Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis

Arthur C. Sletten, Jessica W. Davidson, Busra Yagabasan, Samantha Moores, Michaela Schwaiger-Haber, Hideji Fujiwara, Sarah Gale, Xuntian Jiang, Rohini Sidhu, Susan J. Gelman, Shuang Zhao, Gary J. Patti, Daniel S. Ory and Jean E. Schaffer ()
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Arthur C. Sletten: Washington University in St. Louis
Jessica W. Davidson: Harvard Medical School
Busra Yagabasan: Harvard Medical School
Samantha Moores: Harvard Medical School
Michaela Schwaiger-Haber: Washington University in St. Louis
Hideji Fujiwara: Washington University in St. Louis
Sarah Gale: Washington University in St. Louis
Xuntian Jiang: Washington University in St. Louis
Rohini Sidhu: Washington University in St. Louis
Susan J. Gelman: Washington University in St. Louis
Shuang Zhao: Washington University in St. Louis
Gary J. Patti: Washington University in St. Louis
Daniel S. Ory: Washington University in St. Louis
Jean E. Schaffer: Harvard Medical School

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. Excess lipid causes cell dysfunction and induces cell death through pleiotropic mechanisms that link to oxidative stress. However, pathways that regulate the response to metabolic stress are not well understood. Herein, we show that disruption of the box H/ACA SNORA73 small nucleolar RNAs encoded within the small nucleolar RNA hosting gene 3 (Snhg3) causes resistance to lipid-induced cell death and general oxidative stress in cultured cells. This protection from metabolic stress is associated with broad reprogramming of oxidative metabolism that is dependent on the mammalian target of rapamycin signaling axis. Furthermore, we show that knockdown of SNORA73 in vivo protects against hepatic steatosis and lipid-induced oxidative stress and inflammation. Our findings demonstrate a role for SNORA73 in the regulation of metabolism and lipotoxicity.

Date: 2021
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DOI: 10.1038/s41467-021-25457-y

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