Targeted Analysis of Three Hormonal Systems Identifies Molecules Associated with the Presence and Severity of NAFLD.

ABSTRACT

AIMS: To investigate circulating levels and liver gene expression of 3 hormonal pathways associated with obesity, insulin resistance, and inflammation to identify leads towards potential diagnostic markers and therapeutic targets in patients with nonalcoholic fatty liver disease (NAFLD). METHODS: We compared circulating levels of (1) proglucagon-derived hormones (glucagon-like peptide [GLP]-1, GLP-2, glicentin, oxyntomodulin, glucagon, major proglucagon fragment [MPGF]), (2) follistatins-activins (follistatin-like [FSTL]3, activin B), (3) IGF axis (insulin-like growth factor [IGF]-1, total and intact IGF binding protein [IGFBP]-3 and IGFBP-4, and pregnancy-associated plasma protein [PAPP]-A) in 2 studies (1) 18 individuals with early stage NAFLD versus 14 controls (study 1; early NAFLD study) and in (2) 31 individuals with biopsy proven NAFLD (15 with simple steatosis [SS] and 16 with nonalcoholic steatohepatitis [NASH]), vs 50 controls (24 lean and 26 obese) (study 2). Liver gene expression was assessed in 22 subjects (12 controls, 5 NASH, 5 NASH-related cirrhosis). RESULTS: Patients in early stages of NAFLD demonstrate higher fasting MPGF and lower incremental increase of glicentin during oral glucose tolerance test than controls. In more advanced stages, FSTL3 levels are higher in NASH than simple steatosis and, within NAFLD patients, in those with more severe lobular and portal inflammation. The IGF-1/intact IGFBP-3 ratio is lower in patients with liver fibrosis. Genes encoding follistatin, activin A, activin B, and the IGF-1 receptor are higher in NASH. CONCLUSION: MPGF and glicentin may be involved in early stages of NAFLD, whereas FSTL3 and IGF-1/intact IGFBP3 in the progression to NASH and liver fibrosis respectively, suggesting potential as diagnostic markers or therapeutic targets.