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1,5-Anhydroglucitol Aggravates Acute Liver Failure via the PPARα Signaling Pathway.
Lingjian Zhang1,2, Yaqi Zhang1, Yalei Zhao3
1State 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.
Journal of Clinical and Translational Hepatology
|April 13, 2026
Summary
1,5-anhydroglucitol (1,5AG) worsens acute liver failure (ALF) by inhibiting the PPARα pathway, increasing liver injury and apoptosis. Reducing 1,5AG levels alleviates ALF in mice.
Area of Science:
- Hepatology
- Biochemistry
- Molecular Biology
Background:
- Acute liver failure (ALF) presents a significant clinical challenge with high mortality rates.
- Previous research indicated a correlation between 1,5-anhydroglucitol (1,5AG) levels and patient outcomes in liver failure.
- The specific role and underlying mechanisms of 1,5AG in ALF remained to be elucidated.
Purpose of the Study:
- To investigate the effects of 1,5-anhydroglucitol (1,5AG) on acute liver failure (ALF) in an experimental setting.
- To explore the molecular mechanisms by which 1,5AG influences liver injury and hepatocyte apoptosis in ALF.
- To assess the therapeutic potential of modulating 1,5AG levels in ALF.
Main Methods:
- An experimental model of ALF was induced in mice using lipopolysaccharide (LPS) and D-galactosamine (D-GalN).
- 1,5-anhydroglucitol (1,5AG) was administered via gavage prior to ALF induction.
- Pharmacological interventions included empagliflozin to lower 1,5AG levels and peroxisome proliferator-activated receptor alpha (PPARα) agonists to investigate pathway involvement.
Main Results:
- 1,5AG administration exacerbated liver injury, evidenced by increased ALT and AST levels, heightened histological damage, and elevated hepatocyte apoptosis and mortality.
- Transcriptomic and Western blot analyses revealed that 1,5AG significantly inhibited the hepatic PPARα signaling pathway and its downstream target, FGF21.
- Empagliflozin treatment ameliorated liver injury and apoptosis by reducing 1,5AG levels and promoting the PPARα pathway, while PPARα agonists reversed the detrimental effects of 1,5AG.
Conclusions:
- 1,5-anhydroglucitol (1,5AG) exacerbates liver injury in acute liver failure (ALF) mouse models.
- The mechanism involves the inhibition of the hepatic PPARα signaling pathway, leading to increased hepatocyte apoptosis.
- Modulating 1,5AG levels and activating the PPARα pathway represent potential therapeutic strategies for ALF.
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