RT Journal Article
SR Electronic
T1 Silybin restored CYP3A expression through the SIRT2/NF-κB pathway in mouse nonalcoholic fatty liver disease
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP DMD-AR-2021-000438
DO 10.1124/dmd.121.000438
A1 Ran Zhang
A1 Dan Xu
A1 Yirui Zhang
A1 Rui Wang
A1 Na Yang
A1 Yunge Lou
A1 Haokai Zhao
A1 Jiye Aa
A1 Guangji Wang
A1 Yuan Xie
YR 2021
UL http://dmd.aspetjournals.org/content/early/2021/06/28/dmd.121.000438.abstract
AB Silybin is widely used as a hepatoprotective agent in various liver disease therapies and has been previously identified as a CYP3A inhibitor. However, little is known about the effect of silybin on CYP3A and the regulatory mechanism during high-fat-diet (HFD)-induced liver inflammation. In our study, we found that silybin restored CYP3A expression and activity that were decreased by HFD and conditioned medium (CM) from palmitate (PA)-treated Kupffer cells. Moreover, silybin suppressed liver inflammation in HFD-fed mice and inhibited NF-κB translocation into the nucleus through elevation of SIRT2 expression and promotion of p65 deacetylation. This effect was confirmed by overexpression of SIRT2, which suppressed p65 nuclear translocation and restored CYP3A transcription affected by CM. The hepatic NAD+ concentration markedly decreased in HFD-fed mice and CM-treated hepatocytes/HepG2 cells but increased after silybin treatment. Supplementing NMN as an NAD+ donor inhibited p65 acetylation, decreased p65 nuclear translocation, and restored cyp3a transcription in both HepG2 cells and mouse hepatocytes. These results suggest that silybin regulates metabolic enzymes during liver inflammation by a mechanism related to the increase in NAD+ and SIRT2 levels. In addition, silybin enhanced the intracellular NAD+ concentration by decreasing PARP1 expression. In summary, silybin increased NAD+ concentration, promoted SIRT2 expression and lowered p65 acetylation both in vivo and in vitro, which supported the recovery of CYP3A expression. These findings indicate that the NAD+/SIRT2 pathway plays an important role in CYP3A regulation during NAFLD. Significance Statement This research revealed the differential regulation of CYP3A by silybin under physiological and fatty liver pathological conditions. In the treatment of NAFLD, silybin restored, not inhibited, CYP3A expression and activity through the NAD+/SIRT2 pathway in accordance with its anti-inflammatory effect.