Abstract
Lipotoxicity is characterized by the ectopic accumulation of lipids in organs different from adipose tissue. Lipotoxicity is mainly associated with dysfunctional signaling and insulin resistance response in non-adipose tissue such as myocardium, pancreas, skeletal muscle, liver, and kidney. Serum lipid abnormalities and renal ectopic lipid accumulation have been associated with the development of kidney diseases, in particular diabetic nephropathy. Chronic hyperinsulinemia, often seen in type 2 diabetes, plays a crucial role in blood and liver lipid metabolism abnormalities, thus resulting in increased non-esterified fatty acids (NEFA). Excessive lipid accumulation alters cellular homeostasis and activates lipogenic and glycogenic cell-signaling pathways. Recent evidences indicate that both quantity and quality of lipids are involved in renal damage associated to lipotoxicity by activating inflammation, oxidative stress, mitochondrial dysfunction, and cell-death. The pathological effects of lipotoxicity have been observed in renal cells, thus promoting podocyte injury, tubular damage, mesangial proliferation, endothelial activation, and formation of macrophage-derived foam cells. Therefore, this review examines the recent preclinical and clinical research about the potentially harmful effects of lipids in the kidney, metabolic markers associated with these mechanisms, major signaling pathways affected, the causes of excessive lipid accumulation, and the types of lipids involved, as well as offers a comprehensive update of therapeutic strategies targeting lipotoxicity.
Highlights
Lipids are essential biomolecules for cell survival
Adipose tissue Insulin resistance (IR) is characterized by the inadequate lipolysis in adipocytes, whereas hepatic insulin resistance consists of decreased ability to inhibit the production of hepatic glucose in the presence of active lipogenesis [34,35,36]
Endothelial cells: endothelial cells do not seem to be prone to lipid accumulation, their role is essential in the transport of lipids to other tissues, in the renal area, they should be the main source of lipid supply to glomerular cells [118]
Summary
Lipids are essential biomolecules for cell survival. Their role in multiple cellular functions, such as intracellular signaling, transport, immunity, maintenance of cell structure, and metabolism, highlight the importance of lipids in the regulation of cellular homeostasis [1,2,3]. Adipocytes act as fuel tanks for the storage of lipids and triglycerides. In non-adipocytes, which have a limited capacity to metabolize excessive lipids, their accumulation (steatosis) alter homeostasis and promote cell dysfunction [4]. The dysregulation of intracellular homeostasis as a consequence of lipids accumulation is defined as lipotoxicity, a phenomenon characterized by activation of metabolic, inflammatory, and oxidative pathways that can eventually trigger cell death [6]. Throughout this review, we cover different aspects of lipotoxicity: from the causative agents and the roles and types of lipids involved in harmful effects to their potential therapeutic options, with emphasis on diabetic nephropathy (DN) and other chronic kidney diseases (CKD)
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