@article{9f0b0ea51cf2422381963b8dbe8c4253,
title = "BMP4 and Gremlin 1 regulate hepatic cell senescence during clinical progression of NAFLD/NASH",
abstract = "The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.",
author = "Baboota, {Ritesh K.} and Aidin Rawshani and Laurianne Bonnet and Xiangyu Li and Hong Yang and Adil Mardinoglu and Tamar Tchkonia and Kirkland, {James L.} and Anne Hoffmann and Arne Dietrich and Jeremie Boucher and Matthias Bl{\"u}her and Ulf Smith",
note = "Funding Information: We acknowledge financial support from the Knut and Alice Wallenberg Foundation (2020.0118), the Swedish Research Council (202200688), the Novo Nordisk Foundation (0078138), the Heart and Lung Foundation (20220355) and the Swedish Diabetes Research Foundation (DIA2021-588) to U.S. J.L.K. and T.T. were supported by NIH grants R37AG013925, P01AG062413 and R33AG61456; the Connor Fund; Robert P. and Arlene R. Kogod; Robert J. and Theresa W. Ryan; and the Noaber Foundation. We also acknowledge the Centre for Cellular Imaging, University of Gothenburg, as part of the National Microscopy Infrastructure (NMI) (VR-RFI 2016-00968), for support in imaging analysis. We thank Jan Boren and Scott L. Friedman for providing IHH and LX-2 cells, respectively. We thank Piero Pingitore for help with establishing the 3D spheroid cultures. A graphical abstract provided as Supplementary Figure 3 was created and exported with BioRender.com under a paid subscription. Funding Information: We acknowledge financial support from the Knut and Alice Wallenberg Foundation (2020.0118), the Swedish Research Council (202200688), the Novo Nordisk Foundation (0078138), the Heart and Lung Foundation (20220355) and the Swedish Diabetes Research Foundation (DIA2021-588) to U.S. J.L.K. and T.T. were supported by NIH grants R37AG013925, P01AG062413 and R33AG61456; the Connor Fund; Robert P. and Arlene R. Kogod; Robert J. and Theresa W. Ryan; and the Noaber Foundation. We also acknowledge the Centre for Cellular Imaging, University of Gothenburg, as part of the National Microscopy Infrastructure (NMI) (VR-RFI 2016-00968), for support in imaging analysis. We thank Jan Boren and Scott L. Friedman for providing IHH and LX-2 cells, respectively. We thank Piero Pingitore for help with establishing the 3D spheroid cultures. A graphical abstract provided as Supplementary Figure was created and exported with BioRender.com under a paid subscription. Publisher Copyright: {\textcopyright} 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.",
year = "2022",
month = aug,
doi = "10.1038/s42255-022-00620-x",
language = "English (US)",
volume = "4",
pages = "1007--1021",
journal = "Nature Metabolism",
issn = "2522-5812",
publisher = "Springer Berlin",
number = "8",
}