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
{"title":"醛改变 TGF-β 信号传导,诱发肥胖和癌症。","authors":"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","doi":"10.1016/j.celrep.2024.114676","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> 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<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":null,"pages":null},"PeriodicalIF":7.5000,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Aldehydes alter TGF-β signaling and induce obesity and cancer.\",\"authors\":\"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\",\"doi\":\"10.1016/j.celrep.2024.114676\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> 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<sup>-/-</sup> and Aldh2<sup>-/-</sup>Sptbn1<sup>+/-</sup> mice. 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Aldehydes alter TGF-β signaling and induce obesity and cancer.
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.
期刊介绍:
Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted.
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