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Abstract
Vitamin D deficiency or hypovitaminosis D is associated with increased risks of insulin resistance, type 2 diabetes mellitus (T2DM) and its related non-alcoholic fatty liver disease (NAFLD). Meanwhile, inappropriate over-activation of the renin–angiotensin system (RAS) in the liver leads to the hepatic dysfunction and increased risk of T2DM, such as abnormalities in lipid and glucose metabolism. Our previous findings have shown that calcitriol, an active metabolite of vitamin D, reduces hepatic triglyceride accumulation and glucose output in diabetic db/db mice and human hepatocellular cell HepG2 cells under insulin-resistant conditions. Notwithstanding the existence of this evidence, the protective action of vitamin D in the modulation of overexpressed RAS-induced metabolic abnormalities in the liver under insulin resistance remains to be elusive and investigated. Herein, we have reported the potential interaction between vitamin D and RAS; and its beneficial effects on the expression and function of the RAS components in HepG2 cells and primary hepatocytes under insulin-resistance states. Our study findings suggest that hormonal vitamin D (calcitriol) has modulatory action on the inappropriate upregulation of the hepatic RAS under insulin-resistant conditions. If confirmed, vitamin D supplementation might provide a nutraceutical potential as a cost-effective approach for the management of hepatic metabolic dysfunction as observed in T2DM and related NAFLD.
Highlights
Hypovitaminosis D is commonly observed in many countries; it is known to be closely associated with increased insulin resistance, impaired insulin secretion, and poorly controlled glucose homeostasis, and is correlated with the risk of metabolic diseases, such as type 2 diabetes mellitus (T2DM)
Hepatic insulin resistance is a consequence of hepatic adiposity and accounts for the majority of the overall insulin resistance, independent of obesity [4]
Vitamin D is both 25-hydroxylated and activated in the liver by local 1α-hydroxylase and there are fully functional vitamin D receptors (VDR) in Kupffer, stellate and endothelial cells as well as in the hepatocytes [12]. In view of this fact, vitamin D could be expected to exert direct effects on hepatic insulin signalling pathway genes and vitamin D supplementation might have a potential for the management of obesity-associated T2DM and non-alcoholic fatty liver disease (NAFLD) [1]
Summary
Reduced hepatic insulin sensitivity in metabolic syndromes, such as type 2 diabetes (T2DM) and non-alcoholic fatty liver disease (NAFLD) [5], may result directly from reduced insulin receptor numbers or indirectly from reduced insulin action via post-insulin receptor Hypovitaminosis D is associated with increased risks of each component of metabolic syndrome: central obesity, glycemia, blood pressure, adverse lipid profiles, insulin resistance, T2DM, and cardiovascular disease [9,10].
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