The Hepatokine Fetuin-A is increased in PCOS women. Association with metabolic syndrome and regulation by metformin
Mohamed Aghilla1, Raghu Adya1, Bee Tan1,2, Hendrik Lehnert1,3, Khaled Ashawesh4 & Harpal Randeva1
Introduction: Polycystic Ovary Syndrome (PCOS) is associated with insulin resistance, visceral obesity -metabolic syndrome (MS) and non-alcoholic fatty liver disease (NAFLD). Fetuin-A, human protein: α2-Heremans-Schmid glycoprotein is an abundant serum protein exclusively expressed in the liver and has been suggested to act as a link between obesity, insulin resistance (IR), and MS.
Aims: A) To determine levels of Fetuin-A in PCOS women. B) To investigate the effect of metformin on circulating levels and hepatocyte production of Fetuin-A.
Method: In vivo: 83 women with PCOS diagnosed according to Rotterdam 2003 criteria and 39 controls were recruited. 21 PCOS women with PCOS had metformin therapy for 24 weeks. Serum Fetuin -A (measured by ELISA) levels were evaluated before and after metformin therapy. In vitro: HepG2 cells (Human Hepatocellular carcinoma cell line) were cultured in RPMI-1640 media and treated with free fatty acids (FFA) and metformin.
Results: Serum Fetuin-A levels were higher in PCOS women compared to controls (P<0.01). Within the PCOS group, serum Fetuin A levels were higher in those with MS (P= 0.007). 6 months of metformin treatment decreased Fetuin A levels ( P<0.01). Fetuin A was also found to be negatively correlated with adiponectin and positively correlated with HOMA-IR, and hs CRP. In vitro: stimulation of HepG2 cells with FFA led to a significant increase in Fetuin-A levels (P≤0.01) and treatment of these cells with metformin, on the other hand, significantly decreased these levels (P<0.05).
Conclusion: The circulating levels of hepatokine Fetuin A are increased in women with PCOS, which is more pronounced when associated with MS. Metformin decreases Fetuin A in vivo, and also decreases both expression and secretion of Fetuin A from HepG2 cells, which may in part explain how metformin is working in reduction of IR.
Declaration of interest: There is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Funding: No specific grant from any funding agency in the public, commercial or not-for-profit sector.