Chen Bowen, Yuan Chao, Guo Tingting, Liu Jianbin, Yang Bohui, Lu Zengkui
Key Laboratory of Animal Genetics and Breeding on the Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China; Sheep Breeding Engineering Technology Research Center of Chinese Academy of Agricultural Sciences, Lanzhou 730050, China.
Key Laboratory of Animal Genetics and Breeding on the Tibetan Plateau, Ministry of Agriculture and Rural Affairs, Lanzhou Institute of Husbandry and Pharmaceutical Sciences, Chinese Academy of Agricultural Sciences, Lanzhou 730050, China; Sheep Breeding Engineering Technology Research Center of Chinese Academy of Agricultural Sciences, Lanzhou 730050, China.
Genomics. 2024 Nov;116(6):110945. doi: 10.1016/j.ygeno.2024.110945. Epub 2024 Sep 27.
Balanced lipid metabolism can improve the growth performance and meat quality of livestock. The m6A methylation-related genes METTL3 and FTO play important roles in animal lipid metabolism; however, the mechanism through which they regulate lipid metabolism in sheep is unclear.
We established lipid deposition models of hepatocytes and preadipocytes in Hu sheep. In the hepatocyte lipid deposition model, the genes expression levels of FABP4, Accα, ATGL and METTL3, METTL14, and FTO-were significantly up-regulated after lipid deposition (P < 0.05). Transcriptomic and metabolomic analyses showed that lipid deposition had a significant effect on MAPK, steroid biosynthesis, and glycerophospholipid metabolism pathway in hepatocytes. The m6A methylation level decreased but the difference was not significant after METTL3 interference, and the expression levels of FABP4 and ATGL increased significantly (P < 0.05); the m6A methylation level significantly increased following METTL3 overexpression, and LPL and ATGL expression levels significantly decreased (P < 0.05), indicating that overexpression of METTL3 inhibited the expression of lipid deposition-related genes in a m6A-dependent manner. The m6A methylation level was significantly increased, ATGL expression was significantly decreased (P < 0.05), and LPL, FABP4, and Accα expression was not significantly changed following FTO interference (P > 0.05); the m6A methylation level was significantly decreased after FTO overexpression, and LPL, FABP4, and ATGL expression was significantly increased (P < 0.05), indicating that FTO overexpression increased the expression of lipid deposition-related genes in a m6A-dependent manner. Transcriptomic and metabolomic analyses showed that m6A methylation modification mainly regulated lipid metabolism through triglyceride metabolism, adipocytokine signaling, MAPK signaling, and fat digestion and absorption in hepatocytes. In the lipid deposition model of preadipocytes, the regulation of gene expression is the same as that in hepatocytes.
METTL3 significantly inhibited the expression of lipid deposition-related genes, whereas FTO overexpression promoted lipid deposition. Our study provides a theoretical basis and reference for accurately regulating animal lipid deposition by mastering METTL3 and FTO genes to promote high-quality animal husbandry.
脂质代谢平衡可改善家畜的生长性能和肉质。m6A甲基化相关基因METTL3和FTO在动物脂质代谢中发挥重要作用；然而，它们调控绵羊脂质代谢的机制尚不清楚。
我们建立了湖羊肝细胞和前脂肪细胞的脂质沉积模型。在肝细胞脂质沉积模型中，脂质沉积后FABP4、Accα、ATGL以及METTL3、METTL14和FTO的基因表达水平显著上调（P < 0.05）。转录组学和代谢组学分析表明，脂质沉积对肝细胞中的MAPK、类固醇生物合成和甘油磷脂代谢途径有显著影响。METTL3干扰后m6A甲基化水平降低，但差异不显著，FABP4和ATGL的表达水平显著升高（P < 0.05）；METTL3过表达后m6A甲基化水平显著升高，LPL和ATGL表达水平显著降低（P < 0.05），表明METTL3过表达以m6A依赖的方式抑制脂质沉积相关基因的表达。FTO干扰后m6A甲基化水平显著升高，ATGL表达显著降低（P < 0.05），LPL、FABP4和Accα表达无显著变化（P > 0.05）；FTO过表达后m6A甲基化水平显著降低，LPL、FABP4和ATGL表达显著升高（P < 0.05），表明FTO过表达以m6A依赖的方式增加脂质沉积相关基因的表达。转录组学和代谢组学分析表明，m6A甲基化修饰主要通过甘油三酯代谢、脂肪细胞因子信号传导、MAPK信号传导以及肝细胞中的脂肪消化和吸收来调节脂质代谢。在前脂肪细胞脂质沉积模型中，基因表达的调控与肝细胞中的调控相同。
METTL3显著抑制脂质沉积相关基因的表达，而FTO过表达促进脂质沉积。我们的研究为通过掌握METTL3和FTO基因精确调控动物脂质沉积以促进优质畜牧业发展提供了理论依据和参考。
