Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance

• Published in: Nature reviews. Endocrinology Vol. 13; no. 9; pp. 509 - 520
• Main Authors: Meex, Ruth C. R., Watt, Matthew J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2017; Nature Publishing Group
• Subjects: 692/163/2743/137/773; 692/163/2743/393; 692/4020/4021/1607/2750; 692/698/2741/288/2032; alpha-2-HS-Glycoprotein - physiology; Animals; Blood Proteins - physiology; Body weight; Care and treatment; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2; Diet, High-Fat; Disease resistance; Endocrinology; Fatty liver; Fetuin-B - physiology; Glucose tolerance; Hepatocytes; High density lipoprotein; Humans; Hypertriglyceridemia; Insulin; Insulin Resistance; Intolerance; Lipid Metabolism - physiology; Liver - physiopathology; Liver diseases; Medicine & Public Health; Metabolism; Non-alcoholic Fatty Liver Disease - physiopathology; Obesity; Overweight; Phenotypes; Retinol-binding protein; Retinol-Binding Proteins, Plasma - physiology; review-article; Secretion; Selenoprotein P - physiology; Selenoproteins; Skeletal muscle; Steatosis; Vitamin A
• ISSN: 1759-5029; 1759-5037; 1759-5037
• DOI: 10.1038/nrendo.2017.56

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 In this Review, the authors describe the factors that influence the development of hepatic steatosis and discuss the evidence base that links steatosis to insulin resistance. They explore how steatosis alters the secretion of hepatokines from the liver, and how these secretome alterations regulate glucose metabolism and insulin action in non-hepatic tissues. 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.