Sorting Nexin 10 Mediates Metabolic Reprogramming of Macrophages in Atherosclerosis Through the Lyn-Dependent TFEB Signaling Pathway

Abstract

Rationale: Sorting Nexin 10 (SNX10) has been reported to play a critical role in regulating macrophage function and lipid metabolism. Objective: To investigate the precise role of SNX10 in atherosclerotic diseases and the underlying mechanisms. Methods and Results: SNX10 expression was compared between human healthy vessels and carotid atherosclerotic plaques. Myeloid cell-specific SNX10 knockdown mice were crossed onto the APOE-/- background and atherogenesis (high cholesterol diet-induced) was monitored for 16 weeks. We found that SNX10 expression was increased in atherosclerotic lesions of aortic specimens from humans and APOE-/- mice. Myeloid cell-specific SNX10 deficiency (ΔKO) attenuated atherosclerosis progression in APOE-/- mice. The population of anti-inflammatory monocytes/macrophages was increased in the peripheral blood and atherosclerotic lesions of ΔKO mice. In vitro experiments showed that SNX10 deficiency inhibited foam cell formation through interrupting the internalization of CD36, which requires the interaction of SNX10 and Lyn-AKT. The reduced Lyn-AKT activation by SNX10 deficiency promoted the nuclear translocation of TFEB, thereby enhanced lysosomal biogenesis and LAL activity, resulting in an increase of free fatty acids to fuel mitochondrial fatty acid oxidation. This further promoted the reprogramming of macrophages and shifted toward the anti-inflammatory phenotype. Conclusions: Our data demonstrate for the first time that SNX10 plays a crucial role in diet-induced atherogenesis via the previously unknown link between the Lyn-Akt-TFEB signaling pathway and macrophage reprogramming, suggest that SNX10 may be a potentially promising therapeutic target for atherosclerosis treatment.

The Oncogene Transcription Factor EB Regulates Vascular Functions

“…Interestingly, sorting nexin 10, a protein involved in regulating endosome trafficking, accumulates in atherosclerotic plaques and inhibits TFEB nuclear translocation by promoting AKT-dependent phosphorylation. Deletion of this protein in atherosclerotic macrophages suppresses the AKT pathway and increases the nuclear translocation of TFEB (You et al, 2020).…”

The molecular structure and function of sorting nexin 10 in skeletal disorders, cancers, and other pathological conditions

“…While SNX10 is best recognized for its homeostatic role in the skeletal system, emerging evidence now suggests that it may have an equally important role in the regulation of cancer development (Cervantes‐Anaya et al, 2017; Galvan et al, 2013; Warnecke‐Eberz et al, 2016; Zhang et al, 2018), metabolic disorders (Lind, 2019; You et al, 2020), and inflammation (Armstrong et al, 2019; Lou et al, 2017).…”

“…Furthermore, SNX10 enhancer activity was involved in body fat distribution (Castillejo‐Lopez et al, 2019). Increased expression of SNX10 was found in human atherosclerotic lesions of aortic specimens when compared with human healthy vessels (You et al, 2020). Interestingly, in APOE−/− mice which mimic human atherosclerosis, SNX10 KO specific in myeloid cells attenuated atherosclerosis progression, with demonstrated increased number of anti‐inflammatory monocytes/macrophages (You et al, 2020).…”

“…Increased expression of SNX10 was found in human atherosclerotic lesions of aortic specimens when compared with human healthy vessels (You et al, 2020). Interestingly, in APOE−/− mice which mimic human atherosclerosis, SNX10 KO specific in myeloid cells attenuated atherosclerosis progression, with demonstrated increased number of anti‐inflammatory monocytes/macrophages (You et al, 2020). Mechanistic study revealed that SNX10 deficiency inhibited foam cell formation through interrupting the internalization of CD36.…”

“…Mechanistic study revealed that SNX10 deficiency inhibited foam cell formation through interrupting the internalization of CD36. Furthermore, Lyn‐AKT activation in SNX10 KO cells is attenuated, leading to increased nuclear translocation of transcription factor EB, a master regulator of lysosomal biogenesis, which results in increased lysosomal biogenesis and lysosomal acid lipase enzyme activity, free fatty acids accumulation, and mitochondrial fatty acid oxidation (You et al, 2020).…”