三羧酸循环
中文名称
通路描述
在三羧酸循环（TCA 循环）中，乙酰辅酶 A 的乙酰基团可被完全氧化为 CO2，该过程同时产生一个高能磷酸键（以 GTP 或 ATP 形式）和四个还原当量（三个 NADH + H+ 和一个 FADH2）。随后，电子传递链将 NADH 和 FADH2 氧化以产生九个额外的高能磷酸键（以 ATP 形式）。三羧酸循环的所有反应均发生在线粒体中。八个经典反应介导了从乙酰辅酶 A 和草酰乙酸合成柠檬酸，以及柠檬酸代谢以重新形成草酰乙酸。其中三个反应是可逆的：柠檬酸与异柠檬酸之间的互变、草酸与苹果酸之间的互变，以及苹果酸与草酰乙酸之间的互变。在正常生理条件下，这些逆反应似乎没有作用，但在葡萄糖和谷氨酰胺刺激胰岛素分泌以及癌症代谢中可能发挥作用（例如，Zhang et al., 2020; Jiang et al., 2016）。琥珀酸从琥珀酰辅酶 A 的合成可以与 GDP 或 ADP 的磷酸化偶联，我们注释了这两种反应。两种线粒体异柠檬酸脱氢酶异构体催化异柠檬酸氧化脱羧生成α-酮戊二酸（2-氧戊二酸）：IDH3 催化与 NAD+ 还原偶联的经典反应，而 IDH2 催化与 NADP+ 还原偶联的反应，其正常生理功能尚不清楚。这两个反应均已注释。负责氧化乙酸的反应的循环性质最早由 Hans Krebs 在鸽胸肌的生物化学研究中提出（Krebs et al., 1938; Krebs and Eggleston, 1940）。Ochoa 等人研究了单个反应的许多分子细节，主要通过研究从猪心脏中纯化的酶进行的研究（Ochoa, 1980）。虽然这些酶的人体同源物均已鉴定，但其生物化学特征通常有限，许多关于人类反应的分子细节是从模型系统的研究中推断出来的。研究升高三羧酸循环中间体如琥珀酸和草酰乙酸对的影响，导致了代谢物在驱动癌症进展中的作用被识别（'oncometabolites'）（Pollard et al., 2005; 综述在 Hayashi et al., 2018）。TCA 酶在疾病中的作用由 Kang et al., 2021 综述。
英文描述
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2 EBF2 (Early B-cell factor 2) is a transcription factor that marks committed brown and beige preadipocytes. EBF2 cooperates with PPARG, a master regulator of adipogenesis, to activate the brown/beige adipocyte thermogenic program (inferred from mouse homologs in Rajakumari et al. 2013). In white adipocytes, the activity of EBF2 is negatively regulated by binding of the transcription factor ZNF423, a key transcription factor for white adipocyte differentiation. In brown/beige fate-committed cells, the interaction between ZNF423 and EBF2 is impeded by BMP7, which acts as a positive regulator of brown/beige adipogenesis (inferred from mouse homologs in Shao et al. 2016; Shao et al. 2021). Direct transcriptional targets of EBF2 include PRDM16, UCP1, and PPARA genes. Other marker genes of brown/beige adipocytes, such as CIDEA, PPARGC1A, COX7A, and DIO2 are positively regulated by EBF2 and probably also direct targets of EBF2 (inferred from mouse homologs in Rajakumari et al. 2013; Wang et al. 2014; Stine et al. 2016; Shapira et al. 2017; Lai et al. 2017; Angueira et al. 2020). Based on mouse studies, EBF1 may function partially redundantly with EBF2 in regulation of thermogenesis genes (Angueira et al. 2020). Transcriptional activity of EBF2 is positively regulated by binding of the long noncoding RNA (lncRNA) Blnc1 (inferred from mouse homologs in Zhao et al. 2014; Mi et al. 2017). Based on mouse studies, EBF2 was reported to recruit the BAF chromatin remodeling complex to activate the transcription of target genes (Shapira et al. 2017; Liu et al. 2020). In addition to PPARG, based on mouse studies, EBF2 was reported to cooperate with other transcription factors such as SIX1 during brown/beige adipogenesis (Brunmeir et al. 2016). Besides ZNF423, based on mouse studies, other transcription factors, such as ID1 (Patil et al. 2017) and TLE3 (Pearson et al. 2019), have been reported to act as inhibitors of EBF2-mediated transcription. The transcription factor GATA6 was reported to directly stimulate EBF2 transcription during mouse beige/brown thermogenesis (Jun et al. 2023). Besides BPM7, BPM9-mediated upregulation of FGFR3 (Yamamoto et al. 2022), and FGF11 (Jiang et al. 2023) have been reported as indirect activators of EBF2 transcriptional activity in mouse and goat, respectively. ZAG (Zinc-alpha2-glycoprotein), a tumor secretory factor, has been reported to stimulate EBF2 expression, which contributes to white adipose tissue browning and energy wasting in cancer-related cachexia (Elattar et al. 2018). In the single cell atlas of human white adipose tissue (Emont et al. 2022) it was reported that the EBF2-positive hAd6 white adipocyte subpopulation with UCP1 expression, consistent with the beige profile, shows an association with increased BMI and visceral adiposity. For review, please refer to Wang and Seale 2016.
所含基因
31 个基因