PinX1 Depletion Improves Liver Injury in a Mouse Model of Nonalcoholic Fatty Liver Disease via Increasing Telomerase Activity and Inhibiting Apoptosis.

PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) can inhibit tumor growth by inhibiting telomerase activity. However, only few studies investigated the expression and function of PinX1 in nonalcoholic fatty liver disease (NAFLD). Thus, here we aimed to explore the roles of PinX1 in high-fat diet (HFD)-induced NAFLD in mice and in isolated hepatocytes. The mRNA expression of PinX1 and mTERT as well as telomere length were analyzed by RT-PCR. Pathological changes were detected by HE staining and oil red O staining. Triglyceride, cholesterol, alanine aminotransferase, aspartic aminotransferase, and telomerase activity were detected by ELISA. Hepatocyte apoptosis was determined by TUNEL and flow cytometry, and protein expression was analyzed by western blotting. We found that the expression of PinX1 was upregulated in the HFD group compared with the WT group. PinX1 knockout improved HFD-induced liver injury in mice and exhibited less lipid accumulation in hepatocytes. Moreover, telomere length, telomerase activity, and mTERT expression were significantly reduced in liver tissues of HFD-induced mice and palmitic acid-induced hepatocytes, while PinX1 knockout attenuated the effect. Furthermore, HFD-induced PinX1-/- mice exhibited less hepatocyte apoptosis than HFD-induced WT mice. Besides, PinX1 knockout inhibited the increase of cleaved caspase-3 and cleaved PARP expression in vivo and in vitro. Moreover, inhibition of mTERT reversed the effect of PinX1 knockout in hepatocytes. Taken together, our findings indicate that PinX1 promotes hepatocyte apoptosis and lipid accumulation by decreasing telomere length and telomerase activity in the development of NAFLD. PinX1 might be a target for the treatment of NAFLD.
(© 2021 The Author(s). Published by S. Karger AG, Basel.)