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Growth arrest and DNA damage-inducible 45β (GADD45β) belongs to the GADD45 family which is small acidic proteins in response to cellular stress. GADD45β has already been reported to have excellent capabilities against cancer, innate immunity and neurological diseases. However, there is little information regard GADD45β and non-alcoholic fatty liver disease (NAFLD). In the current work, we found that the expression of GADD45β was markedly decreased in the livers of NAFLD patients via analyzing Gene Expression Omnibus (GEO) dataset and in mouse model through detecting its mRNA in high-fat-high-fructose diet (HFHFr)-fed mice. Moreover, the results from in vivo experiment demonstrated that overexpression of GADD45β by AAV8-mediated gene transfer in HFHFr-fed mouse model could reduce the level of serum and hepatic triglyceride (TG), and alleviate insulin resistance. Subsequently, by combining immunoprecipitation (IP) and mass spectrometry, we identified that HSP72 directly interacted with GADD45β to prevent GADD45β from being degraded by the proteasome pathway. Finally, the benefits of GADD45β in regulating key factors of TG synthesis and insulin signaling pathway were abolished after HSP72 knockdown. In conclusion, GADD45β stabilized by the interaction with HSP72 could alleviate the NAFLD-related pathologies, suggested it might be a potential target for the treatment of NAFLD. [Display omitted] [ABSTRACT FROM AUTHOR]

PCSK9 has emerged as a promising new therapeutic target for hyperlipidemia. The efficacy of PCSK9 siRNA in clinic trials clues the feasibility of exploring more PCSK9 inhibitors based on genetic inhibition in the treatment of hyperlipidemia. MicroRNAs (miRNAs) as a class of endogenous non-coding small RNAs can regulate genes at transcriptional and/or translational level. Here, we screened miRNAs from the prediction of TargetScan database with possible inhibitory activities in PCSK9 protein level via AlphaLISA and Western blotting, in which miR-552-3p was selected out for its strongest inhibitory effect. MiR-552-3p could bind to the 3' untranslated region (3'-UTR) of PCSK9 to inhibit translation and interact with the promoter of PCSK9 to suppress transcription. Further in vitro and in vivo experiments proved the effects of miR-552-3p on PCSK9 and downstream effectors: it could increase LDLR protein level, promote LDL-C uptake in HepG2 cells and lower serum LDL-C in high fat diet (HFD)-fed mice. In conclusion, our findings firstly identified miR-552-3p as a new PCSK9 inhibitor with the dual-inhibition mechanism, which suggested the possible application of miR-552-3p in the treatment of hyperlipidemia. [Display omitted] [ABSTRACT FROM AUTHOR]