Ror1 promotes <scp>PPARα</scp> ‐mediated fatty acid metabolism in astrocytes
Ror1 promotes <scp>PPARα</scp> ‐mediated fatty acid metabolism in astrocytes
复制标题
Ror1促进星形胶质细胞<scp>PPARα</scp>介导的脂肪酸代谢
DOI：
10.1111/gtc.13013
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发表时间：
2023
期刊：
影响因子：
2.1
通讯作者：
Endo Mitsuharu
中科院分区：
文献类型：
--
作者：
Tanaka Yuki;Minami Yasuhiro;Endo Mitsuharu
Ror 1信号在发育形态发生过程中调节细胞极性、迁移、增殖和分化，并在调节胚胎新皮质神经发生中发挥重要作用。然而，出生后Ror 1信号在大脑中的作用在很大程度上仍然未知。在这里，我们发现Ror 1在小鼠新生皮质中的表达水平在出生后时期增加，此时星形胶质细胞成熟并开始表达GFAP。事实上，Ror 1在培养的有丝分裂后成熟星形胶质细胞中高度表达。RNA-Seq分析显示，在培养的星形胶质细胞中表达的Ror 1介导与脂肪酸（FA）代谢相关的基因的上调表达，包括编码肉毒碱棕榈酰转移酶1a（Cpt 1a）的基因，这是线粒体脂肪酸β氧化（FAO）的限速酶。我们还发现，Ror 1促进油酸负荷后培养的星形胶质细胞细胞质中积累的脂滴（LD）的降解，抑制Ror 1的表达会降低线粒体中定位的FA量、细胞内ATP水平和过氧化物酶体增殖物激活受体α（PPARα）靶基因（包括Cpt 1a）的表达水平。总的来说，这些研究结果表明，Ror 1信号促进了PPARα介导的FA代谢相关基因的转录，从而促进了成熟星形胶质细胞中线粒体FAO的LD来源的FA的可用性。
Ror1 signaling regulates cell polarity, migration, proliferation, and differentiation during developmental morphogenesis, and plays an important role in regulating neurogenesis in the embryonic neocortices. However, the role of Ror1 signaling in the brains after birth remains largely unknown. Here, we found that expression levels of Ror1 in the mouse neocortices increase during the postnatal period, when astrocytes mature and start expressing GFAP. Indeed, Ror1 is highly expressed in cultured postmitotic mature astrocytes. RNA‐Seq analysis revealed that Ror1 expressed in cultured astrocytes mediates upregulated expression of genes related to fatty acid (FA) metabolism, including the gene encoding carnitine palmitoyl‐transferase 1a (Cpt1a), the rate‐limiting enzyme of mitochondrial fatty acid β‐oxidation (FAO). We also found that Ror1 promotes the degradation of lipid droplets (LDs) accumulated in the cytoplasm of cultured astrocytes after oleic acid loading, and that suppressed expression ofRor1decreases the amount of FAs localized at mitochondria, intracellular ATP levels, and expression levels of peroxisome proliferator‐activated receptor α (PPARα) target genes, includingCpt1a. Collectively, these findings indicate that Ror1 signaling promotes PPARα‐mediated transcription of FA metabolism‐related genes, thereby facilitating the availability of FAs derived from LDs for mitochondrial FAO in the mature astrocytes.