Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States of America; Shanghai Municipal Center for Disease Control and Prevention, State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, Shanghai, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, PR China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2022 Feb;1867(2):159089. doi: 10.1016/j.bbalip.2021.159089. Epub 2021 Nov 29.
In addition to maintaining bile acid, cholesterol and glucose homeostasis, farnesoid X receptor (FXR) also regulates fatty acid β-oxidation (FAO). To explore the different roles of hepatic and intestinal FXR in liver FAO, FAO-associated metabolites, including acylcarnitines and fatty acids, and FXR target gene mRNAs were profiled using an integrated metabolomic and transcriptomic analysis in control (Fxr), liver-specific Fxr-null (Fxr) and intestine-specific Fxr-null (Fxr) mice, treated either with the FXR agonist obeticholic acid (OCA) or vehicle (VEH). Activation of FXR by OCA treatment significantly increased fatty acyl-CoA hydrolysis (Acot1) and decreased FAO-associated mRNAs in Fxr mice, resulting in reduced levels of total acylcarnitines and relative accumulation of long/medium chain acylcarnitines and fatty acids in liver. Fxr mice responded to OCA treatment in a manner similar to Fxr mice while Fxr mice responded differently, thus illustrating that intestinal FXR plays a critical role in the regulation of hepatic FAO. A significant negative-correlation between intestinal FXR-FGF15 and hepatic CREB-PGC1A pathways was observed after both VEH and OCA treatment, suggesting that OCA-induced activation of the intestinal FXR-FGF15 axis downregulates hepatic PGC1α signaling via inactivation of hepatic CREB, thus repressing FAO. This mechanism was confirmed in experiments based on human recombinant FGF19 treatment and intestinal Fgf15-null mice. This study revealed an important role for the intestinal FXR-FGF15 pathway in hepatic FAO repression.
除了维持胆汁酸、胆固醇和葡萄糖的稳态外，法尼醇 X 受体 (FXR) 还调节脂肪酸 β-氧化 (FAO)。为了探索肝 FXR 和肠 FXR 在肝 FAO、与 FAO 相关的代谢物（包括酰基辅酶 A 和脂肪酸）以及 FXR 靶基因 mRNAs 中的不同作用，我们在对照（Fxr）、肝特异性 Fxr 敲除（Fxr）和肠特异性 Fxr 敲除（Fxr）小鼠中进行了一项整合代谢组学和转录组学分析，这些小鼠用 FXR 激动剂奥贝胆酸 (OCA) 或载体 (VEH) 处理。OCA 处理激活 FXR 可显著增加脂肪酸酰基辅酶 A 水解（Acot1）并降低 Fxr 小鼠与 FAO 相关的 mRNAs，导致总酰基辅酶 A 水平降低，长/中链酰基辅酶 A 和脂肪酸在肝内相对积累。Fxr 小鼠对 OCA 治疗的反应方式与 Fxr 小鼠相似，而 Fxr 小鼠的反应方式不同，因此表明肠 FXR 在调节肝 FAO 中起着关键作用。在 VEH 和 OCA 处理后，观察到肠 FXR-FGF15 和肝 CREB-PGC1A 途径之间存在显著的负相关，这表明 OCA 诱导的肠 FXR-FGF15 轴激活通过失活肝 CREB 下调肝 PGC1α 信号，从而抑制 FAO。该机制在基于人重组 FGF19 处理和肠 Fgf15 敲除小鼠的实验中得到了证实。本研究揭示了肠 FXR-FGF15 途径在肝 FAO 抑制中的重要作用。
