Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; National Center for International Research on Animal Gut Nutrition, National Experimental Teaching Demonstration Center of Animal Science, Nanjing Agricultural University, Nanjing 210095, China.
Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China; National Center for International Research on Animal Gut Nutrition, National Experimental Teaching Demonstration Center of Animal Science, Nanjing Agricultural University, Nanjing 210095, China.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb;1865(2):158548. doi: 10.1016/j.bbalip.2019.158548. Epub 2019 Oct 30.
Maternal undernutrition during late gestation accelerates body fat mobilization to provide more energy for foetal growth and development, which unbalances metabolic homeostasis and results in serious lipid metabolism disorder. However, detailed regulatory mechanisms are poorly understood. Here, a sheep model was used to explore the regulatory role of PPARA/RXRA signalling in hepatic lipid metabolism in undernutrition based on RNA sequencing and cell experiments. KOG function classification showed that lipid transport and metabolism was markedly altered in an undernourished model. In detail, when compared with the controls, fatty acid transport and oxidation and triglyceride metabolism were up-regulated in an undernourished model, while fatty acid synthesis, steroid synthesis, and phospholipid metabolism were down-regulated. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis demonstrated that PPARA/RXRA signalling pathway was altered. Moreover, PPARA signalling associated genes were positively correlated with hepatic non-esterified fatty acid (NEFA) levels, while retinol metabolism associated genes were negatively correlated with blood beta-hydroxybutyric acid (BHBA) levels. Results of primary hepatocytes showed that NEFAs could activate PPARA signalling and facilitate fatty acid oxidation (FAO) and ketogenesis, while BHBA could inhibit RXRA signalling and repress FAO and ketogenesis. Excessively accumulated NEFAs in hepatocytes promoted triglyceride synthesis. Furthermore, activation of PPARA/RXRA signalling by WY14643 and 9-cis-retinoic acid could enhance FAO and ketogenesis and reduce NEFAs accumulation and esterification. Our findings elucidate the regulatory mechanisms of NEFAs and BHBA on lipid metabolism as well as the potential role of the PPARA/RXRA signalling pathway in hepatic lipid metabolism, which may contribute to exploring new strategies to maintain lipid metabolic homeostasis in human beings.
母体妊娠晚期营养不良加速体脂动员，为胎儿生长发育提供更多能量，导致代谢平衡失调，引发严重的脂质代谢紊乱。然而，其详细的调控机制尚不清楚。本研究采用绵羊模型，基于 RNA 测序和细胞实验，探讨了 PPARA/RXRA 信号通路在营养不良状态下肝脏脂质代谢中的调控作用。京都基因与基因组百科全书（KEGG）通路分析显示，PPARA/RXRA 信号通路发生改变。此外，PPARA 信号相关基因与肝脏非酯化脂肪酸（NEFA）水平呈正相关，视黄醇代谢相关基因与血液β-羟丁酸（BHBA）水平呈负相关。原代肝细胞实验结果表明，NEFAs 可激活 PPARA 信号通路，促进脂肪酸氧化（FAO）和酮体生成，BHBA 可抑制 RXRA 信号通路，抑制 FAO 和酮体生成。肝细胞中过量堆积的 NEFAs 促进甘油三酯合成。此外，WY14643 和 9-顺式视黄酸激活 PPARA/RXRA 信号通路可增强 FAO 和酮体生成，减少 NEFAs 堆积和酯化。本研究阐明了 NEFAs 和 BHBA 对脂质代谢的调控机制，以及 PPARA/RXRA 信号通路在肝脏脂质代谢中的潜在作用，这可能有助于探索维持人类脂质代谢平衡的新策略。
