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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Panzitt, K; Jungwirth, E; Vosko, LE; Madreiter-Sokolowski, CT; Madl, T; Tawfik, I; Habisch, H; Krstic, J; Prokesch, A; Karitnig, R; Sucher, R; Erdogan, CY; Vallim, TA; Trauner, M; Fickert, P; Al-Dury, S; Molinaro, A; Moore, DD; Thallinger, GG; Marschall, HU; Wagner, M.
FXR adapts hepatic mitochondrial function to increased substrate oxidation in patients with obesity
SCI TRANSL MED. 2025; 17(811): eadn4558 Doi: 10.1126/scitranslmed.adn4558
Web of Science PubMed FullText FullText_MUG

 

Autor*innen der Med Uni Graz:
Fickert Peter
Habisch Hansjörg
Jungwirth Emilian Rudolf
Karitnig Robert
Krstic Jelena
Madl Tobias
Madreiter-Sokolowski Corina
Panzitt Katrin
Prokesch Andreas
Sucher Robert
Tawfik Ines
Trauner Michael
Vosko Lena Elisabeth
Wagner Martin
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Abstract:
Metabolic pressure shifts signaling pathways of nuclear receptors, including the bile acid receptor FXR, which are sensitive to nutritional inputs. We performed an FXR ChIP-seq-centered multiomic analysis of liver biopsy samples from individuals with or without obesity, who were treated with either placebo or the FXR agonist obeticholic acid, to define metabolic adaptions of FXR signaling pathways. FXR occupied substantially more DNA binding sites in individuals with obesity, and FXR activation by OCA robustly changed the transcriptional output. Integration of ChIP-seq and RNA-seq data showed that mitochondrial function and substrate oxidation were the top metabolic pathways selectively modulated by FXR activation in individuals with obesity. FXR activation restored compromised substrate oxidation by enhancing beta-oxidation and oxidative phosphorylation along with antagonizing ROS production. In line with this, the amount of reduced glutathione in patients with obesity normalized after OCA treatment. In summary, FXR signaling profoundly differs in patients with obesity, consisting of changes in DNA binding profiles and transcriptional programs, which enhance energy substrate utilization in this patient cohort.

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