Molecular Mechanism of Lipotoxicity as an Interesting Aspect in the Development of Pathological States—Current View of Knowledge

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.

Plasma metabolomic characterization of premature ovarian insufficiency

“…Free fatty acids (FFAs) are important energy sources for the body. In some conditions, the disturbance of fatty acid homeostasis promotes the increased release of FFAs and triglycerides stored in tissues such as the liver, skeletal muscles, cardiac muscle, pancreas, kidney and brain, causing direct harmful effects; this is known as lipotoxicity [ 48 ]. Dysregulation of FFA metabolism may contribute to the risk of type 2 diabetes and cardiovascular diseases in POI patients due to the key roles of dysregulation of FFA metabolism in insulin resistance and dyslipidaemia [ 49 ].…”

Lipid Metabolism in Glioblastoma: From De Novo Synthesis to Storage

“…Excess free fatty acids and cholesterol can cause lipotoxicity, leading to cell death when the levels are uncontrolled [ 107 , 108 ]. In the human body, excess fatty acids and cholesterol are sequestered into the adipocytes of fat tissues within specialized organelles known as lipid droplets (LDs) after being converted to triacylglycerol (TAG) and cholesteryl esters (CE) ( Figure 1 ) [ 109 ].…”

The Contribution of Lipotoxicity to Diabetic Kidney Disease

“…If these cytoprotective pathways are surmounted, the released lipid metabolites, including ceramides, sphingolipids, diacylglycerols and long-chain acyl-CoAs, can lead to membrane disruption, aberrant lipid modification and malfunction of proteins, such as transporters and signaling enzymes, ROS generation, ER stress, impaired autophagy and increased apoptosis. These downstream sequelae have recently been extensively reviewed [ 35 , 36 ]; this review instead focuses on upstream lipotoxicity triggers, which may be amenable to interventions that abrogate DKD progression.…”