Sphingolipids and phospholipids in insulin resistance and related metabolic disorders

Key Points

  • Hypercaloric diets lead to the dysregulation of multiple lipid metabolic pathways, which contributes to the onset and progression of metabolic disease

  • Lipidomic studies are starting to decipher the dysregulation of lipid metabolism associated with metabolic disease

  • Lipid metabolic pathways represent potential therapeutic targets to prevent or delay the onset and progression of metabolic disease

  • Further animal studies and clinical trials are required to define the stage of disease at which modulation of lipid metabolism will have maximal efficacy

  • Whether intervention into a single metabolic pathway or multiple pathways will produce optimal results remains to be determined

Abstract

Obesity, insulin resistance, type 2 diabetes mellitus and cardiovascular disease form a metabolic disease continuum that has seen a dramatic increase in prevalence in developed and developing countries over the past two decades. Dyslipidaemia resulting from hypercaloric diets is a major contributor to the pathogenesis of metabolic disease, and lipid-lowering therapies are the main therapeutic option for this group of disorders. However, the fact that dysfunctional lipid metabolism extends far beyond cholesterol and triglycerides is becoming increasingly clear. Lipidomic studies and mouse models are helping to explain the complex interactions between diet, lipid metabolism and metabolic disease. These studies are not only improving our understanding of this complex biology, but are also identifying potential therapeutic avenues to combat this growing epidemic. This Review examines what is currently known about phospholipid and sphingolipid metabolism in the setting of obesity and how metabolic pathways are being modulated for therapeutic effect.

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Figure 1: Partial biosynthetic pathway of glycerolipids and glycerophospholipids.
Figure 2: Structure of alkylglycerols and plasmalogen.
Figure 3: Biosynthetic pathway of plasmalogens.
Figure 4: Partial sphingolipid biosynthetic pathway.
Figure 5: Feedback loops between lipid metabolism and insulin resistance.

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Acknowledgements

P.J.M. is supported by a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

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Both authors contributed equally to the researching data for the article, discussion of the content, writing the article and reviewing and/or editing the article before submission.

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Correspondence to Peter J. Meikle.

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P.J.M. declares no competing interests. S.A.S. is co-founder and scientific adviser of Centaurus Therapeutics Inc.

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Meikle, P., Summers, S. Sphingolipids and phospholipids in insulin resistance and related metabolic disorders. Nat Rev Endocrinol 13, 79–91 (2017). https://doi.org/10.1038/nrendo.2016.169

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