Lipid Research Centre, Laval University, Quebec City, Quebec, Canada.
J Lipid Res. 2011 Mar;52(3):558-65. doi: 10.1194/jlr.M011080. Epub 2010 Dec 1.
Inhibition of cholesterol synthesis by 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) inhibitors has been associated with an increase in intestinal cholesterol absorption. This study examined how HMG-CoAR inhibition by atorvastatin modulates expression of key genes involved in intestinal cholesterol metabolism. A crossover study was conducted in which 22 hyperlipidemic men received atorvastatin, 40 mg/day, or placebo, each for 12 weeks. Gene expression was assessed by real-time PCR using duodenal biopsy samples obtained at the end of each phase of treatment. Treatment with atorvastatin was associated with a 76% reduction in lathosterol and significant increases in sitosterol (70%). Atorvastatin significantly increased intestinal mRNA levels of HMG-CoAR (59%), LDL receptor (LDLR) (52%), PCSK9 (187%), SREBP-2 (44%), and HNF-4α (13%). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 19% and decreased mRNA levels of both ABCG5 and ABCG8 by 14%. Positive correlations were observed between changes in SREBP-2 and HNF-4α expression and concurrent changes in the intestinal mRNA levels of HMG-CoAR, LDLR, and NPC1L1. These results indicate that HMG-CoAR inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDLR, and PCSK9; increases cholesterol absorption; and reduces expression of ABCG5/8; these effects are most likely mediated by upregulation of the transcription factors SREBP-2 and HNF-4α.
3-羟基-3-甲基戊二酰辅酶 A 还原酶(HMG-CoAR)抑制剂抑制胆固醇合成,与肠道胆固醇吸收增加有关。本研究探讨了阿托伐他汀对 HMG-CoAR 的抑制作用如何调节肠道胆固醇代谢关键基因的表达。进行了一项交叉研究,其中 22 名高脂血症男性分别接受阿托伐他汀 40mg/天或安慰剂治疗,各 12 周。在每个治疗阶段结束时,通过实时 PCR 使用十二指肠活检样本评估基因表达。阿托伐他汀治疗与羊毛固醇降低 76%和谷甾醇显著增加(70%)相关。阿托伐他汀显著增加了肠道 HMG-CoAR(59%)、LDL 受体(LDLR)(52%)、PCSK9(187%)、SREBP-2(44%)和 HNF-4α(13%)的 mRNA 水平。此外,阿托伐他汀使 NPC1L1 的肠道 mRNA 水平增加了 19%,并使 ABCG5 和 ABCG8 的 mRNA 水平分别降低了 14%。SREBP-2 和 HNF-4α表达的变化与 HMG-CoAR、LDLR 和 NPC1L1 的肠道 mRNA 水平的同时变化之间存在正相关。这些结果表明,阿托伐他汀抑制 HMG-CoAR 刺激 NPC1L1、LDLR 和 PCSK9 的肠道表达;增加胆固醇吸收;并降低 ABCG5/8 的表达;这些作用很可能是通过上调转录因子 SREBP-2 和 HNF-4α介导的。