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

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.

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.

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.

Our results highlighted the HSF1-UCHL1 transcriptional axis that protects against MASLD through regulation of PPARα protein stability in mice.