1 Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia.
The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry 'omics' approaches and detailed experimentation in cells, mice and humans, we now understand that the liver secretes a wide array of proteins, metabolites and non-coding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of 'hepatokine' biology with a particular focus on delineating previously unappreciated communication between the liverand other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue and pancreas to induce insulin resistance. We also synthesise the limited information which indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for inter-tissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.