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β-Klotho-FGF15 轴调控胎-母胆固醇转运对胎儿生长至关重要。

Feto-maternal cholesterol transport regulated by β-Klotho-FGF15 axis is essential for fetal growth.

机构信息

Department of Aging Science and Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

Laboratory of Molecular Life Science, Institute of Biomedical Research and Innovation, Foundation for Biomedical Research and Innovation at Kobe, Kobe, Japan.

出版信息

Life Sci Alliance. 2023 Aug 4;6(10). doi: 10.26508/lsa.202301916. Print 2023 Oct.

DOI:10.26508/lsa.202301916
PMID:37541847
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10403640/
Abstract

β-Klotho (β-KL) is indispensable to regulate lipid, glucose, and energy metabolism in adult animals. β-KL is highly expressed in the yolk sac, but its role in the developmental stages has not been established. We hypothesized that β-KL is required for metabolic regulation in the embryo and aimed to clarify the role of β-KL during development. Here, we show that β-KL regulates feto-maternal cholesterol transport through the yolk sac by mediating FGF 15 signaling, and also that impairment of the β-KL-FGF15 axis causes fetal growth restriction (FGR). Embryos of knockout (-/-) mice were morphologically normal but exhibited FGR before placental maturation. The body weight of -/- mice remained lower after birth. β-KL deletion reduced cholesterol supply from the maternal blood and led to lipid shortage in the embryos. These phenotypes were similar to those of embryos lacking FGF15, indicating that β-KL-FGF15 axis is essential for growth and lipid regulation in the embryonic stages. Our findings suggest that lipid abnormalities in early gestation provoke FGR, leading to reduced body size in later life.

摘要

β-Klotho（β-KL）对于调节成年动物的脂质、葡萄糖和能量代谢是必不可少的。β-KL 在卵黄囊中高度表达，但它在发育阶段的作用尚未确定。我们假设β-KL 是胚胎代谢调节所必需的，并旨在阐明β-KL 在发育过程中的作用。在这里，我们表明β-KL 通过介导 FGF15 信号转导调节卵黄囊中的胎-母胆固醇转运，并且β-KL-FGF15 轴的损伤导致胎儿生长受限（FGR）。β-KL 敲除（-/-）小鼠的胚胎形态正常，但在胎盘成熟前表现出 FGR。-/- 小鼠的体重在出生后仍较低。β-KL 缺失减少了来自母体血液的胆固醇供应，并导致胚胎中的脂质短缺。这些表型与缺乏 FGF15 的胚胎相似，表明β-KL-FGF15 轴对于胚胎阶段的生长和脂质调节是必不可少的。我们的研究结果表明，早期妊娠的脂质异常引发 FGR，导致后期生活中体型减小。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/9bac8dca048f/LSA-2023-01916_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/a30b251575b8/LSA-2023-01916_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/f49c67585b1e/LSA-2023-01916_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/9ab18132d988/LSA-2023-01916_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/7d49e6bf3c1d/LSA-2023-01916_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/4121cf81e324/LSA-2023-01916_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/abab43392da7/LSA-2023-01916_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/58380e3b13e7/LSA-2023-01916_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/7d025ed50fd0/LSA-2023-01916_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/e23d70ca4be5/LSA-2023-01916_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/8f50a0da8d02/LSA-2023-01916_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/9bac8dca048f/LSA-2023-01916_Fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/a30b251575b8/LSA-2023-01916_Fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/f49c67585b1e/LSA-2023-01916_FigS1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/9ab18132d988/LSA-2023-01916_Fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/7d49e6bf3c1d/LSA-2023-01916_FigS2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/4121cf81e324/LSA-2023-01916_FigS3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/abab43392da7/LSA-2023-01916_Fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/58380e3b13e7/LSA-2023-01916_FigS4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/7d025ed50fd0/LSA-2023-01916_FigS5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/e23d70ca4be5/LSA-2023-01916_Fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/8f50a0da8d02/LSA-2023-01916_FigS6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/db9c/10403640/9bac8dca048f/LSA-2023-01916_Fig5.jpg

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