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

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Autophagy promotes hepatic cystogenesis in polycystic liver disease by depletion of cholangiocyte ciliogenic proteins
Hepatology ( IF 12.9 ) Pub Date : 2021-12-23 , DOI: 10.1002/hep.32298
Anatoliy I. Masyuk ₁ , Tatyana V. Masyuk ₁ , Christy E. Trussoni ₁ , Nicholas E. Pirius ₁ , Nicholas F. LaRusso ₁

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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 autophagy-mediated 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.

中文翻译：

自噬通过消耗胆管细胞纤毛蛋白促进多囊性肝病的肝囊肿形成

多囊性肝病 (PLD) 的特点是有缺陷的胆管细胞纤毛可调节肝囊肿的进行性生长。因为初级纤毛的形成受自噬的影响，通过降解参与纤毛发生的蛋白质，我们假设 PLD 胆管细胞 (PLDC) 中的纤毛缺陷源于自噬介导的纤毛蛋白 ADP-核糖基化因子样蛋白 3 (ARL3) 和 ADP 的消耗-核糖基化因子样蛋白 13B (ARL13B) 和纤毛定位胆汁酸受体武田 G 蛋白偶联受体 5 (TGR5) 的 ARL 依赖性错位，其激活可增强肝囊发生 (HCG)。这里的目的是确定：（1）纤毛发生是否在 PLDC 中受损，与自噬增加有关，并涉及自噬介导的 ARL3 和 ARL13B 消耗；(2) PLDC 纤毛中 ARL3 和 ARL13B 的缺失影响 TGR5 的纤毛定位；(3) 自噬的药理学抑制重建胆管细胞纤毛和 ARL3、ARL3B 和 TGR5 的纤毛定位并降低 HCG。

更新日期：2021-12-23

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