Inhibition of citrate cotransporter Slc13a5/mINDY by RNAi improves hepatic insulin sensitivity and prevents diet-induced non-alcoholic fatty liver disease in mice
| Autor: | Hartmut Ruetten, Sebastian Brachs, Dieter Schmoll, Bodo Brunner, Joachim Spranger, Angelika F. Winkel, Kerstin Jahn-Hofmann, Andreas L. Birkenfeld, Hui Tang, Daniel Margerie |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
HFD high-fat diet Steatosis p perirenal Lipid accumulation White adipose tissue SKM skeletal muscle 600 Technik Medizin angewandte Wissenschaften::610 Medizin und Gesundheit WD western diet chemistry.chemical_compound EGP endogenous glucose production GIR glucose infusion rate Mice INDY/Slc13a5 Non-alcoholic Fatty Liver Disease Citrate transport IEX anion-exchange high-performance liquid chromatography Citrates 2-DG 2-Deoxy-d-glucose RER respiratory exchange ratio Dicarboxylic Acid Transporters mINDY Slc13a5/SLC13A5 Symporters Fatty liver WAT white adipose tissue siINDY mINDY-specific siRNA Original Article RNA Interference e epididymal medicine.medical_specialty lcsh:Internal medicine TCA tricarboxylic acid Biology INDY ‘I'm not dead Yet’ Citric Acid 03 medical and health sciences SCR non-silencing scrambled control siRNA Insulin resistance s subcutaneous FLD fatty liver disease Internal medicine medicine Animals lcsh:RC31-1245 Molecular Biology KO knockout Triglyceride solute carrier family 13 member 5 EE energy expenditure Lipid metabolism Cell Biology HE clamp hyperinsulinemic-euglycemic clamp medicine.disease Lipid Metabolism Diet Mice Inbred C57BL 030104 developmental biology Endocrinology chemistry FA fatty acids siRNA ORO oil red O 2-Deoxy-D-glucose T2D type-2 diabetes |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 5, Iss 11, Pp 1072-1082 (2016) |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2016.08.004 |
| Popis: | Objective Non-alcoholic fatty liver disease is a world-wide health concern and risk factor for cardio-metabolic diseases. Citrate uptake modifies intracellular hepatic energy metabolism and is controlled by the conserved sodium-dicarboxylate cotransporter solute carrier family 13 member 5 (SLC13A5, mammalian homolog of INDY: mINDY). In Drosophila melanogaster and Caenorhabditis elegans INDY reduction decreased whole-body lipid accumulation. Genetic deletion of Slc13a5 in mice protected from diet-induced adiposity and insulin resistance. We hypothesized that inducible hepatic mINDY inhibition should prevent the development of fatty liver and hepatic insulin resistance. Methods Adult C57BL/6J mice were fed a Western diet (60% kcal from fat, 21% kcal from carbohydrate) ad libitum. Knockdown of mINDY was induced by weekly injection of a chemically modified, liver-selective siRNA for 8 weeks. Mice were metabolically characterized and the effect of mINDY suppression on glucose tolerance as well as insulin sensitivity was assessed with an ipGTT and a hyperinsulinemic-euglycemic clamp. Hepatic lipid accumulation was determined by biochemical measurements and histochemistry. Results Within the 8 week intervention, hepatic mINDY expression was suppressed by a liver-selective siRNA by over 60%. mINDY knockdown improved hepatic insulin sensitivity (i.e. insulin-induced suppression of endogenous glucose production) of C57BL/6J mice in the hyperinsulinemic-euglycemic clamp. Moreover, the siRNA-mediated mINDY inhibition prevented neutral lipid storage and triglyceride accumulation in the liver, while we found no effect on body weight. Conclusions We show that inducible mINDY inhibition improved hepatic insulin sensitivity and prevented diet-induced non-alcoholic fatty liver disease in adult C57BL6/J mice. These effects did not depend on changes of body weight or body composition. Graphical abstract Highlights • mINDY/Slc13a5 knockdown was induced by liver-selective siRNA in mice. • Liver-selective knockdown of mINDY improved hepatic insulin sensitivity. • Liver-selective knockdown of mINDY prevented steatosis hepatis. |
| Databáze: | OpenAIRE |
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