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ResearchIn-Press PreviewHepatologyMetabolism Open Access | 10.1172/JCI180310
1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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1Division of Gastroenterology, Duke University, Durham, United States of America
2Department of Molecular Genetics and Microbiology, Duke University, Durham, United States of America
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, United States of America
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Published August 27, 2024 - More info
The burden of senescent hepatocytes correlates with MASLD severity but mechanisms driving senescence, and how it exacerbates MASLD are poorly understood. Hepatocytes become senescent when Smoothened (Smo) is deleted to disrupt Hedgehog signaling. We aimed to determine if the secretomes of Smo-deficient hepatocytes perpetuate senescence to drive MASLD progression. RNA seq analysis confirmed that hepatocyte populations of MASLD livers are depleted of Smo(+) cells and enriched with senescent cells. When fed CDA-HFD, Smo(-) mice had lower antioxidant markers and developed worse DNA damage, senescence, MASH and liver fibrosis than Smo(+) mice. Sera and hepatocyte-conditioned medium from Smo(-) mice were depleted of thymidine phosphorylase (TP), a protein that maintains mitochondrial fitness. Treating Smo(-) hepatocytes with TP reduced senescence and lipotoxicity; inhibiting TP in Smo(+) hepatocytes had the opposite effects and exacerbated hepatocyte senescence, MASH, and fibrosis in CDA-HFD-fed mice. Therefore, we found that inhibiting Hedgehog signaling in hepatocytes promotes MASLD by suppressing hepatocyte production of proteins that prevent lipotoxicity and senescence.