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. 2024 Nov;116(6):110945.
doi: 10.1016/j.ygeno.2024.110945. Epub 2024 Sep 27.

The molecular regulated mechanism of METTL3 and FTO in lipid metabolism of Hu sheep

Bowen Chen  1 , Chao Yuan  1 , Tingting Guo  1 , Jianbin Liu  1 , Bohui Yang  2 , Zengkui Lu  3
Affiliations
Free article

The molecular regulated mechanism of METTL3 and FTO in lipid metabolism of Hu sheep

Bowen Chen et al. Genomics. 2024 Nov.
Free article

Abstract

Background: 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.

Results: 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.

Conclusions: 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.

Keywords: FTO; Lipid metabolism; METTL3; Sheep; m6A methylation.

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Conflict of interest statement

Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Bohui Yang and Zengkui Lu reports financial support was provided by the National Natural Science Foundation of China. Bohui Yang and Zengkui Lu reports financial support was provided by the Chinese Academy of Agricultural Sciences of Technology Innovation Project. Bohui Yang and Zengkui Lu reports financial support was provided by the Modern China Wool Cashmere Technology Research System. Bohui Yang and Zengkui Lu reports financial support was provided by the Science and Technology Program of Gansu Province. Bohui Yang and Zengkui Lu reports financial support was provided by the Central Public-interest Scientific Institution Basal Research Fund. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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