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The role of hepatokines in NAFLD-related extrahepatic diseases: culprit or accomplice?
  1. Ri-Yue Jiang1,
  2. Ling Yang2
  1. 1 Department of Radiation Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
  2. 2 Department of Cardiology, The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China
  1. Correspondence to Dr Ling Yang, Department of Cardiology, The Third Affiliated Hospital of Soochow University, No. 185 Juqian Street, Changzhou 213003, China; czyangling{at}

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We recently read with great interest a review by Adams et al 1 showing that non-alcoholic fatty liver disease (NAFLD) has a profound impact on the onset of extrahepatic diseases, such as cardiovascular diseases and kidney diseases. We fully agree with this conclusion, and the authors have fully elucidated the relationship between NAFLD and extrahepatic diseases. We think that hepatokines produced and secreted by liver may play a critical role in NAFLD-related extrahepatic diseases, which would deepen the understanding of this disease.

Fibroblast growth factor 21 (FGF21), a hepatokine that is mainly secreted by the liver, has beneficial effects for improving metabolic processes.2 It has been well recognised that FGF21 plays a pivotal role in the pathogenesis and therapeutic mechanisms of NAFLD.3 Abnormality in FGF21 would prompt the development of NAFLD. Coincidentally, dysfunctional FGF21 in peripheral blood is highly associated with cardiovascular and cerebrovascular diseases.4 Given the critical role of FGF21 in NAFLD and other diseases, we therefore think that FGF21 abnormality would underlie the mechanisms of NAFLD-related extrahepatic diseases.

Fetuin-A also belong to a class of hepatokines.5 A previous study demonstrated that fetuin-A deficiency is associated with inflammation that could accelerate vascular calcification in patients on dialysis.6 In addition, improvement of fetuin-A could exert facilitating effects on insulin resistance that is highly associated with the onset of NAFLD.7 It is well known that insulin resistance is of great importance for the development of NAFLD. Collectively, improvements of insulin resistance by upregulation of fetuin-A are of great aid in the treatment of NAFLD. Meanwhile, the improvement in insulin resistance is beneficial for extrahepatic diseases.

Selenoprotein P, a 42 kDa glycoprotein, is produced in the liver.8 It has been reported that selenoprotein P impairs insulin signalling and glucose metabolism in the liver, whereas decreasing selenoprotein P could elicit beneficial effects on insulin resistance and glucose tolerance.8 Increased selenoprotein P levels are highly associated with NAFLD. Recently, Ishikura et al 9 demonstrated that selenoprotein P in the physiological concentration range has deleterious effects by inhibiting vascular endothelial growth factor, tubule formation and migration in endothelial cells. We, therefore, infer that inhibiting selenoprotein P may exert physiologically beneficial effects on NAFLD and its related extrahepatic diseases.

There are other hepatokines including angiopoietin-like protein 4 and leucocyte cell-derived chemotaxin 2 that play an important role in the pathogenesis of NAFLD and other diseases.10 Consequently, we think that NAFLD-related extrahepatic diseases are highly associated with abnormal expression of hepatokines. Treatments targeting hepatokines may promise a novel therapeutic strategy for NAFLD-related extrahepatic diseases. Future studies on the role of hepatokines in NAFLD-related extrahepatic diseases are required.


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  • Contributors RYJ and LY conceived the scientific idea and wrote the manuscript.

  • Funding This study was supported by the Program of Bureau of Science and Technology Foundation of Changzhou (No: CJ20159022) and CJ20160030) and Major Science and Technology Projects of Changzhou Municipal Committee of Health and Family Planning (No: ZD201505 and ZD201407).

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

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