Department of Biochemistry, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA.
Commun Biol. 2024 Sep 2;7(1):1075. doi: 10.1038/s42003-024-06773-7.
Subretinal fibrosis permanently impairs the vision of patients with neovascular age-related macular degeneration. Despite emerging evidence revealing the association between disturbed metabolism in retinal pigment epithelium (RPE) and subretinal fibrosis, the underlying mechanism remains unclear. In the present study, single-cell RNA sequencing revealed, prior to subretinal fibrosis, genes in mitochondrial fatty acid oxidation are downregulated in the RPE lacking very low-density lipoprotein receptor (VLDLR), especially the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). We found that overexpression of CPT1A in the RPE of Vldlr mice suppresses epithelial-to-mesenchymal transition and fibrosis. Mechanistically, TGFβ induces fibrosis by activating a Warburg-like effect, i.e. increased glycolysis and decreased mitochondrial respiration through ERK-dependent CPT1A degradation. Moreover, VLDLR blocks the formation of the TGFβ receptor I/II complex by interacting with unglycosylated TGFβ receptor II. In conclusion, VLDLR suppresses fibrosis by attenuating TGFβ-induced metabolic reprogramming, and CPT1A is a potential target for treating subretinal fibrosis.
视网膜下纤维化会永久性损害新生血管性年龄相关性黄斑变性患者的视力。尽管有新的证据表明视网膜色素上皮 (RPE) 代谢紊乱与视网膜下纤维化之间存在关联，但其中的机制仍不清楚。在本研究中，单细胞 RNA 测序显示，在视网膜下纤维化之前，缺乏极低密度脂蛋白受体 (VLDLR) 的 RPE 中的线粒体脂肪酸氧化基因下调，尤其是限速酶肉碱棕榈酰基转移酶 1A (CPT1A)。我们发现，在 Vldlr 小鼠的 RPE 中过表达 CPT1A 可抑制上皮间质转化和纤维化。在机制上，TGFβ 通过激活类似于瓦博格效应（即通过 ERK 依赖性 CPT1A 降解增加糖酵解和减少线粒体呼吸）来诱导纤维化。此外，VLDLR 通过与未糖基化的 TGFβ 受体 II 相互作用来阻断 TGFβ 受体 I/II 复合物的形成。总之，VLDLR 通过减弱 TGFβ 诱导的代谢重编程来抑制纤维化，CPT1A 是治疗视网膜下纤维化的潜在靶点。
