β2-spectrin (SPTBN1) as a therapeutic target for diet-induced liver disease and preventing cancer development

The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated...

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Published in:Science translational medicine 2021-12, Vol.13 (624), p.eabk2267-eabk2267
Main Authors: Rao, Shuyun, Yang, Xiaochun, Ohshiro, Kazufumi, Zaidi, Sobia, Wang, Zhanhuai, Shetty, Kirti, Xiang, Xiyan, Hassan, Md Imtaiyaz, Mohammad, Taj, Latham, Patricia S, Nguyen, Bao-Ngoc, Wong, Linda, Yu, Herbert, Al-Abed, Yousef, Mishra, Bibhuti, Vacca, Michele, Guenigault, Gareth, Allison, Michael E D, Vidal-Puig, Antonio, Benhammou, Jihane N, Alvarez, Marcus, Pajukanta, Päivi, Pisegna, Joseph R, Mishra, Lopa
Format: Article
Language:English
Subjects:
Animals
Biochemical analysis
Caspase-3
Diet, High-Fat - adverse effects
Fibrosis
High fat diet
Lipogenesis
Liver - metabolism
Liver cancer
Liver diseases
Mice
Mice, Inbred C57BL
Neoplasms - metabolism
Non-alcoholic Fatty Liver Disease - genetics
siRNA
Spectrin
Spectrin - metabolism
Sterol regulatory element-binding protein
Sterols
Therapeutic targets
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Summary:The prevalence of nonalcoholic steatohepatitis (NASH) and liver cancer is increasing. De novo lipogenesis and fibrosis contribute to disease progression and cancerous transformation. Here, we found that β2-spectrin (SPTBN1) promotes sterol regulatory element (SRE)–binding protein (SREBP)–stimulated lipogenesis and development of liver cancer in mice fed a high-fat diet (HFD) or a western diet (WD). Either hepatocyte-specific knockout of SPTBN1 or siRNA-mediated therapy protected mice from HFD/WD-induced obesity and fibrosis, lipid accumulation, and tissue damage in the liver. Biochemical analysis suggested that HFD/WD induces SPTBN1 and SREBP1 cleavage by CASPASE-3 and that the cleaved products interact to promote expression of genes with sterol response elements. Analysis of human NASH tissue revealed increased and expression. Thus, our data indicate that SPTBN1 represents a potential target for therapeutic intervention in NASH and liver cancer.
ISSN:1946-6234
1946-6242
1946-3242
DOI:10.1126/scitranslmed.abk2267