Ma Feifei, Hu Lijuan, Yu Ming, Wang Feng
* Department of Nutrition and Food Hygiene, School of Public Health, Tianjin Medical University, Tianjin 300070, China.
† Tianjin Institute of Integrative Medicine for Acute Abdominal Diseases, Nankai Hospital, Tianjin 300100, China.
Am J Chin Med. 2016;44(5):997-1008. doi: 10.1142/S0192415X16500555. Epub 2016 Jul 19.
Hypoxia-inducible factor-1 (HIF-1) is an [Formula: see text] dimeric transcription factor. Because HIF-1[Formula: see text] is instable with oxygen, HIF-1 is scarce in normal mammalian cells. However, HIF-1[Formula: see text] is expressed in pathological conditions such as cancer and obesity. Inhibiting HIF-1[Formula: see text] 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[Formula: see text] 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[Formula: see text] expression was determined by Western blot. We found that emodin inhibited obesity-induced HIF-1[Formula: see text] expression in liver and skeletal muscle but did not regulate HIF-1[Formula: see text] expression in the kidneys or in intra-abdominal fat. In vitro, emodin inhibited HIF-1[Formula: see text] expression in human HepG2 hepatic cells and Y1 adrenocortical cells. Further, we investigated the mechanisms of HIF-1[Formula: see text] expression in emodin-treated HepG2 cells. First, we found that HIF-1[Formula: see text] had normal stability in the presence of emodin. Thus, emodin did not decrease HIF-1[Formula: see text] by stimulating its degradation. Importantly, emodin decreased the activity of the signaling pathways that led to HIF-1[Formula: see text] biosynthesis. Interestingly, emodin increased HIF-1[Formula: see text] mRNA in HepG2 cells. This may be a result of feedback in response to the emodin-induced decrease in the protein of HIF-1[Formula: see text]. In conclusion, emodin decreases hepatic HIF-1[Formula: see text] by inhibiting its biosynthesis.
缺氧诱导因子-1（HIF-1）是一种αβ二聚体转录因子。由于HIF-1α在有氧条件下不稳定，因此在正常哺乳动物细胞中HIF-1含量稀少。然而，HIF-1α在癌症和肥胖等病理状态下表达。抑制HIF-1α可能对这些病症具有治疗价值。在此，我们研究了来源于中国本土的掌叶大黄（也称为中国大黄）的大黄素是否调节HIF-1α表达。对雄性C57BL/6小鼠，无论有无饮食诱导的肥胖，均用大黄素处理两周，而对照小鼠用赋形剂处理。通过蛋白质印迹法测定HIF-1α表达。我们发现大黄素抑制肝脏和骨骼肌中肥胖诱导的HIF-1α表达，但不调节肾脏或腹部脂肪中的HIF-1α表达。在体外，大黄素抑制人HepG2肝细胞和Y1肾上腺皮质细胞中的HIF-1α表达。此外，我们研究了大黄素处理后的HepG2细胞中HIF-1α表达的机制。首先，我们发现在存在大黄素的情况下HIF-1α具有正常稳定性。因此，大黄素不会通过刺激其降解来降低HIF-1α。重要的是，大黄素降低了导致HIF-1α生物合成的信号通路的活性。有趣的是，大黄素增加了HepG2细胞中HIF-1α的mRNA。这可能是对大黄素诱导的HIF-1α蛋白减少的反馈结果。总之，大黄素通过抑制其生物合成来降低肝脏中的HIF-1α。
