Role of PTP1B in the progression of non-alcoholic fatty liver disease

Abstract

[Background and aims]: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B) negatively modulates insulin receptor-mediated signalling and is a therapeutic target for type 2 diabetes and obesity. We have evaluated the impact of PTP1B deftciency in non-alcoholic steatohepatitis (NASH), a severe NAFLD stage. [Materials and Methods]: Histological and molecular characterization of livers from wild-type and PTP1B-deficient mice fed chow (CHD) or methionine/choline-deficient diet (MCD) for 4-8 weeks. A NASH recovery model was established by switching MCD (after 8 weeks) to CHD for 2-7 days. Non-parenchymal liver cells (NPCs) were analyzed by flow cytometry. Oval cells (OCs) were isolated from mouse livers. PTP1B and OCs markers were analyzed in livers from mice, and NASH patients compared to normal livers. [Results]: Wild-type mice fed MCD for 8 weeks exhibited severe NASH with inftltration of NPCs and increased Fgf21, ll6 and ll1b mRNAs in the liver. These parameters returned to normal levels after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH reflected by liver histology and higher increases in NPCs infiltration, and Fgf21 and ll6 mRNAs. Conversely, after switching to CHD, PTP1B deftciency rapidly improved liver histology and fat deposition decreased earlier than in wild-type mice in parallel with higher Cd36 and Cpt1a mRNAs, and serum triglycerides, suggesting increased fatty acid efflux from the liver. Recruitment of NK+ cells and M2 macrophage markers Nere also up-regulated in PTP1B-deficient compared to wild-type livers. lnterestingly, expression of OCs markers (Epcam and Ck19) increased by MCD in both genotypes, being this effect enhanced in PTP1B-deficient livers. OCs lacking PTP1B displayed enhanced proliferative capacity. In NASH patients, hepatic PTP1B mRNA levels correlated with OCs markers. [Conclusion]: PTP1B elicits an opposite role in NASH progression and regression, and might modulate oval cells proliferation during NAFLD progression.