Unknown,Transcriptomics,Genomics,Proteomics

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H3K27ac and H3K4me3 ChIP-Seq of livers from male mice fed a control or high-fat diet and treated with estrogen receptor agonists

ABSTRACT: Metabolic dysfunction-associated steatotic liver disease is the most prevalent liver disease and affects a quarter of the global population. Estrogens are associated to safeguard the liver from metabolic diseases. We fed male mice a control or high-fat diet for 13 weeks which induced fatty liver. We injected a subset of male mice fed a high-fat diet with four different estrogen receptor (ER) agonists for the last three weeks of the high-fat diet, activating ERalpha or ERbeta. Livers were collected and crosslinked using formaldehyde. ChIP-seq against H3K27ac (Abcam #4729, 5ug per IP) or H3K4me3 (Merck 05-1339, 5ug per IP) was performed, followed by library preparation and sequencing on an Illumina NextSeq 500 instrument. RNA-seq of the same individual mice was performed and is accessible under E-MTAB-11833. The mouse identification column ('Sample' followed by number) can be used to match the individual mice between the experiments.

INSTRUMENT(S): NextSeq 500

ORGANISM(S): Mus musculus

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PROVIDER: E-MTAB-11929 | biostudies-arrayexpress |

SECONDARY ACCESSION(S): E-MTAB-11833

REPOSITORIES: biostudies-arrayexpress

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Project description:Hepatic fat accumulation has been widely associated with diabetes and hepatocellular carcinoma (HCC). Here, we aim to characterize the metabolic response that high fat availability elicits in livers prior to development of these diseases. We find that, after a short term on high fat diet, otherwise healthy mice show elevated hepatic glucose metabolization, activated glucose uptake, glycolysis and glucose contribution to serine as well as elevated pyruvate carboxylase activity compared to control diet mice. To understand other changes in the liver tissue after high fat diet exposure, we conducted untargeted transcriptomics and proteomics. This glucose phenotype occurred independent from transcriptional or proteomic programming, which identified increased peroxisomal and lipid metabolism pathways. Interestingly, we observe that high fat diet fed mice exhibit an increased lactate production when challenged with glucose. This trait seems to find a parallel in a human cohort, where we observe a correlation between waist circumference and lactate secretion after an oral glucose bolus across healthy individuals. In an in vitro model of hepatoma cells, we found physiologically relevant palmitate exposure stimulated production of reactive oxygen species (ROS) and glucose uptake, a similar glycolytic phenotype to the in vivo study. This effect is inhibited upon interference with peroxisomal lipid metabolism and ROS production. Furthermore, we find that with exposure to an HCC-inducing hepatic carcinogen, continuation of high fat diet enhances the formation of HCC (100% with resectable tumors) as compared to control (50% with resectable tumors) in mice. However, regardless of the dietary background, all murine tumors showed similar alterations in glucose metabolism compared to those identified in fat exposed non-transformed mouse livers. Further, the presence of tumors in high fat diet exposed mice normalized glucose tolerance. Lipidomics analysis of tumor tissue and liver tissue from high fat diet exposed mice identified tumor tissue enrichment of diacylglycerol (DG) and phosphatidylcholine (PC) species. Some of these species were also increased in high fat diet liver tissue compared to control diet liver tissue. These findings suggest that fat can induce similar metabolic changes in non-transformed liver cells than found in HCC, and that peroxisomal metabolism of lipids may be a factor in driving a glycolytic metabolism In conclusion, we show that normal, non-transformed livers respond to fat by inducing glucose metabolism.

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H3K27ac and H3K4me3 ChIP-Seq of livers from male mice fed a control or high-fat diet and treated with estrogen receptor agonists

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