AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice
| Autor: | Lionel Carneiro, François R Jornayvaz, Christine Sempoux, Corinne Leloup, Jean-Christophe Stehle, Mohamed Asrih, Luc Pellerin, Cendrine Repond |
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| Přispěvatelé: | Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie, Diabétologie et Métabolisme, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Department of Physiology, Université de Lausanne (UNIL), Université Catholique de Louvain (UCL), Département de Physiologie, Pellerin, Luc, Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), Université Catholique de Louvain = Catholic University of Louvain (UCL), the 'Societe francophone du Diabete', the program IdEx Bordeaux ANR-10-IDEX-03-02, the Leenaards Foundation and the Raymond Berger Foundation, Lausanne., Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ), University of Lausanne, Université Catholique de Louvain ( UCL ), Université de Lausanne ( UNIL ) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine AMPK a.u.c Area Under the Curve Hepatic steatosis Haploinsufficiency FA Fatty Acids Mice 0302 clinical medicine AMP-Activated Protein Kinase Kinases NAFLD Non-Alcoholic Fatty Liver Disease S6K Ribosomal protein S6 kinase ddc:616 Symporters Diabetes Fatty liver foie Rd Glucose disappearance rate HFD High Fat Diet obésité Liver Endocrinologie et métabolisme Sterol Regulatory Element Binding Protein 1 LDHB Lactate DeHydrogenase isoform B diabète Monocarboxylic Acid Transporters PC Pyruvate Carboxylase medicine.medical_specialty lcsh:Internal medicine NASH Non-Alcoholic SteatoHepatitis kinase SREBP1 Sterol Regulatory Element Binding Protein 1 030209 endocrinology & metabolism Biology Brief Communication maladie 03 medical and health sciences Animals Fatty Liver/genetics Fatty Liver/metabolism Lactic Acid/metabolism Lipid Metabolism Liver/metabolism Monocarboxylic Acid Transporters/genetics Monocarboxylic Acid Transporters/metabolism Protein Kinases/metabolism Sterol Regulatory Element Binding Protein 1/metabolism Symporters/genetics Symporters/metabolism Lactate NAFLD Obesity stéatose hépatique Downregulation and upregulation SD Standard Diet [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology Internal medicine medicine TAG TriAcylGlycerides Lactic Acid lcsh:RC31-1245 résistance à l'insuline Molecular Biology HGP Hepatic Glucose Production liver nafld diabetes lactate insulin-resistance nonalcoholic steatohepatitis disease obesity ER Stress Endoplasmic Reticulum stress Endocrinology and metabolism GIR Glucose Infusion Rate Lipid metabolism Cell Biology Metabolism medicine.disease Sterol regulatory element-binding protein Fatty Liver AMPK AMP-activated protein kinase 030104 developmental biology Endocrinology MCT1 Monocarboxylate Transporter isoform 1 mTOR mammalian Target Of Rapamycin Steatosis ACC Acetyl-CoA Carboxylase Protein Kinases Drug metabolism [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ROS Reactive Oxygen Species LDHA Lactate DeHydrogenase isoform A |
| Zdroj: | Molecular metabolism, vol. 6, no. 12, pp. 1625-1633 Molecular Metabolism, Vol. 6, No 12 (2017) pp. 1625-1633 Molecular Metabolism, Vol 6, Iss 12, Pp 1625-1633 (2017) Molecular metabolism Molecular metabolism, Elsevier, 2017, 6 (12), pp.1625-1633. ⟨10.1016/j.molmet.2017.10.005⟩ Molecular Metabolism 12 (6), 1625-1633. (2017) Molecular metabolism, Elsevier, 2017, 6 (12), pp.1625-1633. 〈10.1016/j.molmet.2017.10.005〉 Molecular Metabolism |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2017.10.005⟩ |
| Popis: | Objective Hepatic steatosis is the first step leading to non-alcoholic fatty liver disease, which represents a major complication of obesity. Here, we show that MCT1 haploinsufficient mice resist to hepatic steatosis development when fed a high fat diet. They exhibit a reduced hepatic capacity to metabolize monocarboxylates such as lactate compared to wildtype mice. Methods To understand how this resistance to steatosis develops, we used HFD fed wildtype mice with hepatic steatosis and MCT1 haploinsufficient mice to study hepatic metabolism. Results AMPK is constitutively activated in the liver of MCT1 haploinsufficient mice, leading to an inactivation of SREBP1. Therefore, expression of key transcription factors for lipid metabolism, such as PPARα and γ, CHREB, or SREBP1 itself, as well as several enzymes including FAS and CPT1, was not upregulated in these mice when fed a high fat diet. It is proposed that reduced hepatic lactate metabolism is responsible for the protection against hepatic steatosis in MCT1 haploinsufficient mice via a constitutive activation of AMPK and repression of several major elements involved in hepatic lipid metabolism. Conclusion Our results support a role of increased lactate uptake in hepatocytes during HFD that, in turn, induce a metabolic shift stimulating SREBP1 activity and lipid accumulation. Highlights • Lactate uptake causes a shift in LDH isoform expression during HFD. • LDH isoform shift favors a decrease in AMPK activity. • Lactate uptake reduction in MCT1+/− mice blocks LDH isoform shift and leads to AMPK activation. • SREBP activation is prevented in MCT1+/− mice due to AMPK activation. • Decreased expression of SREBP targets involved in lipid metabolism protects against NAFLD. |
| Databáze: | OpenAIRE |
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