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.
Highlights
Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes
Mutant 2E4 cells were isolated from a loss-of-function screen in Chinese hamster ovary (CHO) cells, designed to identify genes critical for fatty acid-induced cell death[20]
We show that cells deficient in SNORA73—generated by promoter trap mutagenesis and independently confirmed by knockdown—are protected from lipotoxic and oxidative stress
Summary
Dyslipidemia and resulting lipotoxicity are pathologic signatures of metabolic syndrome and type 2 diabetes. 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. Through a retroviral promoter trap mutagenesis screen for palmitate-resistance in Chinese hamster ovary (CHO) cells, our lab has discovered noncoding RNAs that control responses to lipotoxic stress These RNAs include the long noncoding RNA (lncRNA), Gadd[7], and the box C/D snoRNAs encoded within the ribosomal protein L13a locus[20,21,22]. While the molecular function of the lncRNA is not well understood, SNORA73A and SNORA73B direct one of several steps in the processing of prerRNAs to produce mature 18S, 5.8S, and 28S rRNAs23 We show that these snoRNAs, but not the SNHG3 lncRNA, are critical for metabolic stress responses and regulate cell metabolism through the mammalian target of rapamycin (mTOR) pathway. Our findings in cultured cells and in vivo elucidate a role for SNORA73 in the regulation of metabolic stress
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