Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes
Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-03-01
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| Series: | EBioMedicine |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420300724 |
| _version_ | 1819162712800755712 |
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| author | Jèssica Latorre Francisco J. Ortega Laura Liñares-Pose José M. Moreno-Navarrete Aina Lluch Ferran Comas Núria Oliveras-Cañellas Wifredo Ricart Marcus Höring You Zhou Gerhard Liebisch P.A. Nidhina Haridas Vesa M. Olkkonen Miguel López José M. Fernández-Real |
| author_facet | Jèssica Latorre Francisco J. Ortega Laura Liñares-Pose José M. Moreno-Navarrete Aina Lluch Ferran Comas Núria Oliveras-Cañellas Wifredo Ricart Marcus Höring You Zhou Gerhard Liebisch P.A. Nidhina Haridas Vesa M. Olkkonen Miguel López José M. Fernández-Real |
| author_sort | Jèssica Latorre |
| collection | DOAJ |
| description | Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled β-oxidation, redirecting FA metabolism from energy storage to expenditure. Interpretation: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associació Catalana de Diabetis (ACD), Sociedad Española de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economía y Competitividad (MINECO), “La Caixa” Foundation, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Keywords: MicroRNAs, AMPK, Hepatocytes, Fatty acid homeostasis, Steatosis |
| first_indexed | 2024-12-22T17:32:36Z |
| format | Article |
| id | doaj.art-6aa13ae9f1304a82a59ada019901c3cd |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-22T17:32:36Z |
| publishDate | 2020-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-6aa13ae9f1304a82a59ada019901c3cd2022-12-21T18:18:35ZengElsevierEBioMedicine2352-39642020-03-0153Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytesJèssica Latorre0Francisco J. Ortega1Laura Liñares-Pose2José M. Moreno-Navarrete3Aina Lluch4Ferran Comas5Núria Oliveras-Cañellas6Wifredo Ricart7Marcus Höring8You Zhou9Gerhard Liebisch10P.A. Nidhina Haridas11Vesa M. Olkkonen12Miguel López13José M. Fernández-Real14Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, Spain; Address for correspondence: FJ. Ortega, PhD.; JM Fernández-Real, MD., PhD. Section of Diabetes, Endocrinology and Nutrition (UDEN), Institut d'Investigació Biomèdica de Girona (IDIBGI), and CIBEROBN, Hospital “Dr. Josep Trueta” of Girona, Spain.Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, SpainInstitute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, GermanySystems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United KingdomInstitute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, GermanyMinerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, FinlandMinerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, FinlandDepartment of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain; M López, PhD. Department of Physiology, CiMUS, Instituto de Investigación Sanitaria de Santiago de Compostela, and CIBEROBN, University of Santiago de Compostela, Spain.Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; CIBER de la Fisiología de la Obesidad y la Nutrición (CIBEROBN), Madrid, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, Spain; Address for correspondence: FJ. Ortega, PhD.; JM Fernández-Real, MD., PhD. Section of Diabetes, Endocrinology and Nutrition (UDEN), Institut d'Investigació Biomèdica de Girona (IDIBGI), and CIBEROBN, Hospital “Dr. Josep Trueta” of Girona, Spain.Background: While the impact of metformin in hepatocytes leads to fatty acid (FA) oxidation and decreased lipogenesis, hepatic microRNAs (miRNAs) have been associated with fat overload and impaired metabolism, contributing to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Methods: We investigated the expression of hundreds of miRNAs in primary hepatocytes challenged by compounds modulating steatosis, palmitic acid and compound C (as inducers), and metformin (as an inhibitor). Then, additional hepatocyte and rodent models were evaluated, together with transient mimic miRNAs transfection, lipid droplet staining, thin-layer chromatography, quantitative lipidomes, and mitochondrial activity, while human samples outlined the translational significance of this work. Findings: Our results show that treatments triggering fat accumulation and AMPK disruption may compromise the biosynthesis of hepatic miRNAs, while the knockdown of the miRNA-processing enzyme DICER in human hepatocytes exhibited increased lipid deposition. In this context, the ectopic recovery of miR-30b and miR-30c led to significant changes in genes related to FA metabolism, consistent reduction of ceramides, higher mitochondrial activity, and enabled β-oxidation, redirecting FA metabolism from energy storage to expenditure. Interpretation: Current findings unravel the biosynthesis of hepatic miR-30b and miR-30c in tackling inadequate FA accumulation, offering a potential avenue for the treatment of NAFLD. Funding: Instituto de Salud Carlos III (ISCIII), Govern de la Generalitat (PERIS2016), Associació Catalana de Diabetis (ACD), Sociedad Española de Diabetes (SED), Fondo Europeo de Desarrollo Regional (FEDER), Xunta de Galicia, Ministerio de Economía y Competitividad (MINECO), “La Caixa” Foundation, and CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN). Keywords: MicroRNAs, AMPK, Hepatocytes, Fatty acid homeostasis, Steatosishttp://www.sciencedirect.com/science/article/pii/S2352396420300724 |
| spellingShingle | Jèssica Latorre Francisco J. Ortega Laura Liñares-Pose José M. Moreno-Navarrete Aina Lluch Ferran Comas Núria Oliveras-Cañellas Wifredo Ricart Marcus Höring You Zhou Gerhard Liebisch P.A. Nidhina Haridas Vesa M. Olkkonen Miguel López José M. Fernández-Real Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes EBioMedicine |
| title | Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes |
| title_full | Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes |
| title_fullStr | Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes |
| title_full_unstemmed | Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes |
| title_short | Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes |
| title_sort | compounds that modulate ampk activity and hepatic steatosis impact the biosynthesis of micrornas required to maintain lipid homeostasis in hepatocytes |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420300724 |
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