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J. Clin. Invest., Aug 27 2024, e180310 | https://doi.org/10.1172/JCI180310
The senescence-associated secretome of hedgehog-deficient hepatocytes drives MASLD progression
Ji Hye Jun1, Kuo Du1, Rajesh Kuma Dutta1, Raquel Maeso-Diaz1, Seh Hoon Oh1, Liuyang Wang2, Guannan Gao3, Ana Ferreira3, Jon Hill3, Steven S Pullen3, Anna Mae Diehl1#
1Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
2Department of Molecular Genetics and Microbiology, Duke University, Durham, North Carolina
3Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, Connecticut
#Corresponding Author: Anna Mae Diehl, M.D.
Abstract
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.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-29)
- 국외 연구진
- 생명과학 > 세포생물학
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