Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8

Weiqing Tang,Yinyan Ma,Lin Jia,Yiannis A Ioannou,Joanna P Davies,Liqing Yu

doi:10.1194/jlr.m800439-jlr200

Abstract

Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L1(-/-)mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols. However, wild-type (WT) mice do not efficiently absorb and accumulate phytosterols either. Cell-based studies show that NPC1L1 is a much weaker transporter for phytosterols than cholesterol. In this study, we examined the role of NPC1L1 in phytosterol and cholesterol trafficking in mice lacking ATP-binding cassette (ABC) transporters G5 and G8 (G5/G8(-/-) mice). G5/G8(-/-) mice develop sitosterolemia, a genetic disorder characterized by the accumulation of phytosterols in blood and tissues. We found that mice lacking ABCG5/G8 and NPC1L1 [triple knockout (TKO) mice] did not accumulate phytosterols in plasma and the liver. TKO mice, like G5/G8(-/-) mice, still had a defect in hepatobiliary cholesterol secretion, which was consistent with TKO versus NPC1L1(-/-) mice exhibiting a 52% reduction in fecal cholesterol excretion. Because fractional cholesterol absorption was reduced similarly in NPC1L1(-/-) and TKO mice, by subtracting fecal cholesterol excretion in TKO mice from NPC1L1(-/-) mice, we estimated that a 25g NPC1L1(-/-) mouse may secrete about 4 mumol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.

Highlights

Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L12/2mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols
NPC1L12/2 and triple knockout (TKO) versus WT mice had a significant reduction in plasma cholesterol levels, which likely resulted from the blockade of intestinal cholesterol absorption, in agreement with our recent finding [44]
Phytosterol levels were undetectable by our methods in some of the WT, NPC1L12/2, and TKO mice that had been fed the synthetic diet for 21 days

Summary

Introduction

Mice lacking Niemann-Pick C1-Like 1 (NPC1L1) (NPC1L12/2mice) exhibit a defect in intestinal absorption of cholesterol and phytosterols. We examined the role of NPC1L1 in phytosterol and cholesterol trafficking in mice lacking ATP-binding cassette (ABC) transporters G5 and G8 (G5/G82/2 mice). G5/G82/2 mice develop sitosterolemia, a genetic disorder characterized by the accumulation of phytosterols in blood and tissues. We found that mice lacking ABCG5/G8 and NPC1L1 [triple knockout (TKO) mice] did not accumulate phytosterols in plasma and the liver. TKO mice, like G5/G82/2 mice, still had a defect in hepatobiliary cholesterol secretion, which was consistent with TKO versus NPC1L12/2 mice exhibiting a 52% reduction in fecal cholesterol excretion. Yu. Genetic inactivation of NPC1L1 protects against sitosterolemia in mice lacking ABCG5/ABCG8.

Methods

Results

Conclusion