Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet
Journal article, 2025

Objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

de novo lipogenesis

Gut microbiota

SREBP-1c

High-sucrose diet

Hepatic steatosis

Zero-fat diet

Metabolomics

Author

Mattias Bergentall

University of Gothenburg

Valentina Tremaroli

University of Gothenburg

Chuqing Sun

University of Gothenburg

Marcus Henricsson

University of Gothenburg

Muhammad Tanweer Khan

University of Gothenburg

Lisa Olsson

University of Gothenburg

Per-Olof Bergh

University of Gothenburg

Chalmers, Life Sciences, Systems and Synthetic Biology

Antonio Molinaro

University of Gothenburg

Adil Mardinoglu

King's College London

Royal Institute of Technology (KTH)

Robert Caesar

University of Gothenburg

Max Nieuwdorp

University of Amsterdam

Fredrik Backhed

University of Gothenburg

Molecular Metabolism

2212-8778 (ISSN)

Vol. 97 102162

Subject Categories (SSIF 2025)

Molecular Biology

Endocrinology and Diabetes

DOI

10.1016/j.molmet.2025.102162

PubMed

40345386

More information

Latest update

6/5/2025 1