Abstract
BackgroundGlucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6-methyladenosine (m6A) and post-transcriptional activation of lipogenic genes. Nutrition is considered the main cause of FLS in the modern poultry industry. Therefore, this study was aimed to investigate whether GR and m6A modification are involved in high-energy and low protein (HELP) diet-induced FLS in laying hens, and if true, what specific m6A sites of lipogenic genes are modified and how GR mediates m6A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken.ResultsLaying hens fed HELP diet exhibit excess (P < 0.05) lipid accumulation and lipogenic genes activation in the liver, which is associated with significantly increased (P < 0.05) GR expression that coincided with global m6A demethylation. Concurrently, the m6A demethylase FTO is upregulated (P < 0.05), whereas the m6A reader YTHDF2 is downregulated (P < 0.05) in the liver of FLS chickens. Further analysis identifies site-specific demethylation (P < 0.05) of m6A in the mRNA of lipogenic genes, including FASN, SREBP1 and SCD. Moreover, GR binding to the promoter of FTO gene is highly enriched (P < 0.05), while GR binding to the promoter of YTHDF2 gene is diminished (P < 0.05).ConclusionsThese results implicate a possible role of GR-mediated transcriptional regulation of m6A metabolic genes on m6A-depenent post-transcriptional activation of lipogenic genes and shed new light in the molecular mechanism of FLS etiology in the chicken.
Highlights
Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6methyladenosine (m6A) and post-transcriptional activation of lipogenic genes
This study was aimed to investigate whether GR and m6A modification are involved in high-energy and low protein (HELP) dietinduced FLS in laying hens, and if yes, what specific m6A sites of lipogenic genes are modified and how GR mediates m6A-dependent lipogenic gene activation in HELP diet-induced FLS in the chicken
Lipogenic genes are activated in the liver of chickens fed HELP diet Chickens fed HELP diet had significantly higher hepatic lipid accumulation compared with their control counterparts, as seen in Oil Red O staining (Fig. 1A) and hepatic TG (Fig. 1B) content (P < 0.05)
Summary
Glucocorticoid receptor (GR) mediated corticosterone-induced fatty liver syndrome (FLS) in the chicken by transactivation of Fat mass and obesity associated gene (FTO), leading to demethylation of N6methyladenosine (m6A) and post-transcriptional activation of lipogenic genes. Fatty liver syndrome (FLS) is a metabolic disease mostly observed in laying hens, which is characterized by increased lipid accumulation in the liver [1]. FLS is caused primarily by an imbalance of hepatic energy influx and efflux. Over-activation of GR pathway leads to transcriptional up-regulation of lipogenic genes, causing hepatic steatosis [13]. We have shown previously that excessive CORT administration causes FLS in chickens, which is characterized by excessive lipid accumulation in the liver [15,16,17]. GR is upregulated in the liver of FLS chickens [15,16,17], yet it remains unknown how GR contributes to diet-induced FLS in the chicken
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