Department of Biochemistry and Molecular Biology, Metabolic Disease Research Center, School of Basic Medicine, Anhui Medical University, Hefei, 230032, China.
Department of Hyperbaric Oxygen, The Second People's Hospital of Hefei, Hefei Hospital Affiliated to Anhui Medical University, Hefei, 230011, China.
Acta Pharmacol Sin. 2023 Jul;44(7):1416-1428. doi: 10.1038/s41401-023-01056-z. Epub 2023 Jan 31.
Non-alcoholic fatty liver disease (NAFLD) is a major health concern worldwide, and the incidence of metabolic disorders associated with NAFLD is rapidly increasing because of the obesity epidemic. There are currently no approved drugs that prevent or treat NAFLD. Recent evidence shows that bavachin, a flavonoid isolated from the seeds and fruits of Psoralea corylifolia L., increases the transcriptional activity of PPARγ and insulin sensitivity during preadipocyte differentiation, but the effect of bavachin on glucose and lipid metabolism remains unclear. In the current study we investigated the effects of bavachin on obesity-associated NAFLD in vivo and in vitro. In mouse primary hepatocytes and Huh7 cells, treatment with bavachin (20 μM) significantly suppressed PA/OA or high glucose/high insulin-induced increases in the expression of fatty acid synthesis-related genes and the number and size of lipid droplets. Furthermore, bavachin treatment markedly elevated the phosphorylation levels of AKT and GSK-3β, improving the insulin signaling activity in the cells. In HFD-induced obese mice, administration of bavachin (30 mg/kg, i.p. every other day for 8 weeks) efficiently attenuated the increases in body weight, liver weight, blood glucose, and liver and serum triglyceride contents. Moreover, bavachin administration significantly alleviated hepatic inflammation and ameliorated HFD-induced glucose intolerance and insulin resistance. We demonstrated that bavachin protected against HFD-induced obesity by inducing fat thermogenesis and browning subcutaneous white adipose tissue (subWAT). We revealed that bavachin repressed the expression of lipid synthesis genes in the liver of obese mice, while promoting the expression of thermogenesis, browning, and mitochondrial respiration-related genes in subWAT and brown adipose tissue (BAT) in the mice. In conclusion, bavachin attenuates hepatic steatosis and obesity by repressing de novo lipogenesis, inducing fat thermogenesis and browning subWAT, suggesting that bavachin is a potential drug for NAFLD therapy.
非酒精性脂肪性肝病 (NAFLD) 是全球范围内的一个主要健康问题，由于肥胖症的流行，与 NAFLD 相关的代谢紊乱的发病率正在迅速增加。目前尚无预防或治疗 NAFLD 的批准药物。最近的证据表明，从 Psoralea corylifolia L. 的种子和果实中分离得到的类黄酮化合物补骨脂素，在人前脂肪细胞分化过程中增加 PPARγ 的转录活性和胰岛素敏感性，但补骨脂素对葡萄糖和脂质代谢的影响尚不清楚。在本研究中，我们研究了补骨脂素在体内和体外对肥胖相关的非酒精性脂肪性肝病的影响。在小鼠原代肝细胞和 Huh7 细胞中，补骨脂素（20 μM）处理显著抑制 PA/OA 或高葡萄糖/高胰岛素诱导的脂肪酸合成相关基因表达的增加以及脂滴的数量和大小。此外，补骨脂素处理显著提高了 AKT 和 GSK-3β的磷酸化水平，改善了细胞中的胰岛素信号活性。在 HFD 诱导的肥胖小鼠中，补骨脂素（30 mg/kg，腹腔注射，每隔一天一次，共 8 周）给药可有效减轻体重、肝重、血糖以及肝和血清甘油三酯含量的增加。此外，补骨脂素给药可显著减轻肝炎症，并改善 HFD 诱导的葡萄糖不耐受和胰岛素抵抗。我们证明补骨脂素通过诱导脂肪产热和褐色皮下白色脂肪组织 (subWAT) 来防止 HFD 诱导的肥胖。我们发现补骨脂素抑制肥胖小鼠肝脏中脂质合成基因的表达，同时促进 subWAT 和棕色脂肪组织 (BAT) 中产热、褐色化和线粒体呼吸相关基因的表达。总之，补骨脂素通过抑制从头脂肪生成、诱导脂肪产热和褐色化 subWAT 来减轻肝脂肪变性和肥胖，表明补骨脂素是治疗 NAFLD 的潜在药物。
