Abstract
The investigation of the human disease sitosterolemia (MIM 210250) has shed light not only on the pathways by which dietary sterols may traffic but also on how the mammalian body rids itself of cholesterol and defends against xenosterols. Two genes, ABCG5 and ABCG8, located at the sitosterolemia locus, each encodes a membrane-bound ABC half-transporter and constitutes a functional unit whose activity has now been shown to account for biliary and intestinal sterol excretion. Knockout mice deficient in Abcg5 or Abcg8 recapitulate many of the phenotypic features of sitosterolemia. During the course of our studies to characterize these knockout mice, we noted that these mice, raised on normal rodent chow, exhibited infertility as well as loss of abdominal fat. We show that, although sitosterolemia does not lead to any structural defects or to any overt endocrine defects, fertility could be restored if xenosterols are specifically blocked from entry and that the loss of fat is also reversed by a variety of maneuvers that limit xenosterol accumulation. These studies show that xenosterols may have a significant biological impact on normal mammalian physiology and that the Abcg5 or Abcg8 knockout mouse model may prove useful in investigating the role of xenosterols on mammalian physiology.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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ATP Binding Cassette Transporter, Subfamily G, Member 5
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ATP Binding Cassette Transporter, Subfamily G, Member 8
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ATP-Binding Cassette Transporters / deficiency*
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ATP-Binding Cassette Transporters / genetics
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Abdominal Fat / cytology
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Abdominal Fat / drug effects*
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Abdominal Fat / metabolism
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Adipocytes / cytology
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Adipocytes / drug effects
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Adipose Tissue, White / drug effects
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Adipose Tissue, White / metabolism
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Animals
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Azetidines / pharmacology
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Cell Size / drug effects
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Dietary Fats / adverse effects*
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Ezetimibe
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Fatty Acids / metabolism
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Female
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Gene Expression Regulation / drug effects
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Gene Knockout Techniques
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Glucose Tolerance Test
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Humans
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Infertility, Female / chemically induced*
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Infertility, Female / genetics
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Infertility, Female / metabolism
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Infertility, Female / pathology
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Infertility, Male / chemically induced*
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Infertility, Male / genetics
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Infertility, Male / metabolism
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Infertility, Male / pathology
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Intestinal Mucosa / metabolism
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Intestines / drug effects
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Lipoproteins / deficiency*
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Lipoproteins / genetics
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Male
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Mice
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Phytosterols / adverse effects*
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Testis / drug effects
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Testis / metabolism
Substances
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ABCG5 protein, mouse
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ABCG8 protein, mouse
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ATP Binding Cassette Transporter, Subfamily G, Member 5
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ATP Binding Cassette Transporter, Subfamily G, Member 8
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ATP-Binding Cassette Transporters
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Azetidines
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Dietary Fats
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Fatty Acids
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Lipoproteins
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Phytosterols
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Ezetimibe