Dietary xenosterols lead to infertility and loss of abdominal adipose tissue in sterolin-deficient mice

Abstract

Journal of Lipid Research Volume 54, 2013397 noncholesterol sterols. These noncholesterol sterols are primarily plant sterols, and the mammalian body prevents the retention of these noncholesterol sterols, only allowing cholesterol to be retained and metabolized by the body. The molecular mechanism(s) by which this occurs was elucidated by studies of the rare genetic disorder sitosterolemia (MIM #210250), which led to the identifi cation of two ABC "half-transporters" that are key to keeping these molecules out of the body ( 4-8 ). The genetic defect in Sitosterolemia results in the increased absorption of dietary sterols, including plant sterols, compounded by a profound inability to excrete biliary or intestinal sterols, thus leading to their retention ( 9-14 ). Mutations in either ABCG5 (sterolin-1) or ABCG8 (sterolin-2) cause the disease ( 5,8,15 ). ABCG5 and ABCG8 are found on the apical surface of enterocytes and hepatocytes ( 16-18 ), function as obligate heterodimers, and are the long-sought-after sterol exporters responsible for biliary and intestinal excretion ( 17,(19)(20)(21)(22)(23)(24). It is becoming increasingly clear that ABCG5/ABCG8 are responsible for preventing accumulation of a host of dietary noncholesterol sterols ( 25 ), and thus, the term "xenosterol" should be used to refer to the class of sterols they prevent from accumulating. Three mouse models for the study of xenosterol/sitosterol traffi cking are now available: a murine model simultaneously defi cient in both Abcg5/Abcg8 ( 22, 24 ), a model lacking only of Abcg8 ( 20 ), and one defi cient in Abcg5 ( 21 ). Despite some differences, all three models recapitulate important sitosterolemic features, such as increased plasma and tissue levels of plant sterols (phytosterols) and massively reduced Abstract The investigation of the human disease sitosterolemia (MIM 210250) has shed light not only on the pathways by which dietary sterols may traffi c 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 membranebound ABC half-transporter and constitutes a functional unit whose activity has now been shown to account for biliary and intestinal sterol excretion. Knockout mice defi cient 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 specifi cally 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 signifi cant biological impact on normal mammalian physiology and that the Abcg5 or Abcg8 knockout mouse model may prove useful in investigating...

Platelet hyperreactivity explains the bleeding abnormality and macrothrombocytopenia in a murine model of sitosterolemia

“…14,18 As shown in Figure 1A-B, Abcg8 Figure 1C) typically associated with human sitosterolemia. 11 These hematologic parameters were nearly identical in Abcg5-deficient mice fed an HS diet (not shown).…”

“…Abcg5-and Abcg8-deficient mice on a C57BL/6J background have been described previously 13,17,18 and have been deposited with Jackson Laboratories. GPIba-null mice 19 were generously provided by Dr. Jerry Ware (University of Arkansas).…”

“…The high plant sterol (HS) diet contains 1% w/w of plant sterols; the low plant sterol diet (LS) contains ,0.01% w/w of plant sterols. 18 …”

Interferon Regulatory Factor 1 Restricts Gammaherpesvirus Replication in Primary Immune Cells

“…Eluates were concentrated under 100% nitrogen, derivatized using a 99:1 solution of N,O-bis(trimethylsilyl) trifluoroacetamide (BSTFA/TMCS) and trimethylchlorosilane (TMCS), and dried under 100% nitrogen. Samples were resuspended in ethyl acetate and analyzed using gas chromatography-mass spectroscopy (GC-MS; Thermo Finnigan DSQ; Thermo Fisher Scientific, Madison, WI) using the conditions described previously (34). 25HC had an m/z of 131.0 with a retention time of 6.26 min, and 24-RS-HC had an m/z of 413.0 and a retention time of 17.80 min; these values were comparable to those reported previously (35).…”

Plant Sterols, Stanols, and Sitosterolemia

“…In addition, PS has been reported to decrease serum estrogen levels in animals and disturb estrogen metabolism, which suggests an indication for reduced fertility (74, 75). PS are proposed to be responsible for modifying fat storage and fertility in ABCG5/G8 knockout mice via disruption of endocrine systems and mammalian physiology; although this claim has not been demonstrated in human subjects (76, 77). Research has shown that exclusion of PS from the diet and blocking dietary sterol absorption with ezetimibe treatment reversed infertility in ABCG5/G8 knockout mice (77).…”