Scholarlink

Background <p>Metabolic dysfunction-associated steatotic liver disease (MASLD) stands as the most widespread chronic liver disorder globally. Histone β-hydroxybutyrylation (Kbhb)—a novel post-translational modification of histones driven by β-hydroxybutyrate (BHB)—has recently been recognized as a key epigenetic modulator. Our study aimed to explore how BHB influences the expression of hepatic lipid metabolism-associated genes in MASLD, and to determine whether histone Kbhb acts as the mechanistic mediator underlying these effects.</p> Methods <p>For in vivo experiments, db/db mice fed a high-fat diet were utilized as the MASLD model. Following BHB intervention, changes in glycolipid metabolism and lipid accumulation in liver were assessed. Hepatic expression of lipid oxidation-related genes (e.g., <i>PPARα</i>) was quantified via qPCR; hepatic Pan-Kbhb and H3K9bhb levels were detected using immunohistochemistry and immunofluorescence. For in vitro experiments, a palmitic acid (PA)-induced AML12 hepatocyte model was established. After BHB treatment, intracellular lipid accumulation was visualized via Oil Red O and BODIPY staining; PPARα and downstream lipid oxidation gene expression was measured by qPCR and Western blotting. Total protein and histone Kbhb were evaluated using immunofluorescence and Western blotting.</p> Results <p>BHB effectively mitigated lipid accumulation in the livers of db/db mice and PA-induced AML12 cells, while upregulating PPARα and its downstream lipid oxidation-related target genes. Simultaneously, BHB elevated total protein Kbhb and histone H3K9bhb modifications in hepatic cells. Critically, blocking Kbhb (via A485, an inhibitor of the acyltransferase P300, or an acyl-CoA synthetase 2 inhibitor) led to significant downregulation of PPARα and its target gene expression.</p> Conclusion <p>BHB alleviates lipid accumulation in the liver of MASLD by promoting the expression of PPARα and its downstream lipid oxidation-related genes in the hepatocytes, which is associated with histone Kbhb modification.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

β-Hydroxybutyrate upregulates hepatic histone β-hydroxybutyrylation modification, promotes the expression of PPARα, and alleviates the hepatic steatosis in MASLD

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年3月22日

查看全文
  • Dongze Li,
  • Li Zhang,
  • Yanqun Li,
  • Jidi Wu,
  • Yulin Mou,
  • Yanqiu He,
  • Tingting Zhou,
  • Qiming Gong,
  • Linqiang Ma,
  • Yong Xu,
  • Wei Huang,
  • Chenlin Gao

摘要

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) stands as the most widespread chronic liver disorder globally. Histone β-hydroxybutyrylation (Kbhb)—a novel post-translational modification of histones driven by β-hydroxybutyrate (BHB)—has recently been recognized as a key epigenetic modulator. Our study aimed to explore how BHB influences the expression of hepatic lipid metabolism-associated genes in MASLD, and to determine whether histone Kbhb acts as the mechanistic mediator underlying these effects.

Methods

For in vivo experiments, db/db mice fed a high-fat diet were utilized as the MASLD model. Following BHB intervention, changes in glycolipid metabolism and lipid accumulation in liver were assessed. Hepatic expression of lipid oxidation-related genes (e.g., PPARα) was quantified via qPCR; hepatic Pan-Kbhb and H3K9bhb levels were detected using immunohistochemistry and immunofluorescence. For in vitro experiments, a palmitic acid (PA)-induced AML12 hepatocyte model was established. After BHB treatment, intracellular lipid accumulation was visualized via Oil Red O and BODIPY staining; PPARα and downstream lipid oxidation gene expression was measured by qPCR and Western blotting. Total protein and histone Kbhb were evaluated using immunofluorescence and Western blotting.

Results

BHB effectively mitigated lipid accumulation in the livers of db/db mice and PA-induced AML12 cells, while upregulating PPARα and its downstream lipid oxidation-related target genes. Simultaneously, BHB elevated total protein Kbhb and histone H3K9bhb modifications in hepatic cells. Critically, blocking Kbhb (via A485, an inhibitor of the acyltransferase P300, or an acyl-CoA synthetase 2 inhibitor) led to significant downregulation of PPARα and its target gene expression.

Conclusion

BHB alleviates lipid accumulation in the liver of MASLD by promoting the expression of PPARα and its downstream lipid oxidation-related genes in the hepatocytes, which is associated with histone Kbhb modification.