Bergentall Mattias, Tremaroli Valentina, Sun Chuqing, Henricsson Marcus, Khan Muhammad Tanweer, Mannerås Holm Louise, Olsson Lisa, Bergh Per-Olof, Molinaro Antonio, Mardinoglu Adil, Caesar Robert, Nieuwdorp Max, Bäckhed Fredrik
Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden.
Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK.
Mol Metab. 2025 Jul;97:102162. doi: 10.1016/j.molmet.2025.102162. Epub 2025 May 7.
Sucrose-rich diets promote hepatic de novo lipogenesis (DNL) and steatosis through interactions with the gut microbiota. However, the role of sugar-microbiota dynamics in the absence of dietary fat remains unclear. This study aimed to investigate the effects of a high-sucrose, zero-fat diet (ZFD) on hepatic steatosis and host metabolism in conventionally raised (CONVR) and germ-free (GF) mice.
CONVR and GF mice were fed a ZFD, and hepatic lipid accumulation, gene expression, and metabolite levels were analyzed. DNL activity was assessed by measuring malonyl-CoA levels, expression of key DNL enzymes, and activation of the transcription factor SREBP-1c. Metabolomic analyses of portal vein plasma identified microbiota-derived metabolites linked to hepatic steatosis. To further examine the role of SREBP-1c, its hepatic expression was knocked down using antisense oligonucleotides in CONVR ZFD-fed mice.
The gut microbiota was essential for sucrose-induced DNL and hepatic steatosis. In CONVR ZFD-fed mice, hepatic fat accumulation increased alongside elevated expression of genes encoding DNL enzymes, higher malonyl-CoA levels, and upregulation of SREBP-1c. Regardless of microbiota status, ZFD induced fatty acid elongase and desaturase gene expression and increased hepatic monounsaturated fatty acids. Metabolomic analyses identified microbiota-derived metabolites associated with hepatic steatosis. SREBP-1c knockdown in CONVR ZFD-fed mice reduced hepatic steatosis and suppressed fatty acid synthase expression.
Sucrose-microbiota interactions and SREBP-1c are required for DNL and hepatic steatosis in the absence of dietary fat. These findings provide new insights into the complex interplay between diet, gut microbiota, and metabolic regulation.
富含蔗糖的饮食通过与肠道微生物群相互作用促进肝脏从头脂肪生成（DNL）和脂肪变性。然而，在无膳食脂肪情况下糖-微生物群动态变化的作用仍不清楚。本研究旨在调查高蔗糖、零脂肪饮食（ZFD）对常规饲养（CONVR）和无菌（GF）小鼠肝脏脂肪变性及宿主代谢的影响。
给CONVR和GF小鼠喂食ZFD，分析肝脏脂质积累、基因表达和代谢物水平。通过测量丙二酰辅酶A水平、关键DNL酶的表达以及转录因子SREBP-1c的激活来评估DNL活性。对门静脉血浆进行代谢组学分析，确定与肝脏脂肪变性相关的微生物群衍生代谢物。为进一步研究SREBP-1c的作用，在喂食ZFD的CONVR小鼠中使用反义寡核苷酸敲低其肝脏表达。
肠道微生物群对于蔗糖诱导的DNL和肝脏脂肪变性至关重要。在喂食ZFD的CONVR小鼠中，肝脏脂肪积累增加，同时编码DNL酶的基因表达升高、丙二酰辅酶A水平升高以及SREBP-1c上调。无论微生物群状态如何，ZFD均可诱导脂肪酸延长酶和去饱和酶基因表达，并增加肝脏单不饱和脂肪酸。代谢组学分析确定了与肝脏脂肪变性相关的微生物群衍生代谢物。在喂食ZFD的CONVR小鼠中敲低SREBP-1c可减轻肝脏脂肪变性并抑制脂肪酸合酶表达。
在无膳食脂肪的情况下，蔗糖-微生物群相互作用和SREBP-1c是DNL和肝脏脂肪变性所必需的。这些发现为饮食、肠道微生物群和代谢调节之间的复杂相互作用提供了新见解。
