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The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice

Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is unc...

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Autores principales: Gart, Eveline, Salic, Kanita, Morrison, Martine C., Giera, Martin, Attema, Joline, de Ruiter, Christa, Caspers, Martien, Schuren, Frank, Bobeldijk-Pastorova, Ivana, Heer, Marianne, Qin, Yan, Kleemann, Robert
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248376/
https://www.ncbi.nlm.nih.gov/pubmed/35782914
http://dx.doi.org/10.3389/fnut.2022.904740
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author Gart, Eveline
Salic, Kanita
Morrison, Martine C.
Giera, Martin
Attema, Joline
de Ruiter, Christa
Caspers, Martien
Schuren, Frank
Bobeldijk-Pastorova, Ivana
Heer, Marianne
Qin, Yan
Kleemann, Robert
author_facet Gart, Eveline
Salic, Kanita
Morrison, Martine C.
Giera, Martin
Attema, Joline
de Ruiter, Christa
Caspers, Martien
Schuren, Frank
Bobeldijk-Pastorova, Ivana
Heer, Marianne
Qin, Yan
Kleemann, Robert
author_sort Gart, Eveline
collection PubMed
description Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2′-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2′-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2′-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2′-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2′-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2′-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2′-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2′-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2′-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2′-fucosyllactose to correct dysmetabolism and insulin resistance.
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spelling pubmed-92483762022-07-02 The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice Gart, Eveline Salic, Kanita Morrison, Martine C. Giera, Martin Attema, Joline de Ruiter, Christa Caspers, Martien Schuren, Frank Bobeldijk-Pastorova, Ivana Heer, Marianne Qin, Yan Kleemann, Robert Front Nutr Nutrition Non-alcoholic fatty liver disease (NAFLD) is a complex multifactorial disorder that is associated with gut dysbiosis, enhanced gut permeability, adiposity and insulin resistance. Prebiotics such as human milk oligosaccharide 2′-fucosyllactose are thought to primarily improve gut health and it is uncertain whether they would affect more distant organs. This study investigates whether 2′-fucosyllactose can alleviate NAFLD development in manifest obesity. Obese hyperinsulinemic Ldlr-/-.Leiden mice, after an 8 week run-in on a high-fat diet (HFD), were treated with 2′-fucosyllactose by oral gavage until week 28 and compared to HFD-vehicle controls. 2′-fucosyllactose did not affect food intake, body weight, total fat mass or plasma lipids. 2′-fucosyllactose altered the fecal microbiota composition which was paralleled by a suppression of HFD-induced gut permeability at t = 12 weeks. 2′-fucosyllactose significantly attenuated the development of NAFLD by reducing microvesicular steatosis. These hepatoprotective effects were supported by upstream regulator analyses showing that 2′-fucosyllactose activated ACOX1 (involved in lipid catabolism), while deactivating SREBF1 (involved in lipogenesis). Furthermore, 2′-fucosyllactose suppressed ATF4, ATF6, ERN1, and NUPR1 all of which participate in endoplasmic reticulum stress. 2′-fucosyllactose reduced fasting insulin concentrations and HOMA-IR, which was corroborated by decreased intrahepatic diacylglycerols. In conclusion, long-term supplementation with 2′-fucosyllactose can counteract the detrimental effects of HFD on gut dysbiosis and gut permeability and attenuates the development of liver steatosis. The observed reduction in intrahepatic diacylglycerols provides a mechanistic rationale for the improvement of hyperinsulinemia and supports the use of 2′-fucosyllactose to correct dysmetabolism and insulin resistance. Frontiers Media S.A. 2022-06-17 /pmc/articles/PMC9248376/ /pubmed/35782914 http://dx.doi.org/10.3389/fnut.2022.904740 Text en Copyright © 2022 Gart, Salic, Morrison, Giera, Attema, de Ruiter, Caspers, Schuren, Bobeldijk-Pastorova, Heer, Qin and Kleemann. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Nutrition
Gart, Eveline
Salic, Kanita
Morrison, Martine C.
Giera, Martin
Attema, Joline
de Ruiter, Christa
Caspers, Martien
Schuren, Frank
Bobeldijk-Pastorova, Ivana
Heer, Marianne
Qin, Yan
Kleemann, Robert
The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title_full The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title_fullStr The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title_full_unstemmed The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title_short The Human Milk Oligosaccharide 2′-Fucosyllactose Alleviates Liver Steatosis, ER Stress and Insulin Resistance by Reducing Hepatic Diacylglycerols and Improved Gut Permeability in Obese Ldlr-/-.Leiden Mice
title_sort human milk oligosaccharide 2′-fucosyllactose alleviates liver steatosis, er stress and insulin resistance by reducing hepatic diacylglycerols and improved gut permeability in obese ldlr-/-.leiden mice
topic Nutrition
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9248376/
https://www.ncbi.nlm.nih.gov/pubmed/35782914
http://dx.doi.org/10.3389/fnut.2022.904740
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