Death by Lipids: role of noncoding RNAs in metabolic stress

Abstract

Nutrient excess is linked to the pathogenesis of complications of obesity and type 2 diabetes. Fatty acid accumulation in non-adipose tissues is initially well tolerated and leverages the nearly universal ability of cells to store fatty acids as triglycerides in lipid droplets. However, lipid overload eventually precipitates cell dysfunction through generation of toxic metabolites, activation of signaling cascades, endoplasmic reticulum stress, and oxidative stress. These pathways contribute to cell death, organ dysfunction and disease pathogenesis. Mechanisms that regulate the transition from adaptive lipid storage to initiation of lipotoxicity are not well understood. New insights have come from genetic screens in model cell culture systems. By leveraging the ability of retroviral promotor trap mutagenesis to disrupt genetic elements regardless of coding potential and using selection for resistance to palmitate-induced cell death, our group discovered that disruption of specific small nucleolar RNAs (snoRNAs) protects against lipotoxic and oxidative stress in cultured cells. By extending our findings to in vivo models, we have demonstrated that knockdown or knockout of these snoRNAs rewires metabolism in ways that increase lipid metabolism, enhance oxidative stress tolerance, and confer resistance to lipotoxicity. Our studies highlight novel roles for snoRNAs as metabolic modulators and suggest that expression and function of this class of intronic non-coding RNAs may have relevance to human health and disease.