Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ.
Tetrahydroxanthohumol, a xanthohumol derivative, attenuates high-fat diet-induced hepatic steatosis by antagonizing PPARγ.
复制标题
DOI：
10.7554/elife.66398
复制
发表时间：
2021-06-15
期刊：
影响因子：
7.7
通讯作者：
Gombart AF
中科院分区：
文献类型：
--
作者：
Zhang Y;Bobe G;Miranda CL;Lowry MB;Hsu VL;Lohr CV;Wong CP;Jump DB;Robinson MM;Sharpton TJ;Maier CS;Stevens JF;Gombart AF
我们先前报道了黄腐酚（XN）及其合成衍生物四氢-XN（TXN）减轻C57 Bl/6 J小鼠中高脂饮食（HFD）诱导的肥胖和代谢综合征。本研究的目的是确定XN和TXN对肝脏中脂质蓄积的影响。未补充TXN的小鼠无法使其热量摄入适应60%HFD，导致肥胖和肝脂肪变性;然而，TXN减少了体重增加并减少了肝脂肪变性。肝组织转录组学研究表明，TXN在体内可拮抗PPARγ的促脂作用。XN和TXN抑制罗格列酮诱导的3 T3-L1细胞分化，同时降低脂肪生成相关基因的表达。过氧化物酶体增殖物激活受体γ（PPARγ）竞争性结合试验表明，XN和TXN与PPARγ结合的IC 50与吡格列酮相似，比油酸强8-10倍。分子对接模拟表明XN和TXN结合在PPARγ配体结合域口袋中。我们的研究结果与XN和TXN作为PPARγ拮抗剂的作用一致。
We previously reported xanthohumol (XN), and its synthetic derivative tetrahydro-XN (TXN), attenuates high-fat diet (HFD)-induced obesity and metabolic syndrome in C57Bl/6J mice. The objective of the current study was to determine the effect of XN and TXN on lipid accumulation in the liver. Non-supplemented mice were unable to adapt their caloric intake to 60% HFD, resulting in obesity and hepatic steatosis; however, TXN reduced weight gain and decreased hepatic steatosis. Liver transcriptomics indicated that TXN might antagonize lipogenic PPARγ actions in vivo. XN and TXN inhibited rosiglitazone-induced 3T3-L1 cell differentiation concomitant with decreased expression of lipogenesis-related genes. A peroxisome proliferator activated receptor gamma (PPARγ) competitive binding assay showed that XN and TXN bind to PPARγ with an IC50 similar to pioglitazone and 8–10 times stronger than oleate. Molecular docking simulations demonstrated that XN and TXN bind in the PPARγ ligand-binding domain pocket. Our findings are consistent with XN and TXN acting as antagonists of PPARγ.