Aldehydes alter TGF-β signaling and induce obesity and cancer

Yang, Xiaochun, Bhowmick, Krishanu, Rao, Shuyun, Xiang, Xiyan, Ohshiro, Kazufumi, Amdur, Richard L, Hassan, Md Imtaiyaz, Mohammad, Taj, Crandall, Keith, Cifani, Paolo, Shetty, Kirti, Lyons, Scott K, Merrill, Joseph R, Vegesna, Anil K, John, Sahara, Latham, Patricia S, Crawford, James M, Mishra, Bibhuti, Dasarathy, Srinivasan, Wang, Xin Wei, Yu, Herbert, Wang, Zhanwei, Huang, Hai, Krainer, Adrian R, Mishra, Lopa (August 2024) Aldehydes alter TGF-β signaling and induce obesity and cancer. Cell Reports, 43 (9). p. 114676. ISSN 2211-1247 (Public Dataset)

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Abstract

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.

Item Type: Paper
Subjects: diseases & disorders > cancer
diseases & disorders
diseases & disorders > neoplasms
diseases & disorders > cancer > cancer types > liver cancer
diseases & disorders > cancer > cancer types
CSHL Authors:
Communities: CSHL Cancer Center Program > Cellular Communication in Cancer Program
CSHL Cancer Center Program > Gene Regulation and Inheritance Program
CSHL labs > Krainer lab
CSHL labs > Lyons lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 31 August 2024
Date Deposited: 09 Sep 2024 13:33
Last Modified: 09 Sep 2024 13:33
Related URLs:
Dataset ID:
URI: https://repository.cshl.edu/id/eprint/41654

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