| It is generally known that non-alcoholic fatty liver disease (NAFLD) and insulin resistance are concomitant with type 2 diabetes (T2DM); however, the underlying mechanism(s) have yet to be fully investigated. In this regard, basic science studies have shown that insulin sensitivity is enhanced by decreasing hepatic triglyceride (TG) contents while targeting at insulin resistance also having beneficial effect on NAFLD. On the other hand, the clinical manifestation of NAFLD and insulin resistance, either alone or in combination, exhibits negative impact on cardiometabolic diseases. As such, investigations into some potentially beneficial factors that are associated with NAFLD and insulin resistance need to be explored. Among these studies, some epidemic evidence has reported that vitamin D deficiency is related to increased risk of insulin resistance and, intriguingly, vitamin D supplementation improves insulin sensitivity in individuals with insulin resistance. More noticeably, lower vitamin D levels are also suggested to be associated with increased histological severity of hepatic steatosis. Indeed, serum vitamin D levels may be an independent predictor for the severity of NAFLD.;To address this issue, animal model of diabetic db/db mice and cell model of HepG2 cells were selected, and the latter were cultured in high-glucose and high-insulin conditions, mimicking insulin resistance in vitro . Calcitriol, the physiologically active form of vitamin D, was employed so as to assess its effects on hepatic lipid and glucose metabolism using in vivo and in vitro systems. On the other hand, the regulatory pathways by which calcitriol might be involved in these processes were further elucidated by pharmacological inhibition and genetic knock-down of the respective genes/proteins of interest in this study.;The results showed that the expression of vitamin D receptor was regulated by glucose and insulin, indicative of its involvement in NAFLD and T2DM and that calcitriol ameliorated insulin resistance as well as reducing hepatic glucose production and triglyceride content. In addition, calcitriol-mediated action on hepatic lipid and glucose metabolism are mediated, at least in part, through stimulation of calcium /calmodulin-dependent protein kinase kinase-beta-AMP-activated protein kinase (Ca2+/CaMKKbeta-AMPK) pathways.;In conclusion this mechanism-driven study has corroborated that vitamin D supplementation is a preventative measure for those people at risk of NAFLD and T2DM.;Notwithstanding the aforementioned findings, the modulatory role of vitamin D in hepatic lipid and glucose metabolism remains to be largely ambiguous. Accordingly, the present project is specifically designed to examine the direct involvement of vitamin D in regulating NAFLD and T2DM and its mechanistic pathway(s) involved in hepatic lipid and glucose metabolism with insulin resistance. |
