| Summary: | 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 μmol of cholesterol daily via the G5/G8 pathway. In conclusion, NPC1L1 is essential for phytosterols to enter the body in mice.
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