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In his landmark 1994 paper, Roger Unger first recognized that lipid overload of pancreatic islets caused “lipotoxic” inhibition of pancreatic β-cell function (1). Unger and colleagues discovered that elevated plasma free fatty acid levels and triglyceride accumulation in pancreatic islets preceded impairment of glucose-induced insulin secretion and systemic hyperglycemia in the Zucker diabetic fatty rat. Moreover, they went on to recapitulate the deleterious effects of excess lipid on β-cell function by incubating primary isolated islets with pathophysiologic levels of free fatty acids. Since this seminal publication, the literature is replete with examples in which ectopic lipid accumulation causes cell dysfunction or triggers cell death [reviewed in (2)].
Beyond rodent models of metabolic disease, emerging evidence suggests that ectopic lipid contributes to the pathophysiology of human disease. Hyperlipidemia in metabolic syndrome and diabetes is associated with lipid accumulation in nonadipose tissues such as the liver and the heart, which precedes organ dysfunction (3, 4). While far less common, inherited disorders of fatty acid oxidation have also been associated with vast increases in lipid stores in the heart that are associated with heart failure and sudden cardiac death (5, 6). Under these pathologic conditions, excessive delivery of fatty acids to the heart overwhelms the relatively limited capacity of this tissue to utilize or safely store excess lipid.
There has been great interest in uncovering the mechanisms through which ectopic lipids lead to cell and organ dysfunction, because of the relevance to human disease, and because these processes provide insights into the regulation of cellular lipid metabolism. Approaches have ranged from mechanistic studies in cultured cells to rodent models to translational investigations in humans. This series will review some of the major responses elicited by lipotoxic conditions and highlight recent advances that contribute to our understanding of the pathophysiology of metabolic diseases.
Cells initially adapt to lipid overload by inducing pathways for catabolism, utilization in biosynthetic pathways, and storage in lipid droplets. Both the endoplasmic reticulum (ER) stress and autophagy pathways facilitate these early beneficial functions. However, in the setting of prolonged or severe lipid overload, these responses turn maladaptive and contribute to cellular demise. In their review of ER stress and autophagy, Han and Kaufman (7) outline the ways in which signaling pathways downstream of three ER transmembrane stress sensors regulate both protein and membrane biosynthesis. However, chronic lipid stress engages arms of the ER stress pathway that promote cell death. A similar progression from adaptive functions in lipid droplet turnover to maladaptive responses that contribute to oxidative stress and insulin resistance are described by Jaishy and Abel (8) in their review of lipids and autophagy.
Other pathways induced under lipotoxic conditions primarily contribute to the progression to cell death. Signaling pathways initiated in hepatocytes in response to lipotoxicity that are particularly relevant to the pathogenesis of nonalcoholic steatohepatitis are reviewed by Hirsova et al (9). Lipid initiated signaling also activates enzymes and mitochondrial metabolism of excess lipid substrates, both of which produce reactive oxygen species (ROS) (10, 11). These ROSs target membrane lipids and triglycerides, yielding α,β polyunsaturated lipid aldehydes that covalently modify other cellular macromolecules. Hauk and Bernlohr (12) discuss the wide-ranging consequences of lipid aldehyde accumulation in lipotoxicity.
While many pathways activated by lipid metabolic stress direct cell-autonomous responses, lipotoxicity is also an important stimulus for systemic inflammatory responses. Ertunc and Hotamisligil (13) review the growing body of evidence that lipid excess promotes low-grade inflammation that is central to the pathogenesis of metabolic diseases.
Restoration of lipid homeostasis is an important primary goal in the approach to metabolic disease, given the pleiotropic deleterious consequences of ectopic lipid accumulation. On the other hand, as we gain a clearer picture of the mechanisms of lipotoxicity, adjunctive therapeutic approaches may effectively target the downstream programs that amplify lipid-induced cell and tissue damage.