Aldehydes alter TGF-β signaling and induce obesity and cancer

Autor: Xiaochun Yang, Krishanu Bhowmick, Shuyun Rao, Xiyan Xiang, Kazufumi Ohshiro, Richard L. Amdur, Md. Imtaiyaz Hassan, Taj Mohammad, Keith Crandall, Paolo Cifani, Kirti Shetty, Scott K. Lyons, Joseph R. Merrill, Anil K. Vegesna, Sahara John, Patricia S. Latham, James M. Crawford, Bibhuti Mishra, Srinivasan Dasarathy, Xin Wei Wang, Herbert Yu, Zhanwei Wang, Hai Huang, Adrian R. Krainer, Lopa Mishra
Jazyk: angličtina
Rok vydání: 2024
Předmět:
Zdroj: Cell Reports, Vol 43, Iss 9, Pp 114676- (2024)
Druh dokumentu: article
ISSN: 2211-1247
85436127
DOI: 10.1016/j.celrep.2024.114676
Popis: Summary: Obesity and fatty liver diseases—metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH)—affect over one-third of the global population and are exacerbated in individuals with reduced functional aldehyde dehydrogenase 2 (ALDH2), observed in approximately 560 million people. Current treatment to prevent disease progression to cancer remains inadequate, requiring innovative approaches. We observe that Aldh2−/− and Aldh2−/−Sptbn1+/− mice develop phenotypes of human metabolic syndrome (MetS) and MASH with accumulation of endogenous aldehydes such as 4-hydroxynonenal (4-HNE). Mechanistic studies demonstrate aberrant transforming growth factor β (TGF-β) signaling through 4-HNE modification of the SMAD3 adaptor SPTBN1 (β2-spectrin) to pro-fibrotic and pro-oncogenic phenotypes, which is restored to normal SMAD3 signaling by targeting SPTBN1 with small interfering RNA (siRNA). Significantly, therapeutic inhibition of SPTBN1 blocks MASH and fibrosis in a human model and, additionally, improves glucose handling in Aldh2−/− and Aldh2−/−Sptbn1+/− mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.
Databáze: Directory of Open Access Journals
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