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Journal of Lipid Research, Vol. 50, 915-923, May 2009
Copyright © 2009 by American Society for Biochemistry and Molecular Biology

Diosgenin stimulation of fecal cholesterol excretion in mice is not NPC1L1 dependent

Ryan E. Temel^*, J. Mark Brown^*, Yinyan Ma^*, Weiqing Tang^*, Lawrence L. Rudel^*, Yiannis A. Ioannou, Joanna P. Davies and Liqing Yu^1,*

^* Department of Pathology, Section on Lipid Sciences, Wake Forest University School of Medicine, Winston-Salem, NC
Department of Human Genetics, Mount Sinai School of Medicine, New York, NY

This work was supported by a Scientist Development Grant from the American Heart Association (0635261N to L.Y.) and the funds from the Department of Pathology at Wake Forest University School of Medicine. Partial support was derived from National Institutes of Health Grant HL-49373.

Published, JLR Papers in Press, January 13, 2009.

¹ To whom correspondence should be addressed. e-mail: lyu{at}wfubmc.edu

Diosgenin exists in some food supplements and herbal medicines and lowers plasma cholesterol by increasing fecal cholesterol excretion. It is believed that diosgenin promotes fecal cholesterol excretion by stimulating biliary cholesterol secretion and decreasing intestinal cholesterol absorption. Niemann-Pick C1-like 1 (NPC1L1) was recently identified as an essential protein for intestinal cholesterol absorption. To determine the relative contribution of biliary secretion and intestinal absorption of cholesterol in diosgenin-stimulated fecal cholesterol excretion, wild-type (WT) and NPC1L1-knockout (L1KO) mice were fed a diet with or without 1% diosgenin. Fecal cholesterol excretion (µmol/day/100 g body weight) increased in diosgenin-fed WT and L1KO mice from 4.2 to 52 and from 63 to 140, respectively. Surprisingly, this increase in diosgenin-treated versus untreated L1KO mice (77) was even greater than that seen in diosgenin-treated versus untreated WT mice (47.8). Additionally, WT and L1KO mice fed the diosgenin diet had similar increases in biliary cholesterol concentration, despite unaltered hepatic expression of the hepatobiliary cholesterol transporter, ATP binding cassette transporters G5 and G8. Facilitated cholesterol excretion in diosgenin-treated WT and L1KO mice was associated with decreased hepatic and plasma cholesterol and increased liver expression of cholesterol synthetic genes. In contrast, diosgenin had no effect on the intestinal expression of NPC1L1 and cholesterol synthetic genes. In an in vitro assay, diosgenin was unable to block NPC1L1-dependent cholesterol uptake. In conclusion, diosgenin stimulation of fecal cholesterol excretion is independent of NPC1L1-mediated cholesterol absorption.

Supplementary key words bile • intestine • feces

Abbreviations: ABC, ATP binding cassette transporter; EGFP, enhanced green fluorescent protein; HMGCR, HMG-CoA reductase; HMGCS, HMG-CoA synthase; HPβCD, hydroxypropyl-β-cyclodextrin; L1KO, Niemann-Pick C1-Like 1-knockout; MβCD, methyl-β-cyclodextrin; NPC1L1, Niemann-Pick C1-Like 1; PXR, pregnane X receptor; qPCR, quantitative PCR; SREBP2, sterol regulatory element binding protein 2; WT, wild-type

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