Abstract
It has been suggested that Hepatitis C virus (HCV) core protein is associated with metabolic disorders of liver cell. However, the precise mechanism is still unclear. The aim of the present study was to explore the impact of HCV core protein on hepatocyte metabolism by HepG2 and the possible involvement of long non-coding (lnc) RNAs in this process. The effect of HCV core protein on lncRNAs expression was examined with quantitative RT-PCR (qRT-PCR). Manipulation of HVC core protein and lncRNA HOTAIR was to evaluate the role of interaction between them on cell metabolism-related gene expression and cellular metabolism. The potential downstream Sirt1 signal was examined by western blotting and qRT-PCR. Our data suggested that suppression of HOTAIR abrogates HCV core protein-induced reduction in Sirt1 and differential expression of glucose- and lipid-metabolism-related genes. Also it benefits for metabolic homoeostasis of hepatocyte indicated by restoration of cellular reactive oxygen species (ROS) level and NAD/NADH ratio. By manipulation of HOTAIR, we concluded that HOTAIR negatively regulates Sirt1 expression through affecting its promotor methylation. Moreover, overexpression of Sirt1 reverses pcDNA-HOTAIR-induced glucose- and lipid-metabolism-related gene expression. Our study suggests that HCV core protein causes dysfunction of glucose and lipid metabolism in liver cells through HOTAIR-Sirt1 signalling pathway.
Highlights
Chronic hepatic infection with hepatitis C virus (HCV) is one of the most common chronic liver diseases and affects 1 % to more than 3 % residents in different regions of the world [1]
Core protein promotes HOAIR expression in HepG2 We detected ectopic expression of liver disease-specific long non-coding RNAs (lncRNAs) in HCV core protein overexpression treated HepG2. pcDNA-core transfection led to up-regulation of core protein (Figure 1A)
In Figure 1(B), results from quantitative RT-PCR (qRT-PCR) showed that HCV core overexpression contributed to significantly upregulation of lncRNA HOTAIR; it had no effect on relative expression of H19, MALAT1, CMPK2, Lethe and BST2
Summary
Chronic hepatic infection with hepatitis C virus (HCV) is one of the most common chronic liver diseases and affects 1 % to more than 3 % residents in different regions of the world [1]. The initially pathological basics for these progresses largely focus on extensive glucose, lipid and cholesterol metabolic abnormalities of hepatocyte in response to chronic HCV infection [4,5]. HCV core protein-induced serine phosphorylation of insulin receptor substrate-1; stimulated insulin resistance and caused decreased glucose uptake. This phenomenon was demonstrated by a HCV core protein transgenic mouse model experiment, in which suggested that HCV core protein contributes to the development of insulin resistance through suppressing activation of insulin receptor substrate [6]. As for lipid metabolism, HCV core protein can inhibit both microsomal triacylglycerol (TG) transfer protein activity and secretion of very low-density lipoprotein (VLDL) [7]. To data, the clear mechanism underlying this regulatory action has not been defined yet
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