Compounds that modulate AMPK activity and hepatic steatosis impact the biosynthesis of microRNAs required to maintain lipid homeostasis in hepatocytes
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
Affiliations
Jèssica Latorre
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
Francisco J. Ortega
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.
Laura Liñares-Pose
Department of Physiology, CiMUS, University of Santiago de Compostela, Instituto de Investigación Sanitaria, Santiago de Compostela, Spain
José M. Moreno-Navarrete
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
Aina Lluch
Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, Spain
Ferran Comas
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
Núria Oliveras-Cañellas
Institut d'Investigació Biomèdica de Girona (IDIBGI), Girona, Spain; Department of Diabetes, Endocrinology and Nutrition (UDEN), Hospital of Girona “Dr Josep Trueta”, Girona, Spain
Wifredo Ricart
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
Marcus Höring
Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
You Zhou
Systems Immunity Research Institute, Cardiff University, Cardiff, United Kingdom; Division of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom
Gerhard Liebisch
Institute of Clinical Chemistry and Laboratory Medicine, Regensburg University Hospital, Regensburg, Germany
P.A. Nidhina Haridas
Minerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, Finland
Vesa M. Olkkonen
Minerva Foundation Institute for Medical Research, Biomedicum 2 U, Helsinki, Finland; Department of Anatomy, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Miguel López
Department 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.
José M. Fernández-Real
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, Steatosis
