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The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state

Nature Reviews Endocrinology volume 15, pages 689–700 (2019)Cite this article

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A Publisher Correction to this article was published on 09 March 2020

This article has been updated

Abstract

Nonalcoholic fatty liver disease (NAFLD) is an increasing global public health burden. NAFLD is strongly associated with type 2 diabetes mellitus, obesity and cardiovascular disease and begins with intrahepatic triacylglycerol accumulation. Under healthy conditions, the liver regulates lipid metabolism to meet systemic energy needs in the fed and fasted states. The processes of fatty acid uptake, fatty acid synthesis and the intracellular partitioning of fatty acids into storage, oxidation and secretion pathways are tightly regulated. When one or more of these processes becomes dysregulated, excess lipid accumulation can occur. Although genetic and environmental factors have been implicated in the development of NAFLD, it remains unclear why an imbalance in these pathways begins. The regulation of fatty acid partitioning occurs at several points, including during triacylglycerol synthesis, lipid droplet formation and lipolysis. These processes are influenced by enzyme function, intake of dietary fats and sugars and whole-body metabolism, and are further affected by the presence of obesity or insulin resistance. Insight into how the liver controls fatty acid metabolism in health and how these processes might be affected in disease would offer the potential for new therapeutic treatments for NAFLD to be developed.

Key points

  • Intrahepatic triacylglycerol (IHTAG) accumulation occurs through an imbalance between fatty acid uptake and synthesis and fatty acid disposal; however, the exact mechanisms by which this occurs in humans are poorly understood.

  • Insulin signalling seems to be an important factor that links intrahepatic and extrahepatic fatty acid metabolism; hepatic insulin signalling regulates pathways linked to fatty acid uptake, synthesis and storage.

  • Both non-esterified fatty acid delivery and fatty acid synthesis through de novo lipogenesis seem to be upregulated during IHTAG accumulation, which might be worsened by high saturated fat and high free sugar intake, respectively.

  • Secretion of IHTAG as VLDL–TAG and partitioning into oxidation pathways might have a dynamic response, depending on disease state; the regulation of the pathways requires further investigation.

  • Dietary composition influences insulin levels as well as tissue nutrient exposure; the interaction between these pathways requires optimization of physiologically relevant models of hepatic fat and carbohydrate metabolism.

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Fig. 1: Hepatic and whole-body pathways of fatty acid metabolism.
Fig. 2: Overview of hepatocellular partitioning of fatty acids.

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Change history

  • 09 March 2020

    An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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Acknowledgements

L.H. is a British Heart Foundation Senior Research Fellow in Basic Science (BHF/15/56/31645).

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  1. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Headington, Oxford, UK

    Leanne Hodson & Pippa J. Gunn

  2. Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK

    Leanne Hodson & Pippa J. Gunn

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Hodson, L., Gunn, P.J. The regulation of hepatic fatty acid synthesis and partitioning: the effect of nutritional state. Nat Rev Endocrinol 15, 689–700 (2019). https://doi.org/10.1038/s41574-019-0256-9

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