Relationship between hepatic and systemic angiopoietin-like 3, hepatic Vitamin D receptor expression and NAFLD in obesity

Background & Aims Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide and an independent risk factor for cardiovascular mortality. Angiopoietin-like proteins (ANGPTLs) are targets for vitamin D receptor (VDR)-mediated gene transcription and this axis may promote NAFLD. ANGPTL3 is a hepatokine which inhibits lipoprotein lipase and its experimentally induced inactivation reduces hepatosteatosis. Little is known on ANGPTL3 in human NAFLD and no data exist on its relationship with hepatic VDR/VD-related genes. The aim of this research was to investigate hepatic ANGPTLs and VDR/VD-related gene expression in human obesity in relation to NAFLD. Methods We conducted a cross-sectional investigation on forty obese subjects with/without NAFLD. We evaluated hepaticANGPTL3,ANGPTL4,ANGPTL8,LPL,VDR,CYP27A1andCYP2R1mRNA expression in liver biopsies by RT-PCR; VDR expression was further investigated by immunohistochemistry; circulating ANGPTL3 was measured by Milliplex assay. Results Compared to non-NAFLD, NAFLD individuals had significantly higher hepaticVDR,ANGPTL3andLPLexpression.ANGPTL3correlated with steatosis grade,LPL, VDR,CYP27A1andCYP2R1expression. Plasma ANGPTL3 concentrations were positively associated with clinical/histological markers of NAFLD/NASH and with hepaticANGPTL3expression. Greater hepaticVDRexpression was the main determinant of hepaticANGPTL3after adjusting for multiple confounders. Conclusions HepaticANGPTL3expression correlates with greater VDR expression, presence and severity of NAFLD and translates in increased circulating ANGPTL3, likely as a result of its modulation by up-regulated hepatic VDR in NAFLD. This study provides novel insights to potential mechanisms underlying ANGPTLs-mediated ectopic fat accumulation and NAFLD development in obesity.