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Identifying the role of Acox1 in metabolism and inflammation in non-alcoholic fatty liver disease through mRNA-sequencing.

ABSTRACT: Purpose: To identify the impact of Acox1 on cellular metabolism and inflammation related to non-alcoholic fatty liver disease, within the context of obesogenic dietary stress. Methods: Hepatic mRNA profiles were obtained in triplicate for control and Acox1Lampe1 mice on chow diet or obesogenic diet. Profiles were generated using the Illumina HiSeq2000, reads that passed quality inspection were processed through the TopHap/Cufflinks pipeline. Results: Approximately 20million reads per sample were aligned to the mm8 mouse genome, using annotations provided by Ensembl. Testing between control and Acox1Lampe1 mice on control and obesogenic diets was performed using a 2-way ANOVA, with a p-value cutoff of 0.05 and FC of 1.5. We observed a significant alteration of hepatic gene expression in Acox1Lampe1 mutant mice, a pattern that was exacerbated by the obesogenic diet. Among significant genes, we observed an enrichment of those known to teb associated with inflammatory responses, leukocyte activation and adhesion, and abnormal liver physiology, regeneration, and development. Conclusion: Through next generation sequencing of hepatic tissues from control and Acox1Lampe1 mutant mice on control and obesogenic diets, we demonstrate that Acox1 regulates both metabolism and inflammation, the interplay of which correlates with increased hepatocellular damage and impared hepatic mitochondrial function.

ORGANISM(S): Mus musculus

PROVIDER: GSE89626 | GEO | 2018/05/09

REPOSITORIES: GEO

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Project description:This dataset contains proteomic data from mice with high or low weight gain in response to a high fat diet. Both host and microbial proteins are present. In the supplemental, there are also tables and supplementary files that can be used for replicating the bioinformatic analysis. Abstract: Consumption of refined high-fat, low-fiber diets promotes development of obesity and its associated consequences. While genetics play an important role in dictating susceptibility to such obesogenic diets, mice with nearly uniform genetics exhibit marked heterogeneity in their extent of obesity in response to such diets. This suggests non-genetic determinants play a role in diet-induced obesity. Hence, we sought to identify parameters that predict, and/or correlate with, development of obesity in response to an obesogenic diet. We assayed behavior, metabolic parameters, inflammatory markers/cytokines, microbiota composition, and the fecal metaproteome, in a cohort of mice (n=50) prior to, and the 8 weeks following, administration of an obesogenic high-fat low-fiber diet. Neither behavioral testing nor quantitation of inflammatory markers broadly predicted severity of diet-induced obesity. Although, the small subset of mice that exhibited basal elevations in serum IL-6 (n=5) were among the more obese mice in the cohort. While fecal microbiota composition changed markedly in response to the obesogenic diet, it lacked the ability to predict which mice were relative prone or resistant to obesity. In contrast, fecal metaproteome analysis revealed functional and taxonomic differences among the proteins associated with proneness to obesity. Targeted interrogation of microbiota composition data successfully validated the taxonomic differences seen in the metaproteome. While future work will be needed to determine the breadth of applicability of these associations to other cohorts of animals and humans, this study nonetheless highlights the potential power of gut microbial proteins to predict and perhaps impact development of obesity.

Project description:Obesity has been shown to increase risk for cardiovascular disease and type-2 diabetes. In addition, it has been implicated in aggravation of neurological conditions such as Alzheimer’s. In the model organism Drosophila melanogaster, a physiological state mimicking diet-induced obesity can be induced by subjecting fruit flies to a solid medium disproportionately higher in sugar than protein (HSD) or that has been supplemented with a rich source of saturated fat (HFD). These flies can exhibit increased circulating glucose levels, increased triglyceride content, insulin-like peptide resistance, and behavior indicative of neurological decline, such as decreased climbing ability. We subjected Oregon-R-C flies to variants of the HSD, HFD, or normal (control) diet (ND), followed by a total RNA extraction from fly heads of each diet group for the purpose of Poly-A selected RNA-Sequencing. We targeted at least 50 million paired-end, stranded reads of 75 basepairs in size, and analyzed 4 biological replicates per dietary condition. Our objective was to identify the effects of obesogenic diets on transcriptome patterns, how they differed between obesogenic diets, and identify genes that may relate to pathogenesis accompanying an obesity-like state. Functional annotation and enrichment analysis among genes whose expression was significantly affected by the obesogenic diets indicated an overrepresentation of genes associated with immunity, metabolism, and hemocyanin in the HFD group, and CHK, cell cycle activity, and DNA binding and transcription in the HSD group. Heat map representation of genes affected by both diets illustrated a large fraction of differentially expressed genes between the two diet groups. Diets high in sugar and diets high in fat both have notableeffects on the Drosophila transcriptome in head tissue. The impacted genes, and how they may relate to pathogenesis in the Drosophila obesity-like state, warrant further experimental investigation. Our results also indicate differences in the effects of the HFD and HSD on expression profiles in head tissue of Oregon-R-C flies, despite the reportedly similar phenotypic impacts of the diets.

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Identifying the role of Acox1 in metabolism and inflammation in non-alcoholic fatty liver disease through mRNA-sequencing.

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