Polycystic liver disease: The interplay of genes causative for hepatic and renal cystogenesis

Masyuk, Tatyana V.; Masyuk, Anatoliy I.; LaRusso, Nicholas F.

doi:10.1002/hep.29708

Cited by 14 publications

(9 citation statements)

References 9 publications

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“…The mechanisms of HCG consist of primary (mutations in PLD-causative genes), secondary (initiation of cyst formation), and tertiary (progression of HCG) molecular and cellular events in cholangiocytes. [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.…”

Section: Discussionmentioning

confidence: 99%

“…PLD is the most common hepatic manifestation of autosomal-dominant (ADPKD) and autosomalrecessive (ARPKD) polycystic kidney diseases and, rarely, occurs as autosomal-dominant polycystic liver disease (ADPLD). [1][2][3][4][5] ADPKD affects between 1 in 400 and 1 in 1000 persons in the general population, and ~94% of patients with ADPKD develop PLD. [4] There are no regulatory approved drugs for PLD, largely because the molecular and cellular mechanisms of hepatic cystogenesis (HCG) are complex and obscure.…”

Section: Introductionmentioning

confidence: 99%

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

Masyuk

Trussoni

et al. 2022

Hepatology

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Backgrounds and Aims: Polycystic liver disease (PLD) is characterized by defective cholangiocyte cilia that regulate progressive growth of hepatic cysts. Because formation of primary cilia is influenced by autophagy through degradation of proteins involved in ciliogenesis, we hypothesized that ciliary defects in PLD cholangiocytes (PLDCs) originate from autophagy-mediated depletion of ciliogenic proteins ADP-ribosylation factor-like protein 3 (ARL3) and ADP-ribosylation factor-like protein 13B (ARL13B) and ARL-dependent mislocation of a ciliary-localized bile acid receptor, Takeda G-protein-coupled receptor 5 (TGR5), the activation of which enhances hepatic cystogenesis (HCG). The aims here were to determine whether: (1) ciliogenesis is impaired in PLDC, is associated with increased autophagy, and involves autophagymediated depletion of ARL3 and ARL13B; (2) depletion of ARL3 and ARL13B in PLDC cilia impacts ciliary localization of TGR5; and (3) pharmacological inhibition of autophagy re-establishes cholangiocyte cilia and ciliary localization of ARL3, ARL3B, and TGR5 and reduces HCG. Approach and Results: By using liver tissue from healthy persons and patients with PLD, in vitro and in vivo models of PLD, and in vitro models of ciliogenesis, we demonstrated that, in PLDCs: ciliogenesis is impaired; autophagy is enhanced; ARL3 and ARL13B are ubiquitinated by HDAC6, depleted in cilia, and present in autophagosomes; depletion of ARL3 and ARL13B impacts ciliary localization of TGR5; and pharmacological inhibition of autophagy with mefloquine and verteporfin re-establishes cholangiocyte cilia and ciliary localization of ARL3, ARL13B, and TGR5 and reduces HCG.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Masyuk

Trussoni

et al. 2022

Hepatology

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“…In some cases, this could explain why cysts are formed in the liver but not in the kidneys. 12,18,26,53,54 Within the primary cilium, the bidirectional transport of substances along the axoneme is guaranteed by intraflagellar transport (IFT). There are two main modalities of IFT: the intraflagellar transport complex B (IFT-B), which interacts with kinesin to mediate anterograde intraflagellar transport, and the intraflagellar transport complex A (IFT-A), which interacts with dynein to mediate retrograde intraflagellar transport.…”

Section: Ciliary Dysfunctionmentioning

confidence: 99%

“…In some cases, this could explain why cysts are formed in the liver but not in the kidneys. 12 , 18 , 26 , 53 , 54 …”

Section: Pathophysiologymentioning

confidence: 99%

Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment

Norcia¹,

Watanabe²,

Filho³

et al. 2022

HMER

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Polycystic liver disease (PLD) is a clinical condition characterized by the presence of more than 10 cysts in the liver. It is a rare disease Of genetic etiology that presents as an isolated disease or assoc\iated with polycystic kidney disease. Ductal plate malformation, ciliary dysfunction, and changes in cell signaling are the main factors involved in its pathogenesis. Most patients with PLD are asymptomatic, but in 2-5% of cases the disease has disabling symptoms and a significant reduction in quality of life. The diagnosis is based on family history of hepatic and/or renal polycystic disease, clinical manifestations, patient age, and polycystic liver phenotype shown on imaging examinations. PLD treatment has evolved considerably in the last decades. Somatostatin analogues hold promise in controlling disease progression, but liver transplantation remains a unique curative treatment modality.

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“…Among these four types, PCLD1 and PCLD2 are the most common types of PCLD. Mutations in PRKCSH and SEC63 could explain 20%-41% of the cases (Van Keimpema et al, 2011;Gevers and Drenth, 2013;Masyuk et al, 2018). ADPKD and PCLD are both autosomal dominant diseases, which means most of the patients may carry a de novo mutation or have a positive family history.…”

Section: Introduction Pld and Pcldmentioning

confidence: 99%

Molecular Mechanisms of Isolated Polycystic Liver Diseases

Yu¹,

Shen²,

et al. 2022

Front. Genet.

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Polycystic liver disease (PLD) is a rare autosomal dominant disorder including two genetically and clinically distinct forms: autosomal dominant polycystic kidney disease (ADPKD) and isolated polycystic liver disease (PCLD). The main manifestation of ADPKD is kidney cysts, while PCLD has predominantly liver presentations with mild or absent kidney cysts. Over the past decade, PRKCSH, SEC63, ALG8, and LRP5 have been candidate genes of PCLD. Recently, more candidate genes such as GANAB, SEC61B, and ALR9 were also reported in PCLD patients. This review focused on all candidate genes of PCLD, including the newly established novel candidate genes. In addition, we also discussed some other genes which might also contribute to the disease.

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Polycystic liver disease: The interplay of genes causative for hepatic and renal cystogenesis

Cited by 14 publications

References 9 publications

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

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

Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment

Molecular Mechanisms of Isolated Polycystic Liver Diseases

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