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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Elsevier
2025-07-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877825000699 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Mattias Bergentall |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-de9f5e1747ce4b86a73821fff4aeb83f |
| institution | DOAJ |
| issn | 2212-8778 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj-art-de9f5e1747ce4b86a73821fff4aeb83f2025-08-20T03:10:31ZengElsevierMolecular Metabolism2212-87782025-07-019710216210.1016/j.molmet.2025.102162Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose dietMattias Bergentall0Valentina Tremaroli1Chuqing Sun2Marcus Henricsson3Muhammad Tanweer Khan4Louise Mannerås Holm5Lisa Olsson6Per-Olof Bergh7Antonio Molinaro8Adil Mardinoglu9Robert Caesar10Max Nieuwdorp11Fredrik Bäckhed12Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, SwedenScience 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, UKWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden; Corresponding author.Department of (Experimental) Vascular Medicine, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the NetherlandsWallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden; Department of Clinical Physiology Region Västra Götaland, Sahlgrenska University Hospital Gothenburg Sweden, Sweden; Corresponding author. Wallenberg Laboratory, Department of Molecular and Clinical Medicine and Sahlgrenska Center for Cardiovascular and Metabolic Research, University of Gothenburg, Gothenburg, SE-413 45, Sweden.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.http://www.sciencedirect.com/science/article/pii/S2212877825000699de novo lipogenesisGut microbiotaHepatic steatosisHigh-sucrose dietMetabolomicsSREBP-1c |
| spellingShingle | 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 Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet Molecular Metabolism de novo lipogenesis Gut microbiota Hepatic steatosis High-sucrose diet Metabolomics SREBP-1c |
| title | Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet |
| title_full | Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet |
| title_fullStr | Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet |
| title_full_unstemmed | Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet |
| title_short | Gut microbiota mediates SREBP-1c-driven hepatic lipogenesis and steatosis in response to zero-fat high-sucrose diet |
| title_sort | gut microbiota mediates srebp 1c driven hepatic lipogenesis and steatosis in response to zero fat high sucrose diet |
| topic | de novo lipogenesis Gut microbiota Hepatic steatosis High-sucrose diet Metabolomics SREBP-1c |
| url | http://www.sciencedirect.com/science/article/pii/S2212877825000699 |
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