13, 37 In HCV-infected patients, increased hepatic SHP, MTP, NTCP, and CYP7A1 mRNA was observed, and FXR, G6P, and PEPCK mRNA levels did not change. This finding suggests that the FXR-SHP-CYP7A1 regulatory loop is totally compromised in HCV-infected Selleckchem R428 liver. The observed changes could be due to HCV infection. Alternatively, such changes could be adaptive host responses
in order to minimize liver injury. MTP is essential for hepatic lipoprotein assembly and secretion, and VLDL is important for HCV secretion from the infected cells.23 In addition, bile acid via FXR promotes genotype 1 HCV replication.38, 39 Thus, all these alterations are related to HCV life cycle. Activation of CAR ameliorates hyperglycemia by suppressing glucose production and stimulating glucose uptake and usage in the liver and improves steatosis by inhibiting hepatic lipogenesis and inducing β-oxidation.40 In our hepatitis C patients, CAR was significantly up-regulated and this was accompanied by decreased SREBP-1c and increased GLUT2 expression. This finding suggests that CAR may play a significant role in lipid and glucose metabolism in HCV-infected livers. In ethanol-fed mice, hepatic PPARα-mediated signaling Y-27632 molecular weight is decreased.41–43 In addition, AMPK activity and fatty acid synthesis-related genes are down-regulated.44 In the HCV-infected patients who had a history of drinking, our results showed that PPARα and RXRα expression levels were increased, with concomitant up-regulation
of their target genes involved in fatty acid oxidation and hepatic uptake and intracellular trafficking. Species difference may account for the differential findings. There were both current and noncurrent drinkers in group B, but no significant difference could be found in gene expression between the two groups (Supporting Table 2). This suggests the possibility of active drinking in “noncurrent drinkers”. In addition, the gene expression alteration does not seem to be caused 上海皓元医药股份有限公司 by differences in disease severity because there was no difference in liver panel, severity of fibrosis, or inflammation in these two cohorts (Supporting Table 3). Although PPARα and RXRα and their target genes were up-regulated in patients
with a history of alcohol drinking, the genes involved in antioxidant and inflammatory pathways did not change their expression level significantly (Supporting Fig. 2B). This result does not support the hypothesis that alcohol and HCV synergize through increasing PPARα activity, lipid peroxidation, oxidative stress, and thus liver injury. Other mechanisms have been proposed to explain the synergism of HCV infection and alcohol intake. For example, alcohol impairs the intracellular innate immune response in human hepatocytes and promotes HCV infection and replication.45 Multivariate analysis showed an independent association between the hepatic mRNA levels of FAS, FGF21, and IL-10 with HCV RNA. All these genes are regulated by nuclear receptors or coregulators.