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<p>Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24&#xa0;h after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two intensive care unit (ICU) databases (the Medical Information Mart for Intensive Care IV [MIMIC-IV] and the eICU Collaborative Research Database [eICU-CRD]). AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (SCD1, FASN, ACLY, ACACA) were uniformly suppressed rather than upregulated. ApoB and MTTP, proteins essential for very-low-density lipoprotein (VLDL) assembly, were significantly downregulated, while ApoE showed a concordant downward trend (adjusted p = 0.072). Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. These data are consistent with ER stress-associated impairment of VLDL export contributing to AKI-induced hepatic steatosis. Clinical cohort analyses across two independent ICU databases identify a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury. </p>

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ER stress-mediated impairment of hepatic lipid export is associated with steatosis in AKI-induced remote liver injury

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月29日

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  • Minghua Li,
  • Runze Ni,
  • Kristof Williams,
  • Miriame Melaika,
  • Lucas Eli Sun,
  • Liying Fu,
  • Vijay Subramanian,
  • Kiran Dhanireddy,
  • Ruisheng Liu

摘要

Acute kidney injury (AKI) frequently causes remote organ injury including hepatic steatosis, yet whether lipid accumulation reflects increased synthesis or impaired clearance has not been resolved. We used a murine ischemia-reperfusion AKI model. Unbiased liver proteomics was performed at 24 h after reperfusion, and dysregulated pathways were identified by Gene Set Enrichment Analysis. Results were validated by Western blotting, qPCR, and immunohistochemistry. These findings were complemented by retrospective analysis of two intensive care unit (ICU) databases (the Medical Information Mart for Intensive Care IV [MIMIC-IV] and the eICU Collaborative Research Database [eICU-CRD]). AKI significantly increased serum ALT and AST and induced hepatic lipid accumulation. Proteomic analysis revealed that key lipogenic enzymes (SCD1, FASN, ACLY, ACACA) were uniformly suppressed rather than upregulated. ApoB and MTTP, proteins essential for very-low-density lipoprotein (VLDL) assembly, were significantly downregulated, while ApoE showed a concordant downward trend (adjusted p = 0.072). Plasma triglycerides were decreased while liver triglycerides were increased, consistent with impaired hepatic lipid export. As in renal tubular cells, AKI also disrupted ER protein folding homeostasis in the liver, triggering ER stress. This was evidenced by upregulated levels of the ER chaperone GRP78, increased XBP1 splicing indicative of UPR activation, and elevated expression of the ER stress-induced pro-apoptotic transcription factor CHOP, suggesting that prolonged ER stress may also promote hepatocyte cell death. TLR4/MyD88 signaling was activated, yet inflammatory cytokines were paradoxically reduced, accompanied by Kupffer cell depletion (decreased F4/80) and monocyte infiltration (increased CD68). In 6,996 propensity-matched ICU patients (MIMIC-IV), AKI independently increased the risk of clinically significant liver injury 4-fold (adjusted OR = 4.41). Analysis of 22,727 patients across 208 hospitals (eICU-CRD) identified a lipid dissociation pattern: elevated triglycerides alongside decreased total cholesterol, HDL, and LDL, with dose-dependent scaling across KDIGO stages. These data are consistent with ER stress-associated impairment of VLDL export contributing to AKI-induced hepatic steatosis. Clinical cohort analyses across two independent ICU databases identify a dual metabolic insult: enhanced peripheral lipid delivery compounds impaired hepatic export, amplifying hepatic lipid retention. ER stress and lipid export machinery represent potential therapeutic targets for AKI-associated liver injury.