SISANews

L'atorvastatina aumenta l'espressione intestinale della proteina Niemann-Pick C1-like 1

La proteina Niemann-Pick C1 (NPLC1L1) è espressa sulla membrana degli enterociti e svolge un ruolo cruciale nell'assorbimento del colesterolo e degli steroli vegetali. Dopo atorvastatina, la sintesi di NPLC1L1 è risultata aumentare e questo spiega un fatto ben noto e cioè che l'assorbimento di colesterolo aumenta in parallelo con la riduzione della sua sintesi endogena. Il fenomeno contrasta il pieno effetto dell'inibizione della sintesi del colesterolo da parte delle statine sulla concentrazione plasmatica delle LDL. In questo studio è stato osservato anche un altro effetto dell'atorvastatina: l'aumento della PCSK9, una proteasi incaricata di degradare il recettore delle LDL di cui si è già parlato in SISANews del 23 febbraio. Aumento di NPLC1L1 e di PCSK9 sono pertanto due fenomeni che con meccanismo diverso tendono a ristabilire l'omeostasi del metabolismo del colesterolo disturbata dalla statina.

Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Tremblay AJ, Lamarche B, Lemelin V, Hoos L, Benjannet S, Seidah NG, Davis HR Jr, Couture P.

J Lipid Res 2011;52:558-65

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-4a (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-4a 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-4a.

J Lipid Res 2011;52:558-65