Loss of SNORA73 reprograms cellular metabolism and protects against steatohepatitis

• Published in: Nature communications Vol. 12; no. 1; pp. 5214 - 17
• Main Authors: Sletten, Arthur C., Davidson, Jessica W., Yagabasan, Busra, Moores, Samantha, Schwaiger-Haber, Michaela, Fujiwara, Hideji, Gale, Sarah, Jiang, Xuntian, Sidhu, Rohini, Gelman, Susan J., Zhao, Shuang, Patti, Gary J., Ory, Daniel S., Schaffer, Jean E.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/31; 13/89; 38; 38/91; 631/337/384/521; 631/45/287; 692/699/317; 96; Animals; Apoptosis; Cell death; Cell Death - drug effects; CHO Cells; Cricetulus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Dyslipidemia; Fatty liver; Fatty Liver - drug therapy; Fatty Liver - genetics; Fatty Liver - metabolism; Homeostasis; Humanities and Social Sciences; Inflammation; Lipid Metabolism; Lipids; Lipids - pharmacology; Male; Metabolic disorders; Metabolic syndrome; Metabolic Syndrome - metabolism; Metabolism; Mice; Mice, Inbred C57BL; multidisciplinary; Nucleoli; Oxidation resistance; Oxidative metabolism; Oxidative stress; Oxidative Stress - drug effects; Protective Agents - pharmacology; Rapamycin; Ribonucleic acid; RNA; RNA, Long Noncoding; RNA, Small Nucleolar - genetics; RNA, Small Nucleolar - metabolism; Science; Science (multidisciplinary); Signal Transduction - drug effects; snoRNA; Steatosis; TOR protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-25457-y

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. 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.