Section snippets

Background and context

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects up to one-third of the global population, yet effective therapeutic options remain limited.¹ This unmet clinical need has driven significant interest in the development of pharmacological therapies for MASLD, including small-molecule inhibitors targeting acetyl-CoA carboxylase (ACC). These inhibitors have demonstrated potential in preclinical studies by reducing hepatic lipid accumulation and fibrosis.^2,3ACC, a key enzyme

Objectives, methods, and findings

Deja et al. hypothesized that malonyl-CoA may have broader metabolic roles beyond its established functions in fatty acid synthesis and oxidation. Specifically, they proposed that it may regulate gluconeogenesis by influencing metabolic substrates and enzymatic pathways. Using liver-specific genetic and pharmacological approaches, combined with targeted metabolomics and stable isotope tracing, the authors systematically explored the effects of ACC1/2 inhibition on hepatic metabolism.Their

Significance of findings

Taken together, the findings by Deja et al. provide critical new insights into the multifaceted roles of ACC inhibition in hepatic metabolism. Beyond its established effects on DNL and β-oxidation, the authors clearly demonstrated that ACC also acts as a key regulator of gluconeogenesis, mediating its effects via acetyl-CoA activation of pyruvate carboxylase and increased availability of gluconeogenic substrates through intrahepatic proteolysis.This study raises several important questions for

Financial support

Dr. Luukkonen was supported by the Academy of Finland (350545), the Sigrid Jusélius Foundation, the Novo Nordisk Foundation (NNF22OC0074397), the Emil Aaltonen Foundation, the Finnish Medical Foundation, the Wilhelm and Else Stockmann's Foundation and the Early Career Investigator fund of the University of Helsinki.

Declaration of AI-assisted technologies in the writing process

During the preparation of this work the author used ChatGPT in order to proofread the manuscript. After using this tool, the author reviewed and edited the content as needed and takes full responsibility for the content of the publication.

Conflict of interest

The author has served as a consultant for AstraZeneca, Boehringer Ingelheim and Bluejay Therapeutics. He is on the speakers' bureau for Novartis, Johnson & Johnson and Sandoz.Please refer to the accompanying ICMJE disclosure forms for further details.

中文翻译：

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乙酰辅酶 A 羧化酶抑制的隐藏代谢效应

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 背景和背景

代谢功能障碍相关脂肪性肝病 （MASLD） 影响了全球多达三分之一的人口，但有效的治疗选择仍然有限。 ¹ 这种未满足的临床需求推动了人们对 MASLD 药物治疗开发的浓厚兴趣，包括靶向乙酰辅酶 A 羧化酶 （ACC） 的小分子抑制剂。这些抑制剂在临床前研究中通过减少肝脏脂质积累和纤维化显示出潜力。 ^{2 3} ACC，一种关键酶

研究目的、方法和发现

Deja 等人假设丙二酰辅酶 A 可能具有更广泛的代谢作用，超出了其在脂肪酸合成和氧化中的既定功能。具体来说，他们提出它可能通过影响代谢底物和酶途径来调节糖异生。利用肝脏特异性遗传学和药理学方法，结合靶向代谢组学和稳定同位素示踪，作者系统探讨了 ACC1/2 抑制对肝脏代谢的影响。他们

 检查结果的意义

综上所述，Deja 等人的发现为 ACC 抑制在肝脏代谢中的多方面作用提供了重要的新见解。除了对 DNL 和 β-氧化的既定影响外，作者还清楚地证明 ACC 还充当糖异生的关键调节因子，通过丙酮酸羧化酶的乙酰辅酶 A 激活和通过肝内蛋白水解增加糖异生底物的可用性来介导其作用。本研究提出了几个重要问题

 财务支持

Luukkonen 博士得到了芬兰科学院 （350545）、Sigrid Jusélius 基金会、诺和诺德基金会 （NNF22OC0074397）、Emil Aaltonen 基金会、芬兰医学基金会、Wilhelm 和 Else Stockmann 基金会以及赫尔辛基大学早期职业研究员基金的支持。

写作过程中 AI 辅助技术的宣言

在准备这项工作的过程中，作者使用 ChatGPT 来校对手稿。使用此工具后，作者根据需要审查和编辑了内容，并对出版物的内容承担全部责任。

 利益冲突

作者曾担任阿斯利康、勃林格殷格翰和 Bluejay Therapeutics 的顾问。他是诺华、强生和山德士的发言人办公室的成员。 请参考随附的ICMJE披露表格以获取更多详细信息。