Hepatology. 2021 Dec 23; doi: 10.1002/hep.32298. Epub 2021 Dec 23.

Autophagy Promotes Hepatic Cystogenesis in Polycystic Liver Disease via Depletion of Cholangiocyte Ciliogenic Proteins.

Hepatology (Baltimore, Md.)

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

PMID: 34942041 DOI: 10.1002/hep.32298

Abstract

BACKGROUNDS & 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 (PLDC) originate from autophagy-mediated depletion of ciliogenic proteins, ARL3 and ARL13B, and ARL-dependent mislocation of a ciliary-localized bile acid receptor, TGR5, activation of which enhances hepatic cystogenesis. The aims here were to determine: i) if ciliogenesis is impaired in PLDC, is associated with increased autophagy, and involves autophagy-mediated depletion of ARL3 and ARL13B; ii) if depletion of ARL3 and ARL13B in PLDC cilia impacts ciliary localization of TGR5; and iii) if pharmacological inhibition of autophagy reestablishes cholangiocyte cilia, ciliary localization of ARL3, ARL3B and TGR5, and reduces hepatic cystogenesis.

APPROACH & RESULTS: By using liver tissue from healthy individuals and patients with PLD, in vitro and in vivo models of PLD, and in vitro models of ciliogenesis, we demonstrated that in PLDC: 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 pharmacologic inhibition of autophagy with mefloquine and verteporfin reestablishes cholangiocyte cilia, ciliary localization of ARL3, ARL13B and TGR5, and reduces hepatic cystogenesis.

CONCLUSION: The intersection between autophagy, defective cholangiocyte cilia, and enhanced hepatic cystogenesis contributes to PLD progression and can be considered a novel target for therapeutic interventions.

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Keywords: Polycystic liver disease; cholangiocytes; ciliogenesis; primary cilia

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• Journal Article