Abstract 14273: Atorvastatin Increases Intestinal Expression of Niemann-Pick C1-Like-1 in Hyperlipidemic Men
Niemann-Pick C1-like-1 (NPC1L1) protein has been shown to play a crucial role in the intestinal uptake of cholesterol and plant sterols. Substantial evidence exists suggesting that inhibition of cholesterol synthesis by HMG CoA reductase inhibitors is associated with a reciprocal increase in cholesterol absorption. However, the impact of HMG CoA reductase inhibitors on expression of key genes involved in intestinal cholesterol absorption has not been studied in humans. To examine how HMG CoA reductase inhibition modulates intestinal expression of NPC1L1 and major genes involved in cholesterol metabolism, we conducted a double-blind randomized cross-over study where 22 hyperlipidemic men received atorvastatin 40 mg/d and placebo, each for 12 weeks. Gene expression was measured by real-time PCR in duodenal biopsies performed at the end of each phase of treatment. Atorvastatin significantly reduced plasma levels of cholesterol, LDL-C and TG by 37%, 50% and 29%, respectively (P<0.0005). Treatment with atorvastatin was also associated with a 76% reduction in lathosterol levels (P<0.0001) and significant increases in campesterol (65%, P<0.0001) and β-sitosterol (70%, P<0.0001) levels. Gene expression studies revealed that atorvastatin significantly increased intestinal mRNA levels of HMG CoA reductase (47%, P<0.0001), LDL receptor (52%, P=0.0007), PCSK9 (187%, P<0.0001), SREBP-2 (44%, P<0.0001) and HNF-4α (13%, P=0.02). Furthermore, atorvastatin significantly increased intestinal mRNA levels of NPC1L1 by 15% (P=0.03) and decreased mRNA levels of ABCG-5 and ABCG-8 by 16% (P=0.04) and 15% (P=0.06), respectively. Atorvastatin treatment was also associated with higher levels of intestinal NPC1L1 protein mass. Positive correlations were observed between changes in SREBP-2 expression and concurrent changes in the intestinal mRNA levels of HMG CoAR (r=0.45, P=0.04), LDLR (r=0.59, P=0.004) and NPC1L1 (r=0.65, P=0.0007). These results indicate that HMG CoA reductase inhibition with atorvastatin stimulates the intestinal expression of NPC1L1, LDL receptor, PCSK9, increases cholesterol absorption and reduces expression of ABCG-5/8, these effects being most likely mediated by overexpression of the transcription factors SREBP-2 and HNF-4α.
- © 2010 by American Heart Association, Inc.