期刊
ENDOCRINOLOGY
卷 164, 期 10, 页码 -出版社
ENDOCRINE SOC
DOI: 10.1210/endocr/bqad128
关键词
glucocorticoid receptor; lipid metabolism; gene expression; liver
Hepatic lipid metabolism is affected by circadian regulation and disruption of the glucocorticoid receptor (GR) leads to hepatic steatosis. In this study, an acute hepatocyte-specific GR knockout model was used to investigate the role of GR in temporal hepatic lipid metabolism. Lipidomics analysis revealed impaired regulation of triglycerides, fatty acids, and sphingolipids in the absence of GR. Dysregulation of lipid metabolism was found to be associated with altered gene expression and increased lipid droplet formation.
Hepatic lipid metabolism is highly dynamic, and disruption of several circadian transcriptional regulators results in hepatic steatosis. This includes genetic disruption of the glucocorticoid receptor (GR) as the liver develops. To address the functional role of GR in the adult liver, we used an acute hepatocyte-specific GR knockout model to study temporal hepatic lipid metabolism governed by GR at several preprandial and postprandial circadian timepoints. Lipidomics analysis revealed significant temporal lipid metabolism, where GR disruption results in impaired regulation of specific triglycerides, nonesterified fatty acids, and sphingolipids. This correlates with increased number and size of lipid droplets and mildly reduced mitochondrial respiration, most noticeably in the postprandial phase. Proteomics and transcriptomics analyses suggest that dysregulated lipid metabolism originates from pronounced induced expression of enzymes involved in fatty acid synthesis, & beta;-oxidation, and sphingolipid metabolism. Integration of GR cistromic data suggests that induced gene expression is a result of regulatory actions secondary to direct GR effects on gene transcription.
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