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- Title
The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression.
- Authors
Breternitz, Wiebke; Sandkühler, Friedrich; Grohmann, Frauke; Hampe, Jochen; Brosch, Mario; Herrmann, Alexander; Schafmayer, Clemens; Meinhardt, Christian; Schreiber, Stefan; Arlt, Alexander; Geismann, Claudia
- Abstract
Obesity and obesity-associated diseases represent one of the key health challenges of our time. In this context, aberrant hepatic lipid accumulation is a central pathological aspect of non-alcoholic fatty liver disease (NAFLD). By comparing methylation signatures of liver biopsies before and after bariatric surgery, we recently demonstrated the strong enrichment of differentially methylated heat shock factor 1 (HSF1) binding sites (>400-fold) in the process of liver remodeling, indicating a crucial role of HSF1 in modulating central aspects of NAFLD pathogenesis. Using cellular models of NAFLD, we were able to show that HSF1 is activated during fat accumulation in hepatocytes, mimicking conditions in patients before bariatric surgery. This induction was abolished by starving the cells, mimicking the situation after bariatric surgery. Regarding this connection, carnitine palmitoyltransferase 1 isoform A (CTP1a), a central regulator of lipid beta-oxidation, was identified as a HSF1 target gene by promoter analysis and HSF1 knockdown experiments. Finally, pharmacological activation of HSF1 through celastrol reduced fat accumulation in the cells in a HSF1-dependent manner. In conclusion, we were able to confirm the relevance of HSF1 activity and described a functional HSF1-CPT1a pathway in NAFLD pathogenesis.
- Subjects
NON-alcoholic fatty liver disease; HEAT shock factors; CARNITINE palmitoyltransferase; BARIATRIC surgery; FAT cells
- Publication
Cells (2073-4409), 2022, Vol 11, Issue 21, p3504
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells11213504