Waku Tsuyoshi, Hagiwara Toru, Tamura Natsuko, Atsumi Yuri, Urano Yasuomi, Suzuki Mikiko, Iwami Takuya, Sato Katsuya, Yamamoto Masayuki, Noguchi Noriko, Kobayashi Akira
Laboratory for Genetic Code, Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1-3 Miyakodani, Tatara, Kyotanabe, Kyoto 610-0394, Japan.
Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Kyoto 610-0394, Japan.
iScience. 2021 Sep 28;24(10):103180. doi: 10.1016/j.isci.2021.103180. eCollection 2021 Oct 22.
Lipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of the gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.
脂质，如胆固醇和脂肪酸，会影响细胞信号传导、能量储存和膜的形成。胆固醇通过甲羟戊酸途径进行生物合成，代谢异常会导致代谢疾病。虽然分子机制尚不清楚，但已有研究表明转录因子NRF3与肥胖存在遗传关联。在此，我们发现NRF3在依赖固醇调节元件结合蛋白2（SREBP2）的甲羟戊酸途径中上调基因表达。我们进一步揭示，NRF3的过表达不仅会降低羊毛甾醇（一种胆固醇前体）的水平，还会诱导编码一种酶的基因表达，该酶参与从法尼基焦磷酸（FPP，一种羊毛甾醇前体）生成香叶基香叶基焦磷酸（GGPP）的过程。NRF3的过表达还通过RAB5介导的巨胞饮作用过程增强胆固醇摄取，这是一种大量的液相内吞途径。此外，我们发现GGPP处理消除了NRF3敲低介导的中性脂质增加。这些结果揭示了NRF3在依赖SREBP2的甲羟戊酸途径中的潜在作用，即通过诱导巨胞饮作用促进胆固醇摄取，并通过产生GGPP抑制脂肪生成。
