蛇床子素通过激活过氧化物酶体增殖物激活受体α调节肝细胞内脂肪酸代谢  

Osthole regulates fatty acid metabolism in hepatocytes by activation of PPARα

作　　者：沈洪[1] 周峰[2] 薛洁[3] 谢梅林[3] 

机构地区：[1]湖州师范学院医学院药理学教研室,浙江湖州313000 [2]苏州市第五人民医院药剂科,江苏苏州215006 [3]苏州大学药学院药理学系,江苏苏州215123

出　　处：《中国药理学与毒理学杂志》2013年第2期174-179,共6页Chinese Journal of Pharmacology and Toxicology

基　　金：浙江省自然科学基金(Y2100755)~~

摘　　要：目的探讨蛇床子素是否通过激活过氧化物酶体增殖物激活受体(PPAR)α调节肝细胞内的脂肪酸代谢。方法 大鼠肝细胞在用蛇床子素12.5～100μmol.L-1作用24 h后,用比色法测定细胞内甘油三酯(TG)和游离脂肪酸(FFA)含量,用逆转录聚合酶链反应法测定PPARαmRNA表达的变化。PPARα抑制剂MK886 1μmo.lL-1预处理肝细胞2 h后,观察蛇床子素100μmo.lL-1作用24 h后对细胞内TG和FFA含量以及PPARα调控的靶基因包括固醇调节元件结合蛋白(SREBP)-1/2、脂肪酸合酶(FAS)、二脂酰甘油酰基转移酶(DGAT)、肉碱软脂酰转移酶(CPT)-1a、脂肪酸转运蛋白(FATP)4和肝脂肪酸结合蛋白(L-FABP)mRNA表达的影响。结果 蛇床子素12.5～100μmol.L-1可明显降低肝细胞内TG和FFA的含量(P<0.01),同时也能明显增加肝细胞内PPARαmRNA的表达(P<0.01)。在用PPARα抑制剂MK886预处理后,蛇床子素降低肝细胞内TG和FFA的作用则明显被减弱(P<0.01),同时抑制SREBP-1/2,FAS和DGAT mRNA表达的作用明显减弱或完全消失(P<0.01),增加CPT-1a,FATP4和L-FABPmRNA表达的作用也明显减弱或完全消失(P<0.01)。结论 蛇床子素通过激活肝细胞中PPARα后可降低细胞中的TG和FFA含量,其机制与激活PPARα后随后抑制SREBP-1/2,FAS和DGAT的基因表达以及增加CPT-1a,FATP4和L-FABP的基因表达有关。OBJECTIVE To determine whether osthole regulates fatty acid metabolism in hepato- cytes of rats by activating peroxisome proliferator-activated receptor （PPAR） α. METHODS Rat hepa- tocytes were cultured and treated with osthole 12.5 -100 pmol. L-1 for 24 h, before triglycerides （TG） and free fatty acid （FFA） contents in hepatocytes were determined by colorimetric method. PPARa mRNA expression was determined by reverse transcription polymerase chain reaction. In order to deter- mine whether the lipid-regulating effect of osthole was associated with activation of PPARα, hepatocytes were pretreated with PPARa inhibitor MK886 1 μmol· L-1 for 2 h before incubation with osthole 100 μmol·L-1 for 24 h. TG and FFA contents, PPARα-regulated target genes including sterol regulatory element-binding protein （SREBP）-1/2, fatty acid synthase （FAS）, diacylglycerol acyltransferase （DGAT）, carnitine palmitoyltransferase （ CPT）-lα, fatty acid transporter protein （FATP） 4, and liver fatty acid binding protein （L-FABP） mRNA expressions in hepatocytes were examined. RESULTS Osthole 12.5 -100 μmol·L-1 could significantly reduce TG and FFA contents and enhance the PPARα mRNA expression in hepatocytes of rats（ P 〈0.01 ）, but reduction of TG and FFA contents were signifi- cantly alleviated after pretreatment with PPARα inhibitor MK886 （ P 〈 0.01 ）. Similarly, the reduction of SREBP-1/2, FAS and DGAT mRNA expressions as well as the increment of CPT-la, FATPa and L-FABP mRNA expressions in hepatocytes of rats by osthole were also alleviated or abrogated after pretreatment with PPARα inhibitor MK886 （ P 〈0.01 ）. CONCLUSION Osthole can decrease TG and FFA contents in hepatocytes. The mechanisms might be associated with activation of PPARα, subse- quent reduction of SREBP-1/2, FAS and DGAT gene expressions and increment of CPT-la, FATP4 and L-FABP gene expressions.

关 键 词：蛇床子素 脂肪酸 过氧化物酶体增殖物激活受体Α 肝细胞 

分 类 号：R285.5[医药卫生—中药学] R963[医药卫生—中医学]