Browsing by Author "Morales, MG"

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    Effects of hepatic expression of the high-density lipoprotein receptor SR-BI on lipoprotein metabolism and female fertility
    (ENDOCRINE SOC, 2006) Yesilaltay, A; Morales, MG; Amigo, L; Zanlungo, S; Rigotti, A; Karackattu, SL; Donahee, MH; Kozarsky, KF; Krieger, M
    The etiology of human female infertility is often uncertain. The sterility of high-density lipoprotein (HDL) receptor-negative (SR-BI-/-) female mice suggests a link between female infertility and abnormal lipoprotein metabolism. SR-BI-/- mice exhibit elevated plasma total cholesterol [ with normalsized and abnormally large HDL and high unesterified to total plasma cholesterol (UC:TC) ratio]. We explored the influence of hepatic SR-BI on female fertility by inducing hepatic SR-BI expression in SR-BI-/- animals by adenovirus transduction or stable transgenesis. For transgenes, we used both wild-type SR-BI and a double-point mutant, Q402R/Q418R (SR-BI-RR), which is unable to bind to and mediate lipid transfer from wild-type HDL normally, but retains virtually normal lipid transport activities with low-density lipoprotein. Essentially wild-type levels of hepatic SR-BI expression in SR-BI-/- mice restored to nearly normal the HDL size distribution and plasma UC: TC ratio, whereas approximately 7- to 40- fold overexpression dramatically lowered plasma TC and increased biliary cholesterol secretion. In contrast, SR-BI-RR overexpression had little effect on SR-BI-/- mice, but in SR-BI-/- mice, it substantially reduced levels of abnormally large HDL and normalized the UC: TC ratio. In all cases, hepatic transgenic expression restored female fertility. Overexpression in SR-BI-/- mice of lecithin: cholesterol acyl transferase, which esterifies plasma HDL cholesterol, did not normalize the UC: TC ratio, probably because the abnormal HDL was a poor substrate, and did not restore fertility. Thus, hepatic SR- BImediated lipoprotein metabolism influences murine female fertility, raising the possibility that dyslipidemia might contribute to human female infertility and that targeting lipoprotein metabolism might complement current assisted reproductive technologies.
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    NPC2 is expressed in human and murine liver and secreted into bile: Potential implications for body cholesterol homeostasis
    (WILEY, 2006) Klein, A; Amigo, L; Retamal, MJ; Morales, MG; Miquel, JF; Rigotti, A; Zanlungo, S
    The liver plays a critical role in the metabolism of lipoprotein cholesterol and in controlling its elimination through the bile. Niemann-Pick type C 2 (NPC2), a cholesterol-binding protein, is key for normal intracellular trafficking of lipoprotein cholesterol, allowing its exit from the endolysosomal pathway into the metabolically active pool of the cell. In addition, NPC2 is a secretory protein from astrocytes and epididymal cells. Although NPC2 mRNA is detected in the liver, plasma and biliary NPC2 protein levels and function have not been reported. This study demonstrates that NPC2 is present in murine and human plasma and bile. In addition, hepatic NPC2 protein expression was dramatically increased in NPC1-deficient mice but not regulated by cholesterol feeding or pharmacological modulation of various nuclear receptors involved in cholesterol and bile acid metabolism. Interestingly, biliary NPC2 levels were 3-fold increased in gallstone-susceptible C57BL6/J versus gallstone-resistant BALB/c mice. Furthermore, NPC2 was exclusively found in the cholesterol pro-nucleating ConA-binding fraction of human bile. In conclusion, NPC2 is secreted from the liver into bile and plasma, where it may have a functional role in cholesterol transport in normal and disease conditions.