Kim Sang Hee, Park Woo Yong, Kim Beomsu, Kim Jin-Hyung, Song Gahee, Park Ja Yeon, Jiao Wenjun, Jung Se Jin, Ahn Kwang Seok, Kwak Hyun Jeong, Um Jae-Young
Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea.
Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
J Biol Chem. 2025 Mar;301(3):108181. doi: 10.1016/j.jbc.2025.108181. Epub 2025 Jan 10.
FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.
由Nh1r4编码的法尼酯X受体（FXR）是一种在调节胆汁酸、脂质和葡萄糖代谢中起关键作用的核受体。先前的研究表明，在肝脏和小肠中激活FXR可能对肥胖和代谢性疾病具有保护作用。本研究证明了FXR-ApoC2通路在促进白色脂肪组织（WAT）褐变中的重要作用。通过用FXR激动剂法尼醇处理增加FXR，可上调米色脂肪细胞标志物，包括解偶联蛋白1（UCP1）、过氧化物酶体增殖物激活受体γ共激活因子1α（PGC1α）和含锌指结构的PR结构域蛋白16（PRDM16），并增加米色脂肪细胞和冷暴露小鼠中FXR靶基因ApoC2的表达。然而，在成熟白色脂肪细胞中未观察到这些效应。值得注意的是，敲低FXR会导致米色脂肪细胞中UCP1、PGC1α、PRDM16和ApoC2的表达显著降低。在研究核受体视黄酸X受体α（RXRα）与FXR在转录调控中的相互作用时，发现敲低RXRα在米色脂肪生成过程中并不影响FXR的表达。我们进一步研究了在ApoC2过表达情况下米色相关标志物的表达是否会改变，以确定FXR与ApoC2调节相关的作用机制。前脂肪细胞和米色脂肪细胞中ApoC2的过表达均导致UCP1和PGC1α的表达显著增加。这些结果表明，FXR介导的ApoC2通路通过诱导前脂肪细胞生成米色脂肪，在WAT褐变中起重要作用。
