AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice
| العنوان: | AMPK activation caused by reduced liver lactate metabolism protects against hepatic steatosis in MCT1 haploinsufficient mice |
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| المؤلفون: | Lionel Carneiro, François R Jornayvaz, Christine Sempoux, Corinne Leloup, Jean-Christophe Stehle, Mohamed Asrih, Luc Pellerin, Cendrine Repond |
| المساهمون: | 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 ) |
| المصدر: | 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 |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 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 |
| الوصف: | 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. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2212-8778 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::845a9eee5fd517d81211c0a9c97bf132Test https://serval.unil.ch/notice/serval:BIB_1E26E53BF1FETest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....845a9eee5fd517d81211c0a9c97bf132 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22128778 |
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