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Aster-B–dependent estradiol synthesis protects female mice from diet-induced obesity
Xu Xiao, … , John W.R. Schwabe, Peter Tontonoz
Xu Xiao, … , John W.R. Schwabe, Peter Tontonoz
Published January 4, 2024
Citation Information: J Clin Invest. 2024;134(4):e173002. https://doi.org/10.1172/JCI173002.
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Research Article Metabolism Article has an altmetric score of 6

Aster-B–dependent estradiol synthesis protects female mice from diet-induced obesity

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Abstract

Aster proteins mediate the nonvesicular transport of cholesterol from the plasma membrane (PM) to the endoplasmic reticulum (ER). However, the importance of nonvesicular sterol movement for physiology and pathophysiology in various tissues is incompletely understood. Here we show that loss of Aster-B leads to diet-induced obesity in female but not in male mice, and that this sex difference is abolished by ovariectomy. We further demonstrate that Aster-B deficiency impairs nonvesicular cholesterol transport from the PM to the ER in ovaries in vivo, leading to hypogonadism and reduced estradiol synthesis. Female Aster-B–deficient mice exhibit reduced locomotor activity and energy expenditure, consistent with established effects of estrogens on systemic metabolism. Administration of exogenous estradiol ameliorates the diet-induced obesity phenotype of Aster-B–deficient female mice. These findings highlight the key role of Aster-B–dependent nonvesicular cholesterol transport in regulating estradiol production and protecting females from obesity.

Authors

Xu Xiao, John P. Kennelly, An-Chieh Feng, Lijing Cheng, Beatriz Romartinez-Alonso, Alexander Bedard, Yajing Gao, Liujuan Cui, Stephen G. Young, John W.R. Schwabe, Peter Tontonoz

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Figure 2

Ovarian Aster-B is recruited to the PM by cholesterol loading.

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Ovarian Aster-B is recruited to the PM by cholesterol loading.
(A) RNA-S...
(A) RNA-Seq expression of Gramd1b in adult C57BL/6J mouse bone marrow-derived macrophages treated with LXR agonist GW3965 and in adult C57BL/6J mouse ovaries (8 weeks of age). Data was reanalyzed from published RNA-Seq data set and visualized as IGV tracks (GEO accession numbers: macrophage: GSE193118; ovary: GSM900183). Exons that correspond to the first exon of Gramd1b1 and Gramd1b2 are depicted in organ box, respectively. (B) Schematic diagram of 2 different isoforms of Aster-B. Coding exons that are differentially expressed between Aster-B1 and -B2 are depicted in orange. Exons that correspond to the GRAM domains, ASTER domains, and transmembrane (TM) domains are depicted in green, blue, and red respectively. (C–E) Aster-B1 and B2 are aligned based on the GRAM domain that has the same predicted structure in both proteins (C). Alphafold2 structure prediction of GRAM domain of Aster-B1 (D), GRAM domain of Aster-B2 (E), and helical composition analysis of Hb by HeliQuest (E). Nonpolar residues are colored in yellow, positively charged residues are colored in blue, and negatively charged residues are shown in red. (F and G) Aster-B1 (F) and Aster-B2 (G) were imaged by confocal microscopy in 10% FBS (left), 1% LPDS (middle), or following 100 μM cholesterol: methyl-b-cyclo-dextrin complexes loading for 1 hour (right). Green, HA tagged Aster-B; red, pan-cadherin. (H) Quantification of Aster-B colocalization with PM. n = 32 WT and 32 Aster-B–KO mice. (I) 3H-CE formation in GFP-control and Aster-B2 overexpressed in Aster-A/B/C triple–KO cells. (J) Expression levels of the indicated genes in GFP-control and Aster-B2 overexpressed in Aster-A/B/C triple–KO cells that had been cultured with 10% FBS or 1% LPDS for 16 hours. Cholesterol loading was performed by using 10 μM cholesterol: methyl-b-cyclodextrin complexes for 4 hours (Chol). All data are presented as mean ± SEM. P values were determined by 2-sided Student’s t test (I). *P < 0.05,**P < 0.01.

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