Kennedy Institute of Rheumatology, University of Oxford, Oxford, UK.
Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
EMBO J. 2023 Mar 15;42(6):e112202. doi: 10.15252/embj.2022112202. Epub 2023 Feb 16.
Lipids play a major role in inflammatory diseases by altering inflammatory cell functions, either through their function as energy substrates or as lipid mediators such as oxylipins. Autophagy, a lysosomal degradation pathway that limits inflammation, is known to impact on lipid availability, however, whether this controls inflammation remains unexplored. We found that upon intestinal inflammation visceral adipocytes upregulate autophagy and that adipocyte-specific loss of the autophagy gene Atg7 exacerbates inflammation. While autophagy decreased lipolytic release of free fatty acids, loss of the major lipolytic enzyme Pnpla2/Atgl in adipocytes did not alter intestinal inflammation, ruling out free fatty acids as anti-inflammatory energy substrates. Instead, Atg7-deficient adipose tissues exhibited an oxylipin imbalance, driven through an NRF2-mediated upregulation of Ephx1. This shift reduced secretion of IL-10 from adipose tissues, which was dependent on the cytochrome P450-EPHX pathway, and lowered circulating levels of IL-10 to exacerbate intestinal inflammation. These results suggest an underappreciated fat-gut crosstalk through an autophagy-dependent regulation of anti-inflammatory oxylipins via the cytochrome P450-EPHX pathway, indicating a protective effect of adipose tissues for distant inflammation.
脂质通过改变炎症细胞的功能在炎症性疾病中发挥主要作用，无论是作为能量底物，还是作为类花生酸等脂质介质。自噬是一种溶酶体降解途径，可限制炎症，已知其对脂质的可用性有影响，但这是否控制炎症仍未得到探索。我们发现，在肠道炎症中，内脏脂肪细胞上调自噬，并且脂肪细胞特异性缺失自噬基因 Atg7 会加剧炎症。虽然自噬减少了脂肪分解游离脂肪酸的释放，但脂肪细胞中主要脂肪分解酶 Pnpla2/Atgl 的缺失并未改变肠道炎症，排除了游离脂肪酸作为抗炎能量底物的可能性。相反，Atg7 缺陷的脂肪组织表现出类花生酸失衡，这是通过 NRF2 介导的 Ephx1 上调驱动的。这种转变减少了脂肪组织中 IL-10 的分泌，这依赖于细胞色素 P450-EPHX 途径，并且降低了循环中 IL-10 的水平，从而加剧了肠道炎症。这些结果表明，通过细胞色素 P450-EPHX 途径依赖自噬的抗炎类花生酸的调节，存在一种被低估的脂肪-肠道串扰，表明脂肪组织对远处炎症具有保护作用。
