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

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

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 d...

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Main Authors: Mattias Bergentall, Valentina Tremaroli, Chuqing Sun, Marcus Henricsson, Muhammad Tanweer Khan, Louise Mannerås Holm, Lisa Olsson, Per-Olof Bergh, Antonio Molinaro, Adil Mardinoglu, Robert Caesar, Max Nieuwdorp, Fredrik Bäckhed
Format: Article
Language:English
Published: Elsevier 2025-07-01
Series:Molecular Metabolism
Subjects:
de novo lipogenesis
Gut microbiota
Hepatic steatosis
High-sucrose diet
Metabolomics
SREBP-1c
Online Access:http://www.sciencedirect.com/science/article/pii/S2212877825000699
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Summary: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.
ISSN:2212-8778

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