title: Hedgehog signaling is a potent regulator of liver lipid metabolism and reveals a GLI-code associated with steatosis.
abstract: Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and is increasing in prevalence. The pathomechanisms, however, are poorly understood. This study assessed the unexpected role of the Hedgehog pathway in adult liver lipid metabolism. Using transgenic mice with conditional hepatocyte-specific deletion of Smoothened in adult mice, we showed that hepatocellular inhibition of Hedgehog signaling leads to steatosis by altering the abundance of the transcription factors GLI1 and GLI3. This steatotic 'Gli-code' caused the modulation of a complex network of lipogenic transcription factors and enzymes, including SREBP1 and PNPLA3, as demonstrated by microarray analysis and siRNA experiments and could be confirmed in other steatotic mouse models as well as in steatotic human livers. Conversely, activation of the Hedgehog pathway reversed the "Gli-code" and mitigated hepatic steatosis. Collectively, our results reveal that dysfunctions in the Hedgehog pathway play an important role in hepatic steatosis and beyond.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Madlen
authors.identifier: 0000-0002-5929-3704
authors.initials: M
authors.lastname: Matz-Soja
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Rennert
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schönefeld
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Aleithe
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Boettger
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schmidt-Heck
authors.affiliation: University Children Hospital, Regensburg University Hospital, Regensburg, Germany.
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Weiss
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Amalya
authors.initials: A
authors.lastname: Hovhannisyan
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zellmer
authors.affiliation: Integrated Research and Treatment Centre Adiposity Diseases, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Klöting
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Angela
authors.initials: A
authors.lastname: Schulz
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, Leipzig University, Leipzig, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kratzsch
authors.affiliation: Leibniz Institute for Natural Product Research and Infection Biology - Hans Knöll Institute, Jena, Germany.
authors.forename: Reinhardt
authors.initials: R
authors.lastname: Guthke
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, Leipzig University, Leipzig, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Gebhardt
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000503:physiopathology*; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000172:deficiency / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1 / Q000378:metabolism*; D000074290:Zinc Finger Protein Gli3
chemical_list: C400551:GLI1 protein, human; C065683:GLI3 protein, human; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D000071676:Zinc Finger Protein GLI1; D000074290:Zinc Finger Protein Gli3
keywords: Hedgehog signalling; NAFLD; biochemistry; cell biology; hepatocytes; human; liver; mouse; smoothened; steatotic Gli-code