Abstract
Free fatty acids (FFAs) play numerous vital roles in the organism, such as contribution to energy generation and reserve, serving as an essential component of the cell membrane, or as ligands for nuclear receptors. However, the disturbance in fatty acid homeostasis, such as inefficient metabolism or intensified release from the site of storage, may result in increased serum FFA levels and eventually result in ectopic fat deposition, which is unfavorable for the organism. The cells are adjusted for the accumulation of FFA to a limited extent and so prolonged exposure to elevated FFA levels results in deleterious effects referred to as lipotoxicity. Lipotoxicity contributes to the development of diseases such as insulin resistance, diabetes, cardiovascular diseases, metabolic syndrome, and inflammation. The nonobvious organs recognized as the main lipotoxic goal of action are the pancreas, liver, skeletal muscles, cardiac muscle, and kidneys. However, lipotoxic effects to a significant extent are not organ-specific but affect fundamental cellular processes occurring in most cells. Therefore, the wider perception of cellular lipotoxic mechanisms and their interrelation may be beneficial for a better understanding of various diseases’ pathogenesis and seeking new pharmacological treatment approaches.
Highlights
The term “lipotoxicity” was first adopted in 1994 by Lee et al in the context of elucidating the pathogenesis of obesity-related β-cell alterations both before and at the onset of type 2 diabetes mellitus (T2DM) [1]
Another study conducted on human umbilical vein endothelial cells (HUVEC) exposed acutely to 1 mM palmitate suggests the possible mechanisms of Free fatty acids (FFAs)-induced NADPH oxidases (NOX) subunit gene expression [78] or the activation of NOX through protein kinase C (PKC)-dependent pathway in bovine aortic smooth muscle cells and endothelial cells treated with 200 μM palmitate for 72 h [79], contributing to increased reactive oxygen species (ROS) production
FFA-induced activation of IRE1 can mediate the activation of NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, an intracellular protein complex that assembles in response to damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs) and catalyzes the cleavage and maturation of cytokines IL-β1 and IL-18
Summary
The term “lipotoxicity” was first adopted in 1994 by Lee et al in the context of elucidating the pathogenesis of obesity-related β-cell alterations both before and at the onset of type 2 diabetes mellitus (T2DM) [1]. Due to further research, lipotoxicity is defined as the harmful effect of high concentrations of lipids and lipid derivatives manifested as a set of metabolic disorders in the cells of non-fatty tissues, causing disturbances in their metabolism and/or loss of function or apoptosis. This phenomenon most often affects the cells of the pancreas, liver, skeletal muscles, heart muscle, and kidneys. Lipotoxicity is relatively well understood in the organs mentioned above, while there are very few comprehensive descriptions of the effects of lipotoxicity on cell metabolism. There are many existing reviews about lipotoxicity concerning the aforementioned organs, this is, to the best of our knowledge, the first review focusing on the description of the cellular mechanism underlying lipotoxicity
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