The HSF1-CPT1a Pathway Is Differentially Regulated in NAFLD Progression
Wiebke Breternitz,
Friedrich Sandkühler,
Frauke Grohmann,
Jochen Hampe,
Mario Brosch,
Alexander Herrmann,
Clemens Schafmayer,
Christian Meinhardt,
Stefan Schreiber,
Alexander Arlt,
Claudia Geismann
Affiliations
Wiebke Breternitz
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
Friedrich Sandkühler
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
Frauke Grohmann
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
Jochen Hampe
Medical Department 1, University Hospital Dresden, Dresden University of Technology (TU Dresden), 01307 Dresden, Germany
Mario Brosch
Medical Department 1, University Hospital Dresden, Dresden University of Technology (TU Dresden), 01307 Dresden, Germany
Alexander Herrmann
Medical Department 1, University Hospital Dresden, Dresden University of Technology (TU Dresden), 01307 Dresden, Germany
Clemens Schafmayer
Department of General, Visceral, Vascular and Transplantation Surgery, University of Rostock, 18057 Rostock, Germany
Christian Meinhardt
Department for Gastroenterology and Hepatology, University Hospital Oldenburg, Klinikum Oldenburg AöR, European Medical School (EMS), 26133 Oldenburg, Germany
Stefan Schreiber
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
Alexander Arlt
Department for Gastroenterology and Hepatology, University Hospital Oldenburg, Klinikum Oldenburg AöR, European Medical School (EMS), 26133 Oldenburg, Germany
Claudia Geismann
Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany
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.
