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Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

AuthorsGonzález-Rodríguez, Águeda; Valdecantos, M. P.; Rada, Patricia; Addante, Annalisa; Barahona, Inés; Rey, Esther; Pardo, Virginia; Ruiz, Laura; Laiglesia, Laura M.; Moreno-Aliaga, María Jesús; García-Monzón, Carmelo; Sánchez, Aránzazu; Valverde, Ángela M.
Oval cells
Issue Date2018
CitationMolecular Metabolism 7: 132-146 (2018)
Abstract[Objectives]: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B), a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH). [Methods]: NASH features were evaluated in livers from wild-type (PTP1BWT) and PTP1B-deficient (PTP1BKO) mice fed methionine/choline-deficient diet (MCD) for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD) for 2–7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. [Results]: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG) levels. Among NPCs, a drop in cytotoxic natural killer T (NKT) subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19) significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. [Conclusions]: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD.
Publisher version (URL)https://doi.org/10.1016/j.molmet.2017.10.008
Identifiersdoi: 10.1016/j.molmet.2017.10.008
e-issn: 2212-8778
Appears in Collections:(IIBM) Artículos
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