Liver-to-kidney apolipoprotein J trans-accumulation exacerbates diabetic renal injury by disrupting TFEB-mediated lipid homeostasis

作者：Duan S, Qin N, Pi J, Huang CP, Sun P, Huang Q, Ke K, Mo Z, Jan HC, Wang HT, Liu WC, Chi LC, Liu L, Shi L, Yang SR, Sun HY · 发表于：Diabetologia · 年份：2026 · DOI：10.1007/s00125-026-06801-7

AIMS/HYPOTHESIS: Ectopic lipid accumulation in renal tubules induces lipotoxicity and contributes to the progression of diabetic kidney disease (DKD). Apolipoprotein J (ApoJ), a glucose-regulated, liver-derived molecular chaperone, is implicated in systemic metabolic homeostasis. This study aimed to investigate the pathophysiological role of ApoJ in the development of DKD. METHODS: Spearman's r analysis was used to evaluate the association between circulating ApoJ concentrations and renal function in a cohort of 201 individuals with type 2 diabetes mellitus. The pathways were identified by proteomic analyses and subsequently validated using gain- and loss-of-function approaches in proximal tubular epithelial HK2 cells, tissue-specific ApoJ-knockout mice and additional mouse models of DKD. RESULTS: In individuals with type 2 diabetes, circulating ApoJ concentrations were positively associated with indices of renal dysfunction. In murine models of DKD, elevated renal ApoJ was accompanied by increased lipid accumulation and structural kidney injury. Mechanistic studies revealed that ApoJ inhibited FBW7-mediated ubiquitination of mammalian target of rapamycin (mTOR), thereby enhancing mTOR interaction with transcription factor EB (TFEB) in HK2 cells under conditions of nutrient excess, leading to lipid imbalance and renal fibrosis. Hepatocyte-specific deletion of ApoJ eliminated circulating ApoJ, prevented its accumulation in renal tubules and ameliorated diabetic kidney injury...