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Multifaceted regulation of hepatic lipid metabolism by YY1.

ABSTRACT: Recent studies suggested that dysregulated YY1 plays a pivotal role in many liver diseases. To obtain a detailed view of genes and pathways regulated by YY1 in the liver, we carried out RNA sequencing in HepG2 cells after YY1 knockdown. A rigid set of 2,081 differentially expressed genes was identified by comparing the YY1-knockdown samples (n = 8) with the control samples (n = 14). YY1 knockdown significantly decreased the expression of several key transcription factors and their coactivators in lipid metabolism. This is illustrated by YY1 regulating PPARA expression through binding to its promoter and enhancer regions. Our study further suggest that down-regulation of the key transcription factors together with YY1 knockdown significantly decreased the cooperation between YY1 and these transcription factors at various regulatory regions, which are important in regulating the expression of genes in hepatic lipid metabolism. This was supported by the finding that the expression of SCD and ELOVL6, encoding key enzymes in lipogenesis, were regulated by the cooperation between YY1 and PPARA/RXRA complex over their promoters.

SUBMITTER: Pan G

PROVIDER: S-EPMC8200296 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Multifaceted regulation of hepatic lipid metabolism by YY1.

Pan Gang G Diamanti Klev K Cavalli Marco M Lara Gutiérrez Ariadna A Komorowski Jan J Wadelius Claes C

Life science alliance 20210607 7

Recent studies suggested that dysregulated <i>YY1</i> plays a pivotal role in many liver diseases. To obtain a detailed view of genes and pathways regulated by YY1 in the liver, we carried out RNA sequencing in HepG2 cells after YY1 knockdown. A rigid set of 2,081 differentially expressed genes was identified by comparing the YY1-knockdown samples (n = 8) with the control samples (n = 14). YY1 knockdown significantly decreased the expression of several key transcription factors and their coactiv ...[more]

PMID: 34099540

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Project description:BackgroundRapid influx of energy caused by fasting/refeeding repeatedly enhances fatty acid synthesis leading to triacylglycerol accumulation and production of reactive oxygen species (ROS), increasing the risk of non-alcoholic steatohepatitis (NASH). Previous studies have reported that the ingestion of butyrate is effective at preventing hepatic disorders, which are accompanied by fat accumulation and inflammation. The aim of this study is to reveal the mechanism of action of butyrate, and thus we investigated the effects of dietary butyrate on the expressions of antioxidant enzymes in the livers of rats during refeeding following fasting.MethodsThirty-seven male rats were divided into six groups (6-7 animals per group): non-fasting, fasting, refeeding with a high sucrose diet as control for 12 or 24 h, and refeeding with a high sucrose diet containing 5% sodium butyrate (NaB) for 12 or 24 h. All groups except the non-fasting group were fasted for 72 h before refeeding. Statistical analysis was conducted among 4 refeeding groups (refeeding with the control diet for 12 or 24 h, and refeeding with a diet containing NaB for 12 or 24 h).ResultsSupplementation with NaB significantly reduced (p < 0.05) fatty acid synthase (Fas) gene expression and increased the expression of the carnitine palmitoyltransferase 1α (Cpt1a) gene, resulting in reduced triacylglycerol content in the livers of rats refed the NaB diet compared with controls at 24 h after the start of refeeding. The mRNA levels of the genes related to glutathione synthesis were significantly higher (p < 0.05) in the livers of the butyrate group than the control group. In addition, the mRNA level of Foxo3a, a transcription factor that regulates the expressions of antioxidant enzymes, was higher in the butyrate group than controls. The acetylation levels of histone H4 around the Foxo3a gene tended to be increased (p = 0.055) by refeeding with the NaB diet.ConclusionNaB supplementation in the diet for refeeding reduced the rate of lipid synthesis and stimulated fatty acid oxidation in the liver, which inhibited fat accumulation and the risk of NASH. The transcriptional regulation of Foxo3a involves histone acetylation around the gene.

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Multifaceted regulation of hepatic lipid metabolism by YY1.

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Multifaceted regulation of hepatic lipid metabolism by YY1.

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