2. Academic Validation
  3. 1,5-Anhydroglucitol Aggravates Acute Liver Failure via the PPARα Signaling Pathway

1,5-Anhydroglucitol Aggravates Acute Liver Failure via the PPARα Signaling Pathway

  • J Clin Transl Hepatol. 2026 Mar 28;14(3):291-300. doi: 10.14218/JCTH.2025.00523.
Lingjian Zhang 1 2,  Yaqi Zhang 1,  Yalei Zhao 3,  Danhua Zhu 1,  Qian Li 1,  Qiuhong Liu 1,  Qingqing Hu 1,  Xiaoxi Ouyang 1,  Lanjuan Li 1
Affiliations

Affiliations

  • 1 State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
  • 2 Department of Infectious Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, Zhejiang, China.
  • 3 Department of Infectious Diseases, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China.
PMID: 41970189 DOI: 10.14218/JCTH.2025.00523
Abstract

Background and aims: Acute liver failure (ALF) is a severe hepatic injury associated with high short-term mortality. Our previous study found that 1,5-anhydroglucitol (1,5AG) levels correlate with clinical outcomes in patients with liver failure. This study aimed to explore the potential effects and mechanisms of 1,5AG in ALF.

Methods: An experimental model of ALF was established using LPS and D-GalN. 1,5AG was administered to mice by gavage before modeling. Empagliflozin was then administered to reduce 1,5AG levels in mice. Peroxisome Proliferator-activated Receptor alpha (PPARα) agonists were also used to explore the role of 1,5AG in mice with liver failure.

Results: 1,5AG pretreatment significantly increased ALT and AST levels, aggravated histological damage and hepatocyte Apoptosis, and increased mortality in ALF mice. Transcriptomic analysis and western blot validation revealed that 1,5AG significantly inhibited the PPARα signaling pathway and its downstream target, Fibroblast Growth Factor 21. Empagliflozin treatment reduced 1,5AG levels, alleviated liver injury and hepatocyte Apoptosis, and promoted the PPARα signaling pathway in ALF. PPARα agonists effectively reversed the effects of 1,5AG on ALF, thereby alleviating liver damage, pathological injury, and hepatocyte Apoptosis.

Conclusions: 1,5AG exacerbated liver injury in ALF mice by inhibiting the hepatic PPARα pathway, thereby promoting hepatocyte Apoptosis.

Keywords

1,5-anhydroglucitol; Acute liver failure; Empagliflozin; Peroxisome proliferator-activated receptor alpha; apoptosis; liver injury.

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