Aldehydes alter TGF-β signaling and induce obesity and cancer

Xiaochun Yang, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Krishanu Bhowmick, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Shuyun Rao, Department of Surgery, George Washington University, Washington, DC 20037, USA.
Xiyan Xiang, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Kazufumi Ohshiro, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Richard L. Amdur, Quantitative Intelligence Unit, The Institutes for Health Systems Science & Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA.
Md Imtaiyaz Hassan, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Taj Mohammad, Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
Keith Crandall, Computational Biology Institute, Department of Biostatistics and Bioinformatics, George Washington University, Washington, DC 20037, USA.
Paolo Cifani, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Kirti Shetty, Department of Gastroenterology and Hepatology, the University of Maryland, School of Medicine, Baltimore, MD 21201, USA.
Scott K. Lyons, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Joseph R. Merrill, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Anil K. Vegesna, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Sahara John, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Patricia S. Latham, Department of Pathology, George Washington University, Washington, DC 20037, USA.
James M. Crawford, Department of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health, Manhasset, NY 11030, USA.
Bibhuti Mishra, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Department of Neurology, Northwell Health, Manhasset, NY 11030, USA.
Srinivasan Dasarathy, Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH 44106, USA.
Xin Wei Wang, Laboratory of Human Carcinogenesis, Liver Cancer Program, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA.
Herbert Yu, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Zhanwei Wang, Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
Hai Huang, Center for Immunology and Inflammation, Feinstein Institutes for Medical Research, Donald and Barbara Zucker School of Medicine at Hofstra, Northwell Health, Manhasset, NY 11030, USA.
Adrian R. Krainer, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
Lopa Mishra, Institute for Bioelectronic Medicine, Divisions of Gastroenterology and Hepatology, Department of Medicine, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY 11030, USA; Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA; Department of Surgery, George Washington University, Washington, DC 20037, USA. Electronic address: lopamishra2@gmail.com.

Document Type

Journal Article

Publication Date

9-24-2024

Journal

Cell reports

Volume

43

Issue

9

DOI

10.1016/j.celrep.2024.114676

Keywords

ALDH2; CP: Cancer; CP: Metabolism; HCC; MASH; SMAD3; SPTBN1; TGF-β; cancer; liver disease; metabolic syndrome; reactive aldehydes

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 Aldh2Sptbn1 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 Aldh2Sptbn1 mice. This study identifies SPTBN1 as a critical regulator of the functional phenotype of toxic aldehyde-induced MASH and a potential therapeutic target.

Department

Surgery

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