<i>METTL3</i> and <i>FTO</i> Regulate Heat Stress Response in Hu Sheep Through Lipid Metabolism via m6A Modification
In an established hepatocyte lipid deposition heat stress model, the expression levels of <i>METTL3</i> and <i>FTO</i> were significantly upregulated (<i>p</i> < 0.05), indicating that <i>METTL3</i> and <i>FTO</i> play important roles in...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-01-01
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| Series: | Animals |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-2615/15/2/193 |
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| Summary: | In an established hepatocyte lipid deposition heat stress model, the expression levels of <i>METTL3</i> and <i>FTO</i> were significantly upregulated (<i>p</i> < 0.05), indicating that <i>METTL3</i> and <i>FTO</i> play important roles in the process of lipid deposition heat stress in hepatocytes. Transcriptome and metabolome analyses showed that lipid deposition heat stress had significant effects on the linoleic acid, linolenic acid, glycerophospholipid, and arachidonic acid metabolic pathways in hepatocytes. After <i>METTL3</i> knockdown, the m6A methylation level decreased, but the difference was not significant (<i>p</i> > 0.05), the <i>FABP4</i> and <i>Accα</i> expression levels increased, and the <i>HSP60</i>, <i>HSP70</i>, and <i>HSP110</i> expression levels decreased significantly. After <i>METTL3</i> overexpression, the m6A methylation level increased significantly and the expression levels of <i>FABP4</i>, <i>ATGL</i>, <i>Accα</i>, <i>HSP60</i>, <i>HSP70</i>, <i>HSP90</i>, and <i>HSP110</i> decreased significantly, indicating that the overexpression of <i>METTL3</i> reduced the expression of heat shock genes by inhibiting the lipid-deposition-related gene expression in an m6A-dependent manner. The m6A methylation level increased significantly after <i>FTO</i> knockdown, while <i>HSP60</i>, <i>HSP110</i>, <i>FABP4</i>, <i>ATGL</i>, and Accα expression levels were significantly reduced. Following <i>FTO</i> overexpression, the m6A methylation level and <i>HSP60</i>, <i>HSP90</i>, and <i>HSP110</i> expression levels significantly decreased, while the <i>ATGL</i> and <i>Accα</i> expression levels significantly increased. This indicates that the overexpression of <i>FTO</i> promoted the expression of lipid-deposition-related genes in an m6A-dependent manner to reduce the expression of heat shock genes. Transcriptome and metabolome sequencing screened a large number of differential genes and metabolites, and a KEGG enrichment analysis showed that m6A methylation mainly regulated heat stress by affecting the TNF, cAMP, MAPK, lipolysis, and synthesis pathways in hepatocytes. In the lipid deposition heat stress model of preadipocytes, the regulation of gene expression was similar to that in hepatocytes. |
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| ISSN: | 2076-2615 |