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<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.
Authors
- Srinivasan Dasarathy (ORCID: https://orcid.org/0000-0003-1774-0104)
- Taj Mohammad (ORCID: https://orcid.org/0000-0002-0399-4835)
- James M. Crawford (ORCID: https://orcid.org/0000-0002-8581-1093)
- Patricia S. Latham (ORCID: https://orcid.org/0000-0003-2782-9444)
- Krishanu Bhowmick (ORCID: https://orcid.org/0000-0001-6213-8230)
- Hai Huang (ORCID: https://orcid.org/0000-0003-2123-6533)
- Xiaochun Yang
- Anil K. Vegesna (ORCID: https://orcid.org/0000-0003-0097-4369)
- Bibhuti Nath Mishra (ORCID: https://orcid.org/0000-0002-3355-7716)
- Kazufumi Ohshiro (ORCID: https://orcid.org/0000-0002-5162-5612)
- Kirti Shetty (ORCID: https://orcid.org/0000-0002-7725-6050)
- Scott K. Lyons (ORCID: https://orcid.org/0000-0003-0139-6054)
- Joseph R. Merrill (ORCID: https://orcid.org/0000-0003-3680-1988)
- Keith A. Crandall (ORCID: https://orcid.org/0000-0002-0836-3389)
- Richard Amdur (ORCID: https://orcid.org/0000-0002-4900-653X)
- Shuyun Rao (ORCID: https://orcid.org/0000-0002-1073-6682)
- Paolo Cifani (ORCID: https://orcid.org/0000-0002-4403-1277)
- Xiyan Xiang (ORCID: https://orcid.org/0000-0002-4746-9522)
- Herbert Yu (ORCID: https://orcid.org/0000-0003-3950-4815)
- Adrian R. Krainer (ORCID: https://orcid.org/0000-0001-9024-9501)
- Sahara John
- Lopa Mishra (ORCID: https://orcid.org/0000-0002-6850-0808)
- Md. Imtaiyaz Hassan (ORCID: https://orcid.org/0000-0002-3663-4940)
- Xin Wei Wang (ORCID: https://orcid.org/0000-0001-9735-606X)
- Zhanwei Wang (ORCID: https://orcid.org/0000-0002-4871-2774)
Institutions
- University of Hawaiʻi at Mānoa (US)
- University of Maryland, Baltimore (US)
- Northwell Health (US)
- Cleveland Clinic (US)
- Feinstein Institute for Medical Research (US)
- University of Hawaii System (US)
- George Washington University (US)
- Cold Spring Harbor Laboratory (US)
- Cancer Center of Hawaii (US)
- Donald & Barbara Zucker School of Medicine at Hofstra/Northwell (US)
- National Cancer Institute (US)
- Center for Cancer Research (US)
- University of Hawaii Cancer Center
- Jamia Millia Islamia (IN)
Publication Details
- Journal
- Cell Reports
- Published
- 2024-08-31
- DOI
- https://doi.org/10.1016/j.celrep.2024.114676
- Citations
- 13
- Primary Topic
- Diet and metabolism studies
- Type
- article
- Field-Weighted Citation Impact
- 4.25
Funders
- George Washington University
- Rockefeller University
- National Institutes of Health
- National Institute on Alcohol Abuse and Alcoholism
- National Cancer Institute