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The role of hepatokines in metabolism

Abstract

The liver is known to be involved in the natural history of the ongoing epidemics of type 2 diabetes mellitus and cardiovascular disease. In particular, the liver has a role in increased glucose production and dysregulated lipoprotein metabolism, conditions that are often found in patients with nonalcoholic fatty liver disease. Additionally, several proteins that are exclusively or predominantly secreted from the liver are now known to directly affect glucose and lipid metabolism. In analogy to the functional proteins released from adipose tissue and skeletal muscle—adipokines and myokines—these liver-derived proteins are known as hepatokines. The first hepatokine that has been proven to have a major pathogenetic role in metabolic diseases is α2-HS-glycoprotein (fetuin-A). Production of this glycoprotein is increased in steatotic and inflamed liver, but not in expanded and dysregulated adipose tissue. Thus, research into this molecule and other hepatokines is expected to aid in differentiating between the contribution of liver and those of skeletal muscle and adipose tissue, to the pathogenesis of type 2 diabetes mellitus and cardiovascular disease.

Key Points

  • Like adipose tissue and skeletal muscle, the liver affects glucose and lipid metabolism by releasing proteins into the circulation; these proteins are termed hepatokines

  • Nonalcoholic fatty liver disease, in particular, is associated with altered production of hepatokines

  • The hepatokine fetuin-A has a major role in the pathophysiology of type 2 diabetes mellitus and cardiovascular disease in humans

  • The novel concept of hepatokines as important contributors to metabolic disease might enable the pathophysiological roles of the liver to be distinguished from those of other tissues

  • Increased understanding of the roles of the liver and hepatokines in metabolic diseases could lead to development of improved targeted strategies for their prevention and treatment

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Figure 1: General roles of liver and adipose tissue in the development of metabolic diseases.
Figure 2: Causes and metabolic consequences of increased production of fetuin-A.
Figure 3: Novel roles of liver and adipose tissue in the development of metabolic diseases.

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Acknowledgements

N. Stefan is currently supported by a Heisenberg Professorship from the Deutsche Forschungsgemeinschaft (DFG 1096/3-1). The sponsor was not directly involved in the generation of this article.

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N. Stefan researched data for the article. Both authors contributed equally to discussions of article content, and writing and editing the manuscript.

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Correspondence to Norbert Stefan.

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Stefan, N., Häring, HU. The role of hepatokines in metabolism. Nat Rev Endocrinol 9, 144–152 (2013). https://doi.org/10.1038/nrendo.2012.258

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