Yasenjian Sibinuer, Shan Su, Zhe Yuqi, Zhang Yuqing, Chai Zhixin
Key Laboratory of Qinghai-Tibetan Plateau Animal Genetic Resource Reservation and Utilization, Chengdu, China.
Sichuan Qinghai-Tibet Plateau Herbivore Livestock Engineering Technology Center, Chengdu, China.
Front Vet Sci. 2025 Aug 26;12:1643818. doi: 10.3389/fvets.2025.1643818. eCollection 2025.
In this study, we investigated the mechanism by which all-trans retinoic acid (ATRA) regulates the hypoxic adaptation of yak subcutaneous adipocytes through a dose-dependent regulation. The effects of different concentrations of ATRA (10 nM-10 μM) on cell proliferation and differentiation, lipid metabolism and key gene expression were analyzed by simulating a hypoxic environment (1% O) . In the hypoxia model, ATRA showed biphasic regulation: the hypoxic environment inhibited cell survival, while low concentrations of ATRA (10-100 nM) significantly enhanced hypoxic cell survival and repaired lipid droplet accumulation by activating the PCNA/PPAR-γ signaling axis; while high concentrations of ATRA (1-10 μM) induced apoptosis and inhibited differentiation by upregulating BAX and inhibited differentiation, and its toxic effects were exacerbated by the hypoxic environment. In addition, a certain concentration (10-100 nM) of ATRA antagonized the hypoxia-induced HIF-1α pathway and regulated hypoxia-induced metabolic reprogramming via PCNA/PPAR-γ. The study revealed a dose-dependent bidirectional regulatory mechanism of ATRA in the hypoxic adaptation of yak adipocytes, which provides a new perspective for analyzing the energy metabolism strategy of plateau species.
在本研究中，我们探究了全反式维甲酸（ATRA）通过剂量依赖性调节来调控牦牛皮下脂肪细胞低氧适应性的机制。通过模拟低氧环境（1% O₂），分析了不同浓度的ATRA（10 nM - 10 μM）对细胞增殖与分化、脂质代谢及关键基因表达的影响。在低氧模型中，ATRA呈现双相调节作用：低氧环境抑制细胞存活，而低浓度的ATRA（10 - 100 nM）通过激活PCNA/PPAR-γ信号轴显著提高低氧细胞的存活率并修复脂滴积累；而高浓度的ATRA（1 - 10 μM）通过上调BAX诱导细胞凋亡并抑制分化，且低氧环境会加剧其毒性作用。此外，一定浓度（10 - 100 nM）的ATRA拮抗低氧诱导的HIF-1α通路，并通过PCNA/PPAR-γ调节低氧诱导的代谢重编程。该研究揭示了ATRA在牦牛脂肪细胞低氧适应中的剂量依赖性双向调节机制，为分析高原物种的能量代谢策略提供了新的视角。
