Glucocorticoid Receptor Deletion in Hepatocytes Disrupts Postprandial Lipid Metabolism

Catarina Mendes Correia, Stine Marie Præstholm, Jesper Foged Havelund, Felix Boel Pedersen, Majken Storm Siersbæk, Morten Frendø Ebbesen, Zach Gerhart-Hines, Joerg Heeren, Jonathan Brewer, Steen Larsen, Blagoy Blagoev, Nils Joakim Færgeman, Lars Grøntved
Endocrinology, Volume 164, Issue 10, October 2023, bqad128
https://doi.org/10.1210/endocr/bqad128

Abstract

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, β-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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