Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
Adv Exp Med Biol. 2024;1460:131-166. doi: 10.1007/978-3-031-63657-8_5.
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
细胞暴露于脂肪酸种类与毒性表型之间的联系仍知之甚少。然而，对人体血浆游离脂肪酸 (FFA) 的结构特征和功能分析表明，FFA 位于毒性簇或对脂毒性应激有转录反应并产生遗传风险因素的簇中。全基因组短发夹 RNA 筛选已经鉴定出 350 多个调节脂毒性的基因。肥胖脂肪中的肥大脂肪细胞既不能进一步扩张以储存饮食中的多余脂肪，也不能抵抗胰岛素的抗脂肪分解作用。除脂肪分解外，将多余的脂肪包装成脂肪滴会导致循环脂肪酸在非脂肪组织中达到毒性水平。非脂肪组织中积累的脂质的有害影响称为脂毒性。尽管甘油三酯是长链非酯化脂肪酸及其产物如神经酰胺和二酰基甘油 (DAG) 的储存功能，但饱和脂肪酸 (SFA) 的棕榈酸部分的过载会提高神经酰胺水平。过量的 DAG 和神经酰胺负荷对多个器官和系统造成有害影响，在肥胖症中诱导慢性炎症。因此，脂毒性炎症导致β细胞死亡和胰岛功能障碍。内质网应激刺激通过激活脂肪细胞中的环腺苷酸单磷酸 (cAMP)/蛋白激酶 A (PKA) 和细胞外信号调节激酶 (Erk) 1/2 信号通路诱导脂肪分解。然而，在肥大脂肪细胞中，棕榈酸诱导的内质网应激-JNK-自噬轴是一种针对 SFA 诱导的内质网应激和细胞死亡的存活机制。内质网定位的酰基辅酶 A (CoA)：甘油-3-磷酸酰基转移酶 (GPAT) 酶是脂毒性的介质，抑制这些酶对内质网应激和细胞死亡具有治疗潜力。脂毒性增加了吞噬棕榈酸的自噬体的数量，从而抑制了自噬体的周转。脂肪酸去饱和促进棕榈酸解毒和储存为甘油三酯。作为糖脂毒性的治疗靶点，除了热量限制和运动外，还有四种不同的药理学方法，包括二甲双胍、胰高血糖素样肽 1 (GLP-1) 受体激动剂、过氧化物酶体增殖物激活受体-γ (PPARγ) 配体噻唑烷二酮和伴侣仍在临床实践中使用。此外，用二十碳五烯酸和二十二碳六烯酸混合物诱导棕色脂肪样表型似乎是治疗脂毒性的一种潜在治疗应用。
