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Targeted Inhibition of HSD17B13 - a new therapeutic option in steatotic liver disease?

ORCID
0000-0002-5162-1048
Affiliation
Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
Kraus, Nico;
Affiliation
Goethe University Frankfurt, Faculty of Medicine, Institute of Biochemistry I, Frankfurt, Germany
Fuhrmann, Dominik C.;
Affiliation
Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
Ohngemach, Magdalena;
Affiliation
Goethe University Frankfurt, Faculty of Medicine, Institute of Cardiovascular Regeneration, Frankfurt, Germany
Schulz, Marcel H.;
Affiliation
Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
Zeuzem, Stefan;
Affiliation
Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
Welsch, Christoph;
Affiliation
Goethe University Frankfurt, University Hospital, Medical Clinic 1, Frankfurt, Germany
Ortiz, Cristina

17-beta-hydroxysteroid dehydrogenase 13 (HSD17B13) is an enzyme associated with lipid droplets and mainly expressed in hepatocytes. Whole genome sequencing has identified HSD17B13 as a potential molecular target with an important role in lipid metabolism. Targeted inhibition of enzyme function therefore is considered a potential therapeutic strategy in the treatment of steatotic liver disease (SLD).
BI-3231, the first selective HSD17B13 inhibitor, was successfully used by Alcober-Boquet, Kraus et al. for in vitro therapy of palmitic acid induced hepatocellular lipotoxicity. The study aimed to investigate the effects of HSD17B13 inhibition using the hepatocyte human cell line (HepG2) and primary mouse hepatocytes in vitro to characterize the role of HSD17B13 in SLD and validate its therapeutic suitability. Lipotoxicity was induced in HepG2 cells and freshly isolated mouse hepatocytes by exposure with palmitic acid and co-incubation with BI-3231 to evaluate the protective effect of HSD17B13 inhibition. Under lipotoxic stress, triglyceride accumulation was significantly reduced in BI-3231 treated cells compared to untreated human and mouse control hepatocytes. In addition, BI-3231 treatment resulted in a significant improvement in hepatocyte proliferation, cell differentiation and lipid homeostasis. Mechanistically, BI-3231 increased mitochondrial respiratory function without affecting β-oxidation. BI-3231 inhibited the lipotoxic effects of palmitic acid treatment in hepatocytes, highlighting the potential of targeting HSD17B13 as a specific therapeutic approach in SLD. We are now further validating our cell culture findings in standardized western diet based animal models of metabolic dysfunction associated steatotic liver disease (MASLD).

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