Scholarlink

<p>Over the past three decades, the global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly increased, leading to significant economic and clinical burdens. However, aside from resmetirom (Rezdiffra™), an oral thyroid hormone receptor-β agonist, there remains a lack of approved targeted pharmacological treatments for MASLD, emphasizing the need for more optimized therapeutic strategies. Given the limitations in the safety and efficacy of the ketogenic diet, β-hydroxybutyrate (β-OHB) has emerged as a crucial regulator in MASLD treatment, but the precise mechanisms underlying its therapeutic effects remain unclear. This study aims to investigate the therapeutic effects of β-OHB on MASLD mice and elucidate the underlying mechanisms. In this study, we demonstrate that β-OHB ameliorates lipid deposition and increases pan-β-hydroxybutyrylation (Kbhb) levels in both MASLD mice and in vitro. Additionally, β-OHB also improves excessive ROS accumulation and enhances mitochondrial respiratory capacity. Furthermore, β-OHB protects against impaired fatty acid oxidation (FAO) activity in MASLD. Proteomic analysis of β-OHB-treated mice identified a significant Kbhb modification at K239 on malate dehydrogenase 2 (MDH2), which was associated with increased MDH2 enzymatic activity. Overall, this study demonstrates β-OHB exhibits therapeutic effects on hepatic steatosis and mitochondrial dysfunction in MASLD mice. We uncover a novel mechanism where β-OHB enhances MDH2 enzymatic activity through Kbhb modification at K239, thereby maintaining mitochondrial homeostasis and alleviating lipid deposition.</p> Graphical abstract <p></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 enhances malate dehydrogenase 2 β-hydroxybutyrylation to alleviate hepatic steatosis in MASLD

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年10月24日

查看全文
  • Jingshu Cai,
  • Wenxuan Li,
  • Chunli Wu,
  • Hongbin Ni,
  • Haiying Ran,
  • Yi Huang,
  • Xiufang Tang,
  • Wenjun He,
  • Yuanfeng Gu,
  • Yuehua You,
  • Jiayu Li,
  • Xiaoqiu Xiao,
  • Li Ma

摘要

Over the past three decades, the global prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) has rapidly increased, leading to significant economic and clinical burdens. However, aside from resmetirom (Rezdiffra™), an oral thyroid hormone receptor-β agonist, there remains a lack of approved targeted pharmacological treatments for MASLD, emphasizing the need for more optimized therapeutic strategies. Given the limitations in the safety and efficacy of the ketogenic diet, β-hydroxybutyrate (β-OHB) has emerged as a crucial regulator in MASLD treatment, but the precise mechanisms underlying its therapeutic effects remain unclear. This study aims to investigate the therapeutic effects of β-OHB on MASLD mice and elucidate the underlying mechanisms. In this study, we demonstrate that β-OHB ameliorates lipid deposition and increases pan-β-hydroxybutyrylation (Kbhb) levels in both MASLD mice and in vitro. Additionally, β-OHB also improves excessive ROS accumulation and enhances mitochondrial respiratory capacity. Furthermore, β-OHB protects against impaired fatty acid oxidation (FAO) activity in MASLD. Proteomic analysis of β-OHB-treated mice identified a significant Kbhb modification at K239 on malate dehydrogenase 2 (MDH2), which was associated with increased MDH2 enzymatic activity. Overall, this study demonstrates β-OHB exhibits therapeutic effects on hepatic steatosis and mitochondrial dysfunction in MASLD mice. We uncover a novel mechanism where β-OHB enhances MDH2 enzymatic activity through Kbhb modification at K239, thereby maintaining mitochondrial homeostasis and alleviating lipid deposition.

Graphical abstract