A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers
Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human he...
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MDPI AG
2022-05-01
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| Series: | Nutrients |
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| Online Access: | https://www.mdpi.com/2072-6643/14/9/1961 |
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| author | Erik Elebring Ville Wallenius Anna Casselbrant Neil G. Docherty Carel W. le Roux Hanns-Ulrich Marschall Lars Fändriks |
| author_facet | Erik Elebring Ville Wallenius Anna Casselbrant Neil G. Docherty Carel W. le Roux Hanns-Ulrich Marschall Lars Fändriks |
| author_sort | Erik Elebring |
| collection | DOAJ |
| description | Background and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853). |
| first_indexed | 2024-03-10T03:48:46Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6643 |
| language | English |
| last_indexed | 2024-03-10T03:48:46Z |
| publishDate | 2022-05-01 |
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| record_format | Article |
| series | Nutrients |
| spelling | doaj.art-67affa1ba5274b579f948225eda3e8652023-11-23T09:01:00ZengMDPI AGNutrients2072-66432022-05-01149196110.3390/nu14091961A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy VolunteersErik Elebring0Ville Wallenius1Anna Casselbrant2Neil G. Docherty3Carel W. le Roux4Hanns-Ulrich Marschall5Lars Fändriks6Institute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, SwedenInstitute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, SwedenInstitute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, SwedenMetabolic Medicine, School of Medicine, Conway Institute, University College Dublin, D04 V1W8 Dublin, IrelandMetabolic Medicine, School of Medicine, Conway Institute, University College Dublin, D04 V1W8 Dublin, IrelandInstitute of Medicine, Department of Molecular and Clinical Medicine, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, SwedenInstitute of Clinical Sciences, Department of Surgery, Sahlgrenska Academy, University of Gothenburg, SE41345 Gothenburg, SwedenBackground and aims: Insights into the nature of gut adaptation after different diets enhance the understanding of how food modifications can be used to treat type 2 diabetes and obesity. The aim was to understand how diets, enriched in fat or carbohydrates, affect glucose absorption in the human healthy jejunum, and what mechanisms are involved. Methods: Fifteen healthy subjects received, in randomised order and a crossover study design, two weeks of iso-caloric high-fat diet (HFD) and high-carbohydrate diet (HCD). Following each dietary period, jejunal mucosa samples were retrieved and assessed for protein expression using immunofluorescence and western blotting. Functional characterisation of epithelial glucose transport was assessed ex vivo using Ussing chambers. Regulation of SGLT1 through histone acetylation was studied in vitro in Caco-2 and human jejunal enteroid monolayer cultures. Results: HFD, compared to HCD, decreased jejunal Ussing chamber epithelial glucose transport and the expression of apical transporters for glucose (SGLT1) and fructose (GLUT5), while expression of the basolateral glucose transporter GLUT2 was increased. HFD also increased protein expression of the ketogenesis rate-limiting enzyme mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase (HMGCS2) and decreased the acetylation of histone 3 at lysine 9 (H3K9ac). Studies in Caco-2 and human jejunal enteroid monolayer cultures indicated a ketogenesis-induced activation of sirtuins, in turn decreasing SGLT1 expression. Conclusion: Jejunal glucose absorption is decreased by a fat-enriched diet, via a ketogenesis-induced alteration of histone acetylation responsible for the silencing of SGLT1 transcription. The work relates to a secondary outcome in ClinicalTrials.gov (NCT02088853).https://www.mdpi.com/2072-6643/14/9/1961jejunummucosamonosaccharideshistone acetylation |
| spellingShingle | Erik Elebring Ville Wallenius Anna Casselbrant Neil G. Docherty Carel W. le Roux Hanns-Ulrich Marschall Lars Fändriks A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers Nutrients jejunum mucosa monosaccharides histone acetylation |
| title | A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers |
| title_full | A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers |
| title_fullStr | A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers |
| title_full_unstemmed | A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers |
| title_short | A Fatty Diet Induces a Jejunal Ketogenesis Which Inhibits Local SGLT1-Based Glucose Transport via an Acetylation Mechanism—Results from a Randomized Cross-Over Study between Iso-Caloric High-Fat versus High-Carbohydrate Diets in Healthy Volunteers |
| title_sort | fatty diet induces a jejunal ketogenesis which inhibits local sglt1 based glucose transport via an acetylation mechanism results from a randomized cross over study between iso caloric high fat versus high carbohydrate diets in healthy volunteers |
| topic | jejunum mucosa monosaccharides histone acetylation |
| url | https://www.mdpi.com/2072-6643/14/9/1961 |
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