Emodin Decreases Hepatic Hypoxia-Inducible Factor-1 alpha by Inhibiting its Biosynthesis

摘要

Hypoxia-inducible factor-1 (HIF-1) is an alpha/beta dimeric transcription factor. Because HIF-1 alpha is instable with oxygen, HIF-1 is scarce in normal mammalian cells. However, HIF-1 alpha is expressed in pathological conditions such as cancer and obesity. Inhibiting HIF-1a may be of therapeutic value for these pathologies. Here, we investigated whether emodin, derived from the herb of Rheum palmatum L, which is also known as Chinese rhubarb, and is native to China, regulates HIF-1 alpha expression. Male C57BL/6 mice without or with diet-induced obesity were treated with emodin for two weeks, while control mice were treated with vehicle. HIF-1 alpha expression was determined by Western blot. We found that emodin inhibited obesity-induced HIF-1 alpha expression in liver and skeletal muscle but did not regulate HIF-1 alpha expression in the kidneys or in intra-abdominal fat. In vitro, emodin inhibited HIF-1 alpha expression in human HepG2 hepatic cells and Y1 adrenocortical cells. Further, we investigated the mechanisms of HIF-1 alpha expression in emodin-treated HepG2 cells. First, we found that HIF-1 alpha had normal stability in the presence of emodin. Thus, emodin did not decrease HIF-1 alpha by stimulating its degradation. Importantly, emodin decreased the activity of the signaling pathways that led to HIF-1 alpha biosynthesis. Interestingly, emodin increased HIF-1 alpha mRNA in HepG2 cells. This may be a result of feedback in response to the emodin-induced decrease in the protein of HIF-1 alpha. In conclusion, emodin decreases hepatic HIF-1 alpha by inhibiting its biosynthesis.