Protein tyrosine phosphatase 1b deficiency protects against hepatic fibrosis by modulating nadph oxidases

Abstract

Inflammation is typically associated with the development of fibrosis, cirrhosis and hepatocellular carcinoma. The key role of protein tyrosine phosphatase 1B ( PTP1B) in inflammatory responses has focused this study in understanding its implication in liver fibrosis. Here we show that hepatic PTP1B mRNA expression increased after bile duct ligation (BDL), while BDL-induced liver fibrosis was markedly reduced in mice lacking Ptpn1 (PTP1B −/− ) as assessed by decreased collagen deposition and α-smooth muscle actin (α-SMA) expression. PTP1B −/− mice also showed a significant increase in mRNA levels of key markers of monocytes recruitment ( Cd68, Adgre1 and Ccl2 ) compared to their wild-type (PTP1B +/+ ) littermates at early stages of injury after BDL. Interestingly, the lack of PTP1B strongly increased the NADPH oxidase (NOX) subunits Nox1/Nox4 ratio and downregulated Cybb expression after BDL, revealing a pro-survival pattern of NADPH oxidase induction in response to liver injury. Chimeric mice generated by transplantation of PTP1B −/− bone marrow (BM) into irradiated PTP1B +/+ mice revealed similar hepatic expression profile of NOX subunits than PTP1B −/− mice while these animals did not show differences in infiltration of myeloid cells at 7 days post-BDL, suggesting that PTP1B deletion in other liver cells is necessary for boosting the early inflammatory response to the BDL. PTP1B −/− BM transplantation into PTP1B +/+ mice also led to a blockade of TGF-β and α-SMA induction after BDL. In vitro experiments demonstrated that deficiency of PTP1B in hepatocytes protects against bile acid-induced apoptosis and abrogates hepatic stellate cells (HSC) activation, an effect ameliorated by NOX1 inhibition. In conclusion, our results have revealed that the lack of PTP1B switches NOX expression pattern in response to liver injury after BDL and reduces HSC activation and liver fibrosis.

Protein tyrosine phosphatase 1B as a therapeutic target for Graves’ orbitopathy in an in vitro model

“…PTP1B blocking using siRNA inhibited the proliferation and activation of hepatic stellate cells induced by TGF-β1 [ 41 ]. PTP1B-depleted hepatocytes showed resistance to TGF-β through the activation of NADPH oxidase 1 [ 42 ]; moreover, hepatic fibrosis in response to cholestatic liver injury was ameliorated by the same mechanism [ 43 ]. In our study on GO orbital fibroblasts, PTPN1 silencing down-regulated all fibrosis-related proteins induced by TGF-β, which was not evident in non-GO fibroblasts.…”

The peripheral CB1 receptor antagonist JD5037 attenuates liver fibrosis via a CB1 receptor/β‐arrestin1/Akt pathway

“…with the same volume of olive oil only. For bile duct ligation (BDL)‐induced hepatic fibrosis (Garcia‐Ruiz et al, ), the peritoneal cavity was opened by laparotomy through a 2‐cm midline incision during isoflurane anaesthesia. The bile duct was carefully isolated, and a 5‐0 suture was placed around the bile duct and tied in two surgical knots, and then another 5‐0 suture was also tied in the similar manner near the hepatic hilum.…”

Evaluation of biomarkers in the studies of keloid tissue after laser therapy

“…В свою очередь, присутствие макрофагов можно оценить по экспрессии гена Adgre1. Белок, кодируемый этим геном, появляется на поверхности клеток в процессе дифференцировки моноцитов в макрофаги, т. е. уже после их попадания в очаг воспаления [33,34]. Кроме того, представляется возможным установить при-…”