kidney but the pathologic consequences of inactivation are defined by the organ’s developmental status, with important clinical implications for our understanding of disease and our approach to therapy. Keywords: Developmental status comparison

2007-12-01 | GSE9167 | GEO

Epigenetic silencing of PKD1 in autosomal dominant polycystic kidney disease

Project description:ADPKD (Autosomal dominant polycystic kidney disease) is the most common inherited disorders and is characterized by growth of numerous cysts filled with fluid in the kidneys. Ultimately, it leads to kidney failure. The mutations of PKD1 and PKD2 account for approximately 85 and 15 percent of ADPKD, respectively. However, the mechanisms related to genetic mutation of PKD1 and PKD2 are still unclear. To investigate altered gene expression levels, Affymetrix microarray was performed using the kidney tissue from normal and ADPKD patients. Total RNAs were isolated from kidney of human normal (49 years old/ male) and ADPKD patients (62 years old/ male, 67 years old/ male) using NucleoSpin® RNA Kit (MACHEREY-NAGEL) according to the manufacturer’s instructions. We used tha Affymetrix GeneChip Human Gene 1.0 ST Array. Per RNA sample, 300 ng was used as the input into the Affymetrix procedure as recommended by the manufacturer's protocol.

2012-02-16 | E-GEOD-35831 | biostudies-arrayexpress

Next Generation Sequencing of Pkd1 mutant kidneys

Project description:This study sough to understand the differential gene expression profile of Pkd1 mutant mice kidneys in the setting of miR 17~92 deletion

2017-06-12 | GSE89764 | GEO

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