Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men

Abstract

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.

Fig. 1.

Individual responses (placebo vs. atorvastatin treatment) of the 22 participants. Data for (A) plasma LDL-C, (B) TG, (C) apoB-48, (D) PCSK9, (E) lathosterol, and (F) sitosterol are shown along with means ± SD (gray symbols). The proportion of participants’ responses moving in the same direction following atorvastatin is also provided for each variable.

Fig. 2.

Individual responses (placebo vs. atorvastatin treatment) of the 22 participants. Data for the expression of (A) HMG-CoAR, (B) LDL receptor, (C) SREBP-2, (D) NPC1L1, (E) ABCG5, and (F) ABCG8 are shown along with means ± SD (gray symbols). The proportion of participants’ responses moving in the same direction following atorvastatin is also provided for each variable.

Fig. 3.

Correlation between changes in intestinal ABCG5 and ABCG8 mRNA expression (A) and correlation between changes in HNF-4α and changes in intestinal SREBP-2 mRNA expression (B) following treatment with atorvastatin, 40 mg/day, versus placebo.

Fig. 4.

Correlation between changes in HMG-CoAR, LDL receptor, and intestinal NPC1L1 mRNA expression and changes in intestinal SREBP-2 (A) and HNF-4α (B) mRNA expression following treatment with atorvastatin, 40 mg/day, versus placebo are shown.