Université Bourgogne Franche-Comté, LNC UMR1231, F-21000 Dijon, France.
INSERM, LNC UMR 1231, F-21000 Dijon, France.
Int J Mol Sci. 2019 Aug 2;20(15):3787. doi: 10.3390/ijms20153787.
Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases.
肝 X 受体 (LXRs) 在脂肪酸 (FA) 代谢中发挥着关键作用。到目前为止，体内 LXR 激活所导致的生脂后果，主要表现为肝脏脂肪变性，这构成了药理学 LXR 激动剂临床开发的一个限制。然而，最近的研究提供了一个不同的视角。除了 FA 的定量积累外，似乎 LXRs 还会引起 FA 谱的定性变化，以及 FA 在细胞脂质种类中的分布变化。因此，LXRs 通过控制 FA 去饱和酶、FA 延长酶、溶血磷脂酰胆碱酰基转移酶 (LPCAT3) 和磷脂转移蛋白 (PLTP)，激活多不饱和脂肪酸 (PUFA) 的产生及其向磷脂的分布。因此，LXRs 以动态方式控制 PUFA 组成和细胞膜的物理化学性质，以及 PUFA 衍生的脂质介质的释放。最近的研究表明，LXR 对 PUFA 和磷脂代谢的调节参与了肝脏中脂生成和脂蛋白分泌的控制。在髓样细胞中，LXR 和 PUFA 代谢之间的相互作用影响炎症反应。重新审视 LXRs 在 FA 代谢中的复杂作用，可能为心脏代谢疾病领域的 LXR 调节剂的开发带来新的机遇。
