Death by lipids: The role of small nucleolar RNAs in metabolic stress

Abstract

Excess fatty acid accumulation in nonadipose tissues leads to cell dysfunction and cell death that is linked to the pathogenesis of inherited and acquired human diseases. Study of this process, known as lipotoxicity, has provided new insights into the regulation of lipid homeostasis and has revealed new molecular pathways involved in lipid-induced cellular stress. The discovery that disruption of specific small nucleolar RNAs protects against fatty acid–induced cell death and remodels metabolism in vivo opens new opportunities for understanding how nutrient signals influence cellular and systemic metabolic homeostasis through RNA biology. Excess fatty acid accumulation in nonadipose tissues leads to cell dysfunction and cell death that is linked to the pathogenesis of inherited and acquired human diseases. Study of this process, known as lipotoxicity, has provided new insights into the regulation of lipid homeostasis and has revealed new molecular pathways involved in lipid-induced cellular stress. The discovery that disruption of specific small nucleolar RNAs protects against fatty acid–induced cell death and remodels metabolism in vivo opens new opportunities for understanding how nutrient signals influence cellular and systemic metabolic homeostasis through RNA biology. Fatty acids perform many critical cellular functions. These amphipathic molecules are building blocks of membrane lipids that demarcate the boundaries of cells and organize biochemical reactions within intracellular organelles. Fatty acids also serve as precursors for the biosynthesis of signaling lipids, such as ceramides and hydroxylated fatty acids, which regulate physiological processes. Moreover, fatty acids are nutrients that can be oxidized to produce ATP or efficiently stored as triglycerides. They are major nutrients for tissues with high energy demands, such as muscle, and a critical source of potential energy for organisms during periods of fasting. Under physiological conditions, cellular fatty acid supplies derive from de novo synthesis, recycling of other lipid classes, and import of exogenous lipids, distinct processes that must be coordinated with cells' needs for these lipids for diverse functions. Failure to balance acquisition and use of fatty acids underlies the pathophysiology of human diseases, ranging from rare monogenic disorders of metabolism to common complications of metabolic syndrome and type 2 diabetes mellitus (T2DM). In the 1970s and 1980s, clinicians discovered that disorders presenting as hypoglycemia in the setting of viral illness or fasting could be linked to mutations in genes encoding enzymes in fatty acid oxidation (1Stanley C.A. Hale D.E. Coates P.M. Hall C.L. Corkey B.E. Yang W. Kelley R.I. Gonzales E.L. Williamson J.R. Baker L. 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