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

Masyuk, Anatoliy I.; Masyuk, Tatyana V.; Trussoni, Christy E.; Pirius, Nicholas E.; LaRusso, Nicholas F.

doi:10.1002/hep.32298

Cited by 10 publications

(8 citation statements)

References 50 publications

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“…Supporting the proposal that defective cilia are linked to BA pathogenesis, we demonstrated that LKO mice have decreased number of cilia, although the direct links between absent Pkd1l1 and reduced ciliary development remain to be understood. Among the possibilities are that since Pkd1l1 is shown in select models to be present in primary cilia and plays a role in ciliary calcium signaling,44 its absence could plausibly lead to aberrant intracellular signaling that induces the development of the reactive ductular phenotype 45. Further, repression of other members of the polycystin family ( Pkd1 and Pkd2 ) causes an elongated/twisted cilia46 rather than an overall decrease in cilia, as seen here.…”

Section: Discussionmentioning

confidence: 74%

Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy

et al. 2023

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Background and Aims: A recent multicenter genetic exploration of the biliary atresia splenic malformation syndrome identified mutations in the ciliary gene PKD1L1 as candidate etiologic contributors. We hypothesized that deletion of Pkd1l1 in developing hepatoblasts would lead to cholangiopathy in mice.Approach and Results: CRISPR-based genome editing inserted loxP sites flanking exon 8 of the murine Pkd1l1 gene. Pkd1l1 Fl/Fl cross-bred with alphafetoprotein-Cre expressing mice to generate a liver-specific intrahepatic Pkd1l1-deficient model (LKO). From embryonic day 18 through week 30, control (Fl/Fl) and LKO mice were evaluated with standard serum chemistries and liver histology. At select ages, tissues were analyzed using RNA sequencing, immunofluorescence, and electron microscopy with a focus on biliary structures, peribiliary inflammation, and fibrosis. Bile duct ligation for 5 days of Fl/Fl and LKO mice was followed by standard serum and liver analytics. Histological analyses from perinatal ages revealed delayed biliary maturation and reduced primary cilia, with progressive cholangiocyte proliferation, peribiliary fibroinflammation, and arterial hypertrophy evident in 7-to 16-week-old LKO versus Fl/Fl livers. Following bile duct ligation, cholangiocyte proliferation, peribiliary fibroinflammation, and necrosis were increased in LKO compared with Fl/Fl livers.Conclusions: Bile duct ligation of the Pkd1l1-deficient mouse model mirrors several aspects of the intrahepatic pathophysiology of biliary atresia in humans including bile duct dysmorphogenesis, peribiliary fibroinflammation, hepatic arteriopathy, and ciliopathy. This first genetically linked model of biliary atresia, the Pkd1l1 LKO mouse, may allow researchers a means to develop a deeper understanding of the pathophysiology of this serious and perplexing disorder, including the opportunity to identify rational therapeutic targets.

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Section: Discussionmentioning

confidence: 74%

Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy

et al. 2023

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“…In fact, activation of TGR5 on cholangiocyte cilia depresses cAMP formation and proliferation while the same signal in non-ciliated cholangiocytes enhances intracellular cAMP and cell growth. The important role of TGR5 as a possible regulator of biliary mass suggests that this receptor is a possible target in human diseases characterized by uncontrolled cholangiocyte growth, such as cholangiocarcinoma[ 25 ] or polycystic liver disease[ 26 ]. More recently, other BA receptors, such as the S1PR2, have been identified on cholangiocytes[ 27 ].…”

Section: Bas/biliary Epithelia Interactionsmentioning

confidence: 99%

Secondary bile acids and the biliary epithelia: The good and the bad

Lenci¹,

Mihalj²,

Signorello³

et al. 2023

World J Gastroenterol

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The biliary tract has been considered for several decades a passive system just leading the hepatic bile to the intestine. Nowadays several researches demonstrated an important role of biliary epithelia ( i.e. cholangiocytes) in bile formation. The study of biliary processes therefore maintains a continuous interest since the possible important implications regarding chronic cholestatic human diseases, such as primary biliary cholangitis or primary sclerosing cholangitis. Bile acids (BAs), produced by the liver, are the most represented organic molecules in bile. The physiologic importance of BAs was initially attributed to their behavior as natural detergents but several studies now demonstrate they are also important signaling molecules. In this minireview the effect of BAs on the biliary epithelia are reported focusing in particular on secondary (deriving by bacterial manipulation of primary molecules) ones. This class of BAs is demonstrated to have relevant biological effects, ranging from toxic to therapeutic ones. In this family ursodeoxycholic and lithocholic acid present the most interesting features. The molecular mechanisms linking ursodeoxycholic acid to its beneficial effects on the biliary tract are discussed in details as well as data on the processes leading to lithocholic damage. These findings suggest that expansion of research in the field of BAs/cholangiocytes interaction may increase our understanding of cholestatic diseases and should be helpful in designing more effective therapies for biliary disorders.

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“…TGR5 is a receptor related to the cAMP signaling pathway and one of the main sensory/signaling proteins of the primary cilium. [100][101][102][103] In PLD, due to the reduced levels of ARL3 and ARL13B, TGR5 is abnormally expressed in the apical region of the primary cilium and its activation promotes an increase in intracellular levels of cAMP, an event that favors the cell proliferation of cystic cholangiocytes and, consequently, the hepatic cystogenesis. Pharmacological inhibition of autophagy by mefloquine and verteporfin restores levels of ARL3 and ARL13B and restores proper localization of TGR5, thus reducing hepatic cystogenesis.…”

Section: Increased Autophagymentioning

confidence: 99%

“…TGR5 is a receptor related to the cAMP signaling pathway and one of the main sensory/signaling proteins of the primary cilium. 100–103 …”

Section: Pathophysiologymentioning

confidence: 99%

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

Cited by 10 publications

References 50 publications

Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy

Liver-restricted deletion of the biliary atresia candidate gene Pkd1l1 causes bile duct dysmorphogenesis and ciliopathy

Secondary bile acids and the biliary epithelia: The good and the bad

Polycystic Liver Disease: Pathophysiology, Diagnosis and Treatment

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