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

Abstract

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 hepatic ANGPTL3, ANGPTL4, ANGPTL8, LPL, VDR, CYP27A1 and CYP2R1 mRNA 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 hepatic VDR, ANGPTL3 and LPL expression. ANGPTL3 correlated with steatosis grade, LPL, VDR, CYP27A1 and CYP2R1 expression. Plasma ANGPTL3 concentrations were positively associated with clinical/histological markers of NAFLD/NASH and with hepatic ANGPTL3 expression. Greater hepatic VDR expression was the main determinant of hepatic ANGPTL3 after adjusting for multiple confounders. Conclusions Hepatic ANGPTL3 expression 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.

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

“…Several studies have observed elevated ANGPTL protein levels in NAFLD patients. Plasma ANGPTL3 levels are higher in biopsy-proven NASH patients [ 92 , 93 ], and plasma [ 94 , 95 ] and hepatic [ 96 ] ANGPTL8 are elevated in patients with fatty liver independent of insulin resistance [ 94 ]. In addition to inhibiting LPL activity, ANGPTL8 seems to favors TG accumulation in hepatocytes.…”

Liver-targeting drugs and their effect on blood glucose and hepatic lipids

“…Angiopoietin-like protein 3 (ANGPTL3) is secreted mainly by the liver and, in this sense, it might be considered a hepatokine. ANGPTL3 acts as dual inhibitor of lipoprotein lipase and endothelial lipase, thereby increasing plasma NEFA, triacylglycerols, LDL-cholesterol and HDL-cholesterol, and its plasma concentration is associated with clinical/ histological markers of NAFLD/NASH and with hepatic ANGPTL3 expression [122]. Evinacumab is an [123,124].…”

Reduced Biliverdin Reductase-A Expression in Visceral Adipose Tissue is Associated with Adipocyte Dysfunction and NAFLD in Human Obesity

“…The diagnosis of NAFLD/NASH was performed on liver biopsies based on validated criteria [65,66]. Experimental procedures for liver fragments examination are detailed in our previous study [67]. Two pathologists blinded to patients' identity performed all the histological analyses.…”