The role of hepatokines in NAFLD

Abstract

Non-alcoholic fatty liver disease (NAFLD) is not only a consequence of insulin resistance, but it is also an important cause of insulin resistance and major non-communicable diseases (NCDs). The close relationship of NAFLD with visceral obesity obscures the role of fatty liver from visceral adiposity as the main pathomechanism of insulin resistance and NCDs. To overcome this limitation, in analogy to the concept of adipokines, in 2008 we introduced the term hepatokines to describe the role of fetuin-A in metabolism. Since then, several other hepatokines were tested for their effects on metabolism. Here we address the dysregulation of hepatokines in people with NAFLD. Then, we discuss pathophysiological mechanisms of cardiometabolic diseases specifically related to NAFLD by focusing on hepatokine-related organ crosstalk. Finally, we propose how the determination of major hepatokines and adipokines can be used for pathomechanism-based clustering of insulin resistance in NAFLD and visceral obesity to better implement precision medicine in clinical practice.

Figure 1.. Causes and cardiometabolic consequences of NAFLD

An unhealthy diet involving a positive energy balance with increased caloric intake, particularly of glucose, fructose, and saturated fat, results in increased hepatic de novo lipogenesis and hepatic inflammation. This process is amplified by a lipodystrophy-like phenotype with expansion of visceral adipose tissue, resulting in increased release of fatty acids and ceramides and a dysregulated pattern of cytokines and adipokines. A genetic predisposition for hepatic lipid accumulation, inflammation, and fibrosis also contributes to the pathogenesis of NAFLD, albeit with wide range of metabolic effects. By increased/decreased secretion of very-low-density lipoproteins (VLDLs) with different amounts of ceramides, increased release of pro-coagulants, increased glucose output, and dysregulated secretion of microRNAs and hepatokines, the fatty liver impacts metabolically important organs and tissues and the cardiovascular system. The arrows shown with the hepatokines indicate increased/decreased organ function mediated by the respective hepatokines. The cardiometabolic pathologies brought about by the endocrine function of the fatty liver also impact the progress of NAFLD.

Figure 2.. Relationships of liver fat/visceral fat/adiponectin/fetuin-A risk clusters

(A and B) Insulin sensitivity and (C–F) cluster parameters. In 185 subjects at increased risk of type 2 diabetes, K-means cluster analyses identified 3 clusters deriving from the parameters of (C) visceral fat content, (D) liver fat content, (E) the adipokine adiponectin, and (F) the hepatokine fetuin-A. The color coding indicates low values in blue, mean values in gray shading, and high values in red. p values for statistical differences between the clusters in Student’s t tests (*p < 0.05, **p < 0.001, ***p < 0.0001). The insert depicts the cluster analysis approach and the 3D biplot of the cluster results.

Figure 3.. Radar charts of the liver fat/visceral fat/adiponectin/fetuin-A risk clusters with insulin sensitivity and the cluster parameters

Depicted are the median values of the Z scores of the parameters insulin sensitivity, measured from the frequently sampled oral glucose tolerance test; liver fat content; visceral fat mass; adiponectin levels; and fetuin-A levels. Insulin sensitivity and adiponectin levels were directionally flipped (−1 × Z score) to yield adverse variable effects. The insert depicts whether the parameters are increased or decreased in the 3 clusters.

Figure 4.. Impact of a positive energy balance and an unhealthy diet on insulin resistance and cardiometabolic diseases via effects on fat mass and distribution and hepatic steatosis

During conditions of a positive energy balance and unhealthy diets, subcutaneous and visceral adipose tissues expand in a manner that is predominantly genetically determined. Subcutaneous (metabolically healthy) obesity is not strongly associated with cardiometabolic diseases, whereas visceral obesity is a strong predictor of these diseases. Increased availability of fatty acids, increased subclinical inflammation, and dysregulation of adipokine production and release are thought to promote insulin resistance, atherosclerosis, and β cell dysfunction. This process is mainly characterized by dysregulated adipokine production and secretion. Accumulation of lipids in the liver is also genetically determined, and two distinct phenotypes have been identified. When hepatic detoxification processes are active, storage of lipids in the liver is not associated with metabolic diseases. By contrast, when lipotoxicity is present, hepatic glucose production increases and lipids are released, with an atherogenic profile. This process is mainly characterized by dysregulated hepatokine production and secretion.