β-hydroxybutyrate inhibits ferroptosis-mediated pancreatic damage in acute liver failure through the increase of H3K9bhb

Cell Reports(2022)

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摘要
Acute pancreatitis and hyperamylasemia are often seen in patients with acute liver failure (ALF). However, the underlying mechanisms remain elusive. This study describes pancreatic tissue damage and exocrine dysfunction in a mouse model of major-liver-resection-induced ALF. The analysis of 1,264 clinical cases of liver failure (LF) showed that the incidence of hyperamylasemia and hyperlipasemia in patients with LF is 5.5% and 20%, respectively. Metabolomic studies indicate that glutathione (GSH)-deficiency-caused ferroptosis contributes to pancreatic damage in mouse ALF. β-hydroxybutyrate (β-HB) is the only metabolite downregulated in the liver, serum, and pancreas. Our data suggest that β-HB protects pancreatic cells and tissues from GSH-deficiency-caused ferroptosis. β-HB administration in ALF mice restores the expression of ferroptosis-suppressor genes through histone H3 lysine 9 β-hydroxybutyrylation (H3K9bhb)-mediated chromatin opening. Our findings highlight β-HB as an endogenous metabolite regulating ferroptosis in the pancreas and extend our understanding of the pathophysiology of ALF-induced pancreatitis.
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acute liver failure,pancreatitic damage,ferroptosis,β-hydroxybutyrate,β-hydroxybutyrylation,H3K9bhb,epigenetic regulation,chromatin opening
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