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Impaired GR expression in liver disrupts feeding induced gene expression, glucose uptake and glycogen storage

ABSTRACT: The transition from a fasted to a fed state is associated with extensive transcriptional remodeling in hepatocytes facilitated by hormonal- and nutritional-regulated transcription factors. Here, we use a liver-specific glucocorticoid receptor (GR) knock-out (L-GRKO) model and primary hepatocytes to investigate the temporal expression of GR target genes in response to feeding. Interestingly, in addition to the well described fasting-regulated genes, we identify a subset of hepatic feeding-induced genes that requires GR for full expression, adding new insights to hepatic GR function. The GR-controlled feeding-induced genes include Gck encoding the glucokinase, which is important for hepatic glucose uptake, utilization and storage. We show that insulin and glucocorticoids cooperatively regulate Gck expression in primary hepatocytes in a GR-dependent manner. ChIP-seq experiments suggest direct GR regulation of Gck by GR occupancy of the promoter and two putative regulatory regions near the Gck gene (Gck -1kb and Gck -4.6kb). Enhancer-reporter assays and CRISPRi suggest that the 4.6kb upstream GR binding site is a functional Gck enhancer. L-GRKO blunts preprandial and early postprandial Gck expression and GR disruption ultimately affects early postprandial hepatic glucose uptake, phosphorylation and glycogen storage. Collectively, our study demonstrates how GR is positively involved in the hepatic feeding response exemplified in the direct regulation of the feeding-induced transcription of glucokinase, important for hepatic glucose metabolism.

ORGANISM(S): Mus musculus Rattus norvegicus

PROVIDER: GSE173723 | GEO | 2021/09/08

REPOSITORIES: GEO

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Project description:Background and Aims: Inflammasome-mediated caspase-1 activity regulates the maturation and release of the pro-inflammatory cytokines interleukin (IL)-1M-CM-^_ and IL-18. Recently, we showed that caspase-1 deficiency strongly reduces high fat diet-induced adiposity although the mechanism is still unclear. We now aimed to elucidate the mechanism by which caspase-1 deficiency reduces modulates resistance to high fat diet-feeding fat accumulation in adipose tissue by focusing on the role of caspase-1 in the regulation of triglyceride (TG)-rich lipoprotein metabolism. Methods: Caspase-1 deficient and wild-type mice (both C57Bl/6 background) were used to determine postprandial TG kinetics, intestinal TG absorption, VLDL-TG production as well as TG clearance, all of which strongly contribute to the supply of TG for storage in adipose tissue. Micro-array and qPCR analysis were used to unravel intestinal and hepatic metabolic pathways involved. Results: Caspase-1 deficiency reduced the postprandial response to an oral lipid load, while tissue specific clearance of TG-rich lipoproteins was not changed. Indeed, an oral olive oil gavage containing [3H]TG revealed that caspase-1 deficiency significantly decreased intestinal chylomicron-TG production and reduced the uptake of [3H]TG-derived FA by liver, muscle, and adipose tissue. Similarly, caspase-1 deficiency reduced the hepatic VLDL-TG production without reducing VLDL-apoB production, despite an elevated hepatic TG content. Pathway analysis revealed that caspase-1 deficiency reduces intestinal and hepatic expression of genes involved in lipogenesis. Conclusions: Absence of caspase-1 reduces assembly and secretion of TG-rich lipoproteins, thereby reducing the availability of TG-derived FA for uptake by peripheral organs including adipose tissue. We anticipate that caspase-1 represents a novel link between innate immunity and lipid metabolism. Keywords: Expression profiling by array Wild-type (WT) and Casp1-null mice were maintained at lab chow. Animals, aged between 14 and 16 weeks (n=3 per genotype), were killed and liver and intestinal segments were removed. Livers were isolated from mice that were fasted over night, whereas intesines were removed from mice 2 hrs after they received an oral lipid load.Total RNA was isolated and subjected to gene expression profiling.

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Impaired GR expression in liver disrupts feeding induced gene expression, glucose uptake and glycogen storage

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