Liver-to-kidney apolipoprotein J trans-accumulation exacerbates diabetic renal injury by disrupting transcription factor EB (TFEB)-mediated lipid homeostasis
Authors' conclusion
Our findings highlight a liver-to-kidney interorgan transfer of pathogenetic ApoJ in diabetic kidney injury and suggest that MK53 represents a potential therapeutic strategy for DKD.
Study context
- Population
- Individuals with T2D (clinical cohort); HK2 proximal tubular epithelial cells; tissue-specific Apolipoprotein J (ApoJ)-knockout mice and other mouse models of diabetic kidney disease (DKD)T2D cohort
- Participants
- 201 individuals
- Outcome
- Role of ApoJ in DKD
Methodological detailsclinical cohort, proteomic analyses, gain- and loss-of-function approaches, tissue-specific knockout mice
- Clinical cohort
- Proteomic analyses
- Gain- and loss-of-function approaches
- Tissue-specific knockout mice
Main finding
As reported in the abstract
- In T2D, circulating ApoJ positively associated with indices of renal dysfunction
- In murine DKD, elevated renal ApoJ accompanied by increased lipid accumulation and structural kidney injury
- ApoJ inhibited FBW7-mediated ubiquitination of mammalian target of rapamycin (mTOR), enhancing mTOR–TFEB interaction in HK2 cells under nutrient excess, leading to lipid imbalance and renal fibrosis
- Hepatocyte-specific ApoJ deletion eliminated circulating ApoJ, prevented its renal tubular accumulation and ameliorated diabetic kidney injury
- ApoJ antagonist MK53 reactivated TFEB-autophagy pathway, restored lipid homeostasis and reduced renal damage in diabetic mice
Original publication
Liver-to-kidney apolipoprotein J trans-accumulation exacerbates diabetic renal injury by disrupting TFEB-mediated lipid homeostasis. Diabetologia. Published 17 July 2026. doi:10.
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