Osteocalcin In Relation To Vascular Endothelial-dependent Relaxation And NAFLD

Part1. Osteocalcin Attenuates high fat diet-inducedImpairment of Endothelium-dependent Relaxation throughAkt/eNOS-dependent PathwayOBJECTIVE Recent studies have demonstrated a protective effect of osteocalcin (OCN)on glucose homeostasis and metabolic syndrome. However, its role in vascular functionremains unknown. This study investigated the contribution of OCN to the pathogenesis ofendothelial dysfunction in the thoracic aorta of apolipoprotein E-deficient (ApoE–KO)mice.METHODS Eight-week-old ApoE-KO mice were given chow or high fat diet (HFD) for12weeks with or without daily intraperitoneal injection of OCN. Intraperitoneal glucosetolerance test (IPGTT)，insulin tolerance test (ITT)，measurement of serum lipid profilesand blood pressure were carried out. Endothelium-dependent relaxation (EDR) wasmeasured by wire myography. Human umbilical vein endothelial cells (HUVECs) wereused to study the role of OCN on eNOS levels in vitro. PI3K inhibitor (LY294002) andAkt inhibitor V were used ex-vivo to determine whether PI3K/Akt/eNOS contributes tothe beneficial effect of OCN for the vascular or not.RESULTS Daily injections of OCN can significantly improve lipid metabolism, glucosetolerance and insulin sensitivity in ApoE-KO mice. In ApoE-KO mice fed with high fatdiet, the OCN-treated mice displayed an improved acetylcholine-stimulated EDRcompared to the vehicle-treated group. In addition, compared to vehicle-treated HUVECs,OCN-treated HUVECs displayed increased activation of the Akt-eNOS signalingpathway, as evidenced by significantly higher levels of phosphorylated Akt and eNOS.Furthermore, a similar beneficial effect of OCN on thoracic aorta was observed using exvivo organ culture of isolated mouse aortic segment. However, this effect was attenuatedupon co-incubation with PI3K inhibitor or Akt inhibitor V.CONCLUSION Our study demonstrates that OCN has an endothelial-protective effectthrough mediating the PI3K/Akt/eNOS signaling pathway. Part2. Relationship between serum osteocalcin levels andnon-alcoholic fatty liver disease in Chinese menOBJECTIVE The present study was designed to investigate the relationship betweenserum osteocalcin levels and non-alcoholic fatty liver disease (NAFLD) in Chinese men.METHODS In all,1558men (21–78years old) were recruited to the study. Serumosteocalcin, glucose and lipid profiles were determined. Demographic and clinicalcharacteristics were recorded. All participants underwent hepatic ultrasonographicexamination.RESULTS Serum osteocalcin levels were significantly lower in subjects with NAFLDthan those without (P <0.01). All study subjects were divided into four subgroupsaccording to quartiles of serum osteocalcin levels. The frequency of NAFLD increasedprogressively with declining serum osteocalcin levels (P for trend <0.01). Serumosteocalcin levels were inversely correlated with NAFLD (P <0.01). However, thesignificant association between serum osteocalcin levels and NAFLD disappeared inlogistic regression analyses. Furthermore, multiple stepwise regression analysis showedthat serum osteocalcin levels were independently associated with serum alanineaminotransferase levels in Chinese men (P <0.01).CONCLUSION The findings of the present study suggest that serum osteocalcin levelsare not directly correlated with NAFLD.