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  • Review Article
  • Published:

Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance

Nature Reviews Endocrinology volume 13, pages 509–520 (2017)Cite this article

Subjects

Key Points

  • Nonalcoholic fatty liver disease (NAFLD) is present in ∼20–40% of adults in the USA, and in ∼70% and >90% of individuals worldwide with overweight or morbid obesity, respectively

  • Hepatic lipid content is regulated by the complex interplay between the delivery of lipids to the liver and the processes of hepatic lipid uptake, synthesis, oxidation and secretion

  • Hepatic fat content is the strongest predictor of insulin resistance in skeletal muscle, hepatic and adipose tissues

  • Hepatokines are proteins secreted by hepatocytes that can influence metabolic processes through autocrine, paracrine and endocrine signalling

  • Hepatic steatosis induces changes in hepatokine secretion that promote insulin resistance and that negatively affect other metabolic processes

  • A better understanding of hepatokine function in hepatic steatosis will inform the prevention, diagnosis and treatment of a range of metabolic diseases, including type 2 diabetes mellitus

Abstract

Hepatic steatosis is an underlying feature of nonalcoholic fatty liver disease (NAFLD), which is the most common form of liver disease and is present in up to ∼70% of individuals who are overweight. NAFLD is also associated with hypertriglyceridaemia and low levels of HDL, glucose intolerance, insulin resistance and type 2 diabetes mellitus. Hepatic steatosis is a strong predictor of the development of insulin resistance and often precedes the onset of other known mediators of insulin resistance. This sequence of events suggests that hepatic steatosis has a causal role in the development of insulin resistance in other tissues, such as skeletal muscle. Hepatokines are proteins that are secreted by hepatocytes, and many hepatokines have been linked to the induction of metabolic dysfunction, including fetuin A, fetuin B, retinol-binding protein 4 (RBP4) and selenoprotein P. In this Review, we describe the factors that influence the development of hepatic steatosis, provide evidence of strong links between hepatic steatosis and insulin resistance in non-hepatic tissues, and discuss recent advances in our understanding of how steatosis alters hepatokine secretion to influence metabolic phenotypes through inter-organ communication.

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Figure 1: Lipid storage and disposal disequilibrium in nonalcoholic fatty liver disease.
Figure 2: Liver steatosis, hepatokine secretion and metabolic dysregulation.

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Acknowledgements

The authors would like to acknowledge the support of the National Health and Medical Research Council (NHMRC) of Australia (ID: APP1061278). M.J.W. is supported by a research fellowship from the NHMRC (ID: APP1077703).

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Authors and Affiliations

  1. Metabolic Disease and Obesity Program and the Department of Physiology, Monash Biomedicine Discovery Institute, Monash University, Wellington Road, Clayton, Victoria, 3800, Australia

    Ruth C. R. Meex & Matthew J. Watt

  2. Department of Human Biology, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht University, Universiteitssingel 50, Maastricht, 6229 ER, The Netherlands

    Ruth C. R. Meex

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Contributions

R.C.R.M. researched the data for the article. M.J.W. and R.C.R.M. contributed to the discussion of the content. M.J.W. and R.C.R.M. contributed equally to writing the article, and to reviewing and/or editing of the manuscript before submission.

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PowerPoint slides

Glossary

Mild hepatic steatosis

Characterized by the storage of excess lipid in the liver and is a component of fatty liver disease.

Nonalcoholic steatohepatitis

(NASH). A form of liver disease that occurs when excess fat is present in the liver accompanied by inflammation and possibly fibrosis.

Triglyceride lipolysis

The breakdown of a triglyceride molecule to produce one glycerol molecule and three fatty acid molecules.

Hepatic portal vein

Blood vessel that carries blood from the gastrointestinal tract, gallbladder, pancreas and spleen to the liver.

Fenofibrate

A drug of the fibrate class that is generally prescribed to patients who cannot take a statin to lower blood levels of cholesterol.

Quercetin

Belongs to a group of plant pigments called flavonoids and is found in many fruits, vegetables, leaves and grains.

Lipodystrophic mice

Mice with a disorder of adipose tissue characterized by a selective loss of body fat.

Haemostasis

The body's response to blood vessel injury and bleeding, which involves the coordinated efforts of platelets and blood-clotting proteins to form a blood clot.

Fibrinolysis

The process by which fibrin is removed from damaged blood vessels, which is important in tissue remodelling and repair after injury.

Dyslipidaemia

A medical condition characterized by abnormal blood levels of lipids, including cholesterol and triglycerides.

Euglycaemic-hyperinsulinaemic clamps

The 'gold-standard' technique used to measure insulin sensitivity in vivo.

Glucose effectiveness

Explains how glucose promotes its own uptake into tissues and accounts for 50% of glucose clearance during an oral glucose tolerance test in normal individuals and 80% in patients with obesity who are insulin resistant.

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Meex, R., Watt, M. Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance. Nat Rev Endocrinol 13, 509–520 (2017). https://doi.org/10.1038/nrendo.2017.56

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