Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

• Main Authors: André J. Tremblay, Benoît Lamarche, Valéry Lemelin, Lizbeth Hoos, Suzanne Benjannet, Nabil G. Seidah, Jr. Harry R. Davis, Patrick Couture
• Format: Article
• Language: English
• Published: Elsevier 2011-03-01
• Series: Journal of Lipid Research
• Subjects: Niemann-Pick C1-like 1; cholesterol metabolism; 3-hydroxy-3-methylglutaryl CoA reductase; intestine; low density lipoprotein receptor
• Online Access: http://www.sciencedirect.com/science/article/pii/S0022227520409368

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.