TFEB regulates murine liver cell fate during development and regeneration

Pastore, Nunzia; Huynh, Tuong; Herz, Niculin J.; Calcagnì, Alessia; Klisch, Tiemo J.; Brunetti, Lorenzo; Kim, Kangho Ho; Giorgi, M. De; Hurley, Ayrea; Carissimo, Annamaria; Mutarelli, Margherita; Aleksieva, Niya; D’Orsi, Luca; Lagor, William R.; Moore, David D.; Settembre, Carmine; Finegold, Milton J.; Forbes, Stuart J.; Ballabio, Andrea

doi:10.1038/s41467-020-16300-x

Cited by 36 publications

(27 citation statements)

References 76 publications

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“…These mice have increased fibrosis and develop liver cysts which mimic a polycystic liver and develop CCA-like phenotype. 121 These findings suggest that TFEB may play a crucial role in determining liver cell fate during development and regeneration, and may also contribute to CCA, which seems independent of its functions in lysosomal biogenesis.…”

Section: Volume_26 Number_4 October 2020mentioning

confidence: 86%

“…119,120 In a recent study, Pastore et al reported that TFEB can drive liver progenitor cell (LPC) differentiation and promote the formation of ductular structures. 121 Among the different cell types in the liver, TFEB is highly expressed in biliary cells. TFEB drives the differentiation of LPC into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation during the mouse liver development or upon regeneration in response to injury.…”

Section: Volume_26 Number_4 October 2020mentioning

confidence: 99%

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Autophagy and liver cancer

et al. 2020

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Autophagy is a highly conserved catabolic process that degrades cytosolic proteins and organelles via formation of autophagosomes that fuse with lysosomes to form autolysosomes, whereby autophagic cargos are degraded. Numerous studies have demonstrated that autophagy plays a critical role in the regulation of liver physiology and homeostasis, and impaired autophagy leads to the pathogenesis of various liver diseases such as viral hepatitis, alcohol associated liver diseases (AALD), non-alcoholic fatty liver diseases (NAFLD), and liver cancer. Recent evidence indicates that autophagy may play a dual role in liver cancer: inhibiting early tumor initiation while promoting progression and malignancy of already formed liver tumors. In this review, we summarized the progress of current understanding of how hepatic viral infection, alcohol consumption and diet-induced fatty liver diseases impair hepatic autophagy. We also discussed how impaired autophagy promotes liver tumorigenesis, and paradoxically how autophagy is required to promote the malignancy and progression of liver cancer. Understanding the molecular mechanisms underlying how autophagy differentially affects liver cancer development and progression may help to design better therapeutic strategies for prevention and treatment of liver cancer.

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Section: Volume_26 Number_4 October 2020mentioning

confidence: 86%

Section: Volume_26 Number_4 October 2020mentioning

confidence: 99%

Autophagy and liver cancer

et al. 2020

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“…However, since AAV-Cre is non-integrating, the viral transgene is lost with cell division, essentially allowing the liver to be repopulated with Hmgcr+ hepatocytes over time. It is also possible that some of the regenerating cells are not hepatocyte-derived, an event that can happen in very severe cases of liver injury (31). Regardless of the cellular source of the Hmgcr+ hepatocytes, there is sufficient metabolic capacity to protect these animals from liver failure.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Recombinant Adeno-associated viruses (AAV) are small non-integrating, non-enveloped, singlestranded DNA viruses that can deliver transgenes to the liver with high efficiency (29). AAV delivery of Cre recombinase is rapidly gaining popularity for inducible deletion of genes in the adult liver (30,31). AAV can also be used to deliver the Clustered regularly interspaced short palindromic repeats by guest, on November 6, 2020 www.jlr.org Downloaded from 6 (CRISPR)/Cas9 genome editing system, which can directly disrupt genes, thus bypassing the need to generate new floxed mouse models (32,33).…”

Section: Introductionmentioning

confidence: 99%

Depletion of essential isoprenoids and ER stress induction following acute liver-specific deletion of HMG-CoA reductase

Giorgi

Jarrett

Burton

et al. 2020

Journal of Lipid Research

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HMG-CoA Reductase (Hmgcr) is the rate-limiting enzyme in the mevalonate pathway and is inhibited by statins. In addition to cholesterol, Hmgcr activity is also required for synthesizing non-sterol isoprenoids, such as dolichol, ubiquinone, farnesylated and geranylgeranylated proteins. Here, we investigated the effects of Hmgcr inhibition on non-sterol isoprenoids in the liver. We have generated new genetic models to acutely delete genes in the mevalonate pathway in the liver using AAV-mediated delivery of Cre-recombinase (AAV-Cre) or CRISPR/Cas9 (AAV-CRISPR). The genetic deletion of Hmgcr by AAV-Cre resulted in extensive hepatocyte apoptosis and compensatory liver regeneration. At the biochemical level, we observed decreased levels of sterols and depletion of the non-sterol isoprenoids, dolichol and ubiquinone. At the cellular level, Hmgcr null hepatocytes showed endoplasmic reticulum (ER) stress and impaired N-glycosylation. We further hypothesized that the depletion of dolichol, essential for N-glycosylation, could be responsible for ER stress. Using AAV-CRISPR, we somatically disrupted Dehydrodolichyl diphosphate synthase subunit (Dhdds), encoding a branch point enzyme required for dolichol biosynthesis. Dhdds null livers showed ER stress and impaired N-glycosylation, along with apoptosis and regeneration. Finally, the combined deletion of Hmgcr and Dhdds synergistically exacerbated hepatocyte ER stress. Our data show a critical role for mevalonate-derived dolichol in the liver, and suggest that dolichol depletion is at least partially responsible for ER stress and apoptosis upon potent Hmgcr inhibition.

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“…Cell differentiation is an indispensable process in development, growth and regeneration of multicellular organisms. In the liver, TFEB induces the differentiation of murine liver stem/progenitor cells into the progenitor/cholangiocyte lineage while inhibiting hepatocyte differentiation through upregulating Sox9, a marker of precursor and biliary cells [8] . In acute promyelocytic leukemia, autophagy is critical for the differentiation of leukemic blasts.…”

Section: Introductionmentioning

confidence: 99%