MLX plays a key role in lipid and glucose metabolism in humans: Evidence from in vitro and in vivo studies.

Autor: Nagarajan SR; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK., Livingstone EJ; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Monfeuga T; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Lewis LC; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Ali SHL; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Chandran A; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Dearlove DJ; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK., Neville MJ; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, UK., Chen L; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Maroteau C; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK., Ruby MA; Novo Nordisk Research Centre Oxford, Innovation Building, Oxford, UK. Electronic address: mwry@novonordisk.com., Hodson L; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospital Trusts, UK. Electronic address: leanne.hodson@ocdem.ox.ac.uk.
Jazyk: angličtina
Zdroj: Metabolism: clinical and experimental [Metabolism] 2023 Jul; Vol. 144, pp. 155563. Date of Electronic Publication: 2023 Apr 21.
DOI: 10.1016/j.metabol.2023.155563
Abstrakt: Background and Aim: Enhanced hepatic de novo lipogenesis (DNL) has been proposed as an underlying mechanism for the development of NAFLD and insulin resistance. Max-like protein factor X (MLX) acts as a heterodimer binding partner for glucose sensing transcription factors and inhibition of MLX or downstream targets has been shown to alleviate intrahepatic triglyceride (IHTG) accumulation in mice. However, its effect on insulin sensitivity remains unclear. As human data is lacking, the aim of the present work was to investigate the role of MLX in regulating lipid and glucose metabolism in primary human hepatocytes (PHH) and in healthy participants with and without MLX polymorphisms.
Methods: PHH were transfected with non-targeting or MLX siRNA to assess the effect of MLX knockdown on lipid and glucose metabolism, insulin signalling and the hepatocellular transcriptome. A targeted association analysis on imputed genotype data for MLX on healthy individuals was undertaken to assess associations between specific MLX SNPs (rs665268, rs632758 and rs1474040), plasma biochemistry, IHTG content, DNL and gluconeogenesis.
Results: MLX knockdown in PHH altered lipid metabolism (decreased DNL (p < 0.05), increased fatty acid oxidation and ketogenesis (p < 0.05), and reduced lipid accumulation (p < 0.001)). Additionally, MLX knockdown increased glycolysis, lactate secretion and glucose production (p < 0.001) and insulin-stimulated pAKT levels (p < 0.01) as assessed by transcriptomic, steady-state and dynamic measurements. Consistent with the in vitro data, individuals with the rs1474040-A and rs632758-C variants had lower fasting plasma insulin (p < 0.05 and p < 0.01, respectively) and TG (p < 0.05 and p < 0.01, respectively). Although there was no difference in IHTG or gluconeogenesis, individuals with rs632758 SNP had notably lower hepatic DNL (p < 0.01).
Conclusion: We have demonstrated using human in vitro and in vivo models that MLX inhibition favored lipid catabolism over anabolism and increased glucose production, despite increased glycolysis and phosphorylation of Akt, suggesting a metabolic mechanism that involves futile cycling.
Competing Interests: Declaration of competing interest EJL, TM, LCL, SHLA, AC, LC, CM and MAR are employees of Novo Nordisk Ltd. All other authors have no conflicts to declare.
(Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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