Journal
NATURE COMMUNICATIONS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-021-25457-y
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Funding
- NIH [R01 DK108357, R01 DK064989, F30 DK120141, T32 HL007275, T32 GM07200]
- Washington University Diabetes Research Center [P30 DK020579]
- Joslin Diabetes Research Center [P30 DK036836]
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The study identified SNORA73 as a protective factor against lipotoxicity and oxidative stress, showing that its deficiency leads to metabolic reprogramming and protection against steatohepatitis in mice. Specifically, disruption of SNORA73 causes resistance to lipid-induced cell death and oxidative stress in cultured cells, with knockdown of SNORA73 in vivo protecting against hepatic steatosis and lipid-induced oxidative stress and inflammation. This demonstrates a role for SNORA73 in regulating metabolism and lipotoxicity.
Lipid induced stress contributes to metabolic diseases. Here the authors identify small nucleolar RNA 73 (SNORA73) in a screen for genes that protect against lipotoxicity and show that deficiency of SNORA73 reprograms oxidative metabolism and protects against steatohepatitis in mice. 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.
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