43 Because most of the HCC cases in our locality PFT�� concentration are associated with HBV infection, our data suggest that increased SIRT2 activity might activate β-catenin, and hence metastasis of HCC, in these patients of which the mutation rate of β-catenin/Axin1/APC is relatively lower. Earlier, we demonstrated that SIRT1 may promote HCC cell growth through its role in telomere maintenance23; our current data further demonstrate a role for SIRT2 in cell migration that may contribute to HCC metastasis. Together, these studies provide a rationale to explore whether pharmacological inhibition of SIRT1 and SIRT2 by a dual SIRT1/SIRT2 inhibitor, such as sirtinol,44

splitomicin,45 and cambinol,46 or their analogs, will be a novel strategy for targeted therapy of HCC overexpressing these sirtuins. We would also like to thank CUHK’s Academic Editor, Dr. David Wilmshurst, for commenting on a draft of this manuscript. Additional Supporting Information may be found in the online version of this article. “
“Chronic alcohol consumption leads to hypertriglyceridemia, which is positively associated with

alcoholic liver disease (ALD). However, whether and how it contributes to the development of fatty liver and liver injury are largely unknown. In this study we demonstrate that chronic alcohol exposure differently regulates the expression of very-low-density lipoprotein receptor (VLDLR) in adipose tissue and the liver. Whereas adipose tissue VLDLR is significantly down-regulated, MCE its hepatic expression is dramatically

increased after chronic alcohol feeding. While HepG2 cells stably overexpressing selleck kinase inhibitor VLDLR manifests increased intracellular triglyceride accumulation, VLDLR-deficient mice are protective against fatty liver and liver injury after chronic alcohol exposure. Mechanistic investigations using both in vitro and in vivo systems reveal that oxidative stress-induced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation plays a critical role in alcohol-induced VLDLR up-regulation in hepatocytes, but not in adipocytes. Oxidative stress enhances VLDLR gene expression and protein abundance in primary hepatocytes, concomitant with the Nrf2 activation. Conversely, Nrf2 gene silencing abrogates oxidative stress-induced VLDLR up-regulation in the liver, but not in adipose tissue. In mice, alcohol exposure induces hepatic oxidative stress and Nrf2 activation. Supplementation of N-acetylcysteine alleviates fatty liver and liver injury induced by chronic alcohol exposure, which is associated with suppressed Nrf2 activation and attenuated VLDLR increase in the liver. Furthermore, in comparison to wild-type counterparts, Nrf2-deficient mice demonstrate attenuated hepatic VLDLR expression increase in response to chronic alcohol exposure. Conclusion: Chronic alcohol consumption differently alters VLDLR expression in adipose tissue and the liver.