HSF1-UCHL1 transcriptional axis protects against MASLD via regulation of PPARα protein stability.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most prevalent chronic liver diseases in modern society. Heat shock factor 1 (HSF1) is a transcription factor that orchestrates cellular responses and closely associate with metabolic diseases. However, the specific hepatic function and mechanism of HSF1 in MASLD is not clearly clarified. METHODS: HSF1 expression levels were examined in genetic, diet-induced, and aging-associated murine MASLD models. Hepatocyte-specific HSF1 knockout (LKO) and active HSF1 overexpression mice were challenged with MASLD and metabolic performances were evaluated. Transcriptome sequencing, screening, chromatin-immunoprecipitation, luciferase assay and co-immunoprecipitation were performed to elucidate the transcriptional and post-translational mechanisms. Rescue experiments with celastrol on Pparα-LKO mice, and Uchl1 or fenofibrate on Hsf1-LKO mice were assessed to reveal the regulatory axis. RESULTS: We found that HSF1 levels were reduced in MASLD mice models under the transcriptional regulation of ATF3. Hsf1-LKO mice showed exacerbated diet- or aging-induced MASLD, whereas hepatic overexpression of active HSF1 alleviated MASLD in both diet-induced and genetic MASLD mice models. Interestingly, RNA-seq revealed that Hsf1 regulated Pparα signaling and Pparα is required for Hsf1 agonist celastrol mediated improvement of β-oxidation. Mechanistically, Hsf1 activated the transcription of Uchl1, a deubiquitinating enzyme, to reduce Pparα ubiquitination for enhanced protein stability. Both Uchl1 overexpression or fenofibrate treatment rescued deteriorated MASLD of Hsf1-LKO mice via Pparα protein stabilization. CONCLUSIONS: Our results highlighted the HSF1-UCHL1 transcriptional axis that protects against MASLD through regulation of PPARα protein stability in mice.