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Heterozygous GAA knockout is nonconsequential on metabolism and the spatial liver transcriptome in high-fat diet induced obese and prediabetic mice

ABSTRACT: The liver is composed of periportal and perivenous hepatocytes that have different metabolic profiles. This study used spatial transcritpomics to identify how high-fat diet induced obesity and heterozygous GAA knockout impacted the periportal and perivenous transcriptome. The spatial transcritpomics analysis revealed that heterozygous GAA knockout had no impact on liver transcriptomes. However, the high-fat diet, compared to the low-fat diet, reduced metabolic pathway gene abundance in both zones, while uniquely reducing ribosome gene abundance in perivenous hepatocytes.

ORGANISM(S): Mus musculus

PROVIDER: GSE284331 | GEO | 2025/01/14

REPOSITORIES: GEO

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Project description:Wild-type and AHR-KO rats harboring a 29-bp deletion mutation in exon 2 of the AHR gene were used in this study. Wild-type and AHR-KO rats were generated from heterozygous breeding stocks generated on a Sprague-Dawley outbred background and maintained at the Hamner Institutes for Health Sciences, Research Triangle Park, North Carolina Persistent activation of the aryl hydrocarbon receptor (AHR) is believed to play a key role in the mode-of-action for TCDD induced rat liver tumorigenesis. It has been hypothesized that the cellular responses of hepatocytes to AHR activation may differ across regions of the liver lobule and that zone-specific effects of AHR agonists may play a role in the pathogenesis of rat liver tumorigenesis. Dose-dependent changes in gene expression were observed in both populations of hepatocytes collected from WT rats which were consistent with activation of AHR signaling. No significant or dose-dependent changes in gene expression were observed in samples from AHR-KO rats. In addition, evidence of inflammatory signaling pathway activation was observed only in centrilobular hepatocytes. Evidence of cell adhesion pathway enrichment was observed only in periportial hepatocytes. Benchmark dose analysis demonstrated that dose-dependent changes in gene expression occurred at lower doses in centrilobular as compared to periportal hepatocytes. These results indicate zone-specific differences in the sensitivity and response of hepatocytes to persistent AHR activation. AHR-KO and WT rats (n = 10 rats/dose/genotype) were dosed by oral gavage (4-5 doses / week, 19 total doses) with varying concentrations of TCDD in corn oil (0, 3, 22, 100, 300, 1000 ng/kg/day). Cryopreserved liver slices collected at necropsy were thawed, cryosectioned (12 Âµm thickness), fixed with ethanol and âquick-stainedâ with hematoxylin. Centrilobular and periportal hepatocytes were collected using laser capture microdissection. Total RNA was extracted, amplified and labeled using low-yield techniques and global transcriptomic profiles were obtained using Affymetrix Gene-Titan peg arrays.

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Heterozygous GAA knockout is nonconsequential on metabolism and the spatial liver transcriptome in high-fat diet induced obese and prediabetic mice

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