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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Identification of eQTLs for Hepatic Xbp1s and Socs3 Gene Expression in Mice fed a High-Fat, High Caloric Diet

ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (p<0.05), while C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ? 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases. Liver samples from eight-week-old AJ and C57BL6J males fed a High Fat High Calorie diet.

ORGANISM(S): Mus musculus

SUBMITTER: Richard Green

PROVIDER: E-GEOD-56987 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Identification of eQTLs for Hepatic Xbp1s and Socs3 Gene Expression in Mice fed a High-Fat, High Caloric Diet

Project description:Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent form of hepatic disease and feeding mice a High-Fat, High-Caloric (HFHC) diet is a standard model of NAFLD. In order to better understand the genetic basis of NAFLD, we conducted an expression quantitative trait locus (eQTL) analysis of mice fed a HFHC diet. 265 (A/J × C57BL/6J) F2 male mice were fed a HFHC diet for 8 weeks. QTL analysis was utilized to identify genomic regions that regulate hepatic gene expression of Xbp1s and Socs3. We identified two overlapping loci for Xbp1 and Socs3 on Chr 1 (164.0-185.4 Mb and 174.4-190.5 Mb, respectively) and Chr 11 (41.1-73.1 Mb and 44.0-68.6 Mb, respectively), and an additional locus for Socs3 on Chr 12 (109.9-117.4 Mb). C57BL/6J-Chr 11A/J/ NaJ mice fed a HFHC diet manifested the A/J phenotype of increased Xbp1s and Socs3 gene expression (p<0.05), while C57BL/6J-Chr 1A/J/ NaJ mice retained the C57BL/6 phenotype. In addition, we replicated the eQTLs on Chr 1 and 12 (LOD scores ? 3.5) using mice from the BXD murine reference panel challenged with CCl4 to induce chronic liver injury and fibrosis. We have identified overlapping eQTLs for Xbp1 and Socs3 on Chr 1 and 11, and consomic mice confirmed that replacing the C57BL/6 with the A/J Chr 11 resulted in an A/J phenotype for Xbp1 and Socs3 gene expression. Identification of the genes for these eQTLs will lead to a better understanding of the genetic factors responsible for NAFLD and potentially other hepatic diseases.

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Project description:Non-alcoholic fatty liver disease (NAFLD) is most prevalent form of liver disease, affecting over 30% of Americans. Perfluoroalkyl substances (PFAS) represent a family of environmental toxicants that have infiltrated the living world. This study explores diet-PFAS interactions and their potential role in the increasing global incidence of NAFLD. Male C57BL/6 mice were fed with either a low-fat diet (11% kcal from fat) or a high fat (58% kcal from fat) high carbohydrate (42g/L) diet with or without PFOS or PFHxS in feed (0.0003% w/w) for 29 weeks. Proteomic, lipidomic, and gene expression measurement techniques were utilized to explore mechanistic pathways. With administration of a high fat high carbohydrate (HFHC) diet, PFOS and PFHxS augmented macrovesicular steatosis, indicative of fatty liver. There was a clear shift in the lipidome of the serum phosphatidylcholines, phosphatidylethanolamines, and triglycerides with PFAS exposure. Finally, chain length exerted significant influence on tissue partitioning and the resulting hepatic gene and protein signatures of PFHxS and PFOS in vivo.

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Effects of NAFLD/NASH on hepatic gene expression.

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2014-01-03 | E-GEOD-53381 | biostudies-arrayexpress

Hepatocyte RNA-seq analysis in liver-specific XBP1 knockout mice fed a high fat sugar diet

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2022-01-03 | GSE190947 | GEO

Changes of hepatic gene expression in C57BL/6N male mice fed high-fat high-calorie fructose (HFHC) diet for 8 weeks

Project description:In murine NAFL/NASH models, high-fat high-calorie fructose (HFHC) diet fed for 16 weeks induces hepatic steatosis, inflammatory cells infilatration and early stage fibrosis. In addition, HFHC diet 16 weeks but not 8 weeks is accompanied with weight gain and insulin resistance. The aim of this study is to determine the gene expression changes in mouse liver by HFHC diet for 8weeks.

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Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (pituitary bulk RNA seq)

Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese mouse, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.

2024-04-30 | GSE263188 | GEO

Sparcl1 promotes nonalcoholic steatohepatitis progression through upregulation of CCL2

Project description:1. White adipose tissues (WAT) are capable of secreting not only fatty acids but also a class of secretory proteins that modulate the homeostasis of distant organs, including the liver. To identify potential WAT-enriched secretory factors involved in NASH progression, C57BL/6 male mice were fed with a normal chow diet or HFHC diet for two different periods: 12 weeks and 28 weeks. Then, we compared the expression profile of epididymal WAT (eWAT) from mouse models of NAFL and NASH above mentioned by RNA-Sequencing analysis. 2. To investigate the contribution of Sparcl1 in the pathogenesis of NASH, male C57BL/6J mice were fed a HFHC diet for 12 weeks, and then intraperitoneal injected with saline or recombinant Sparcl1 protein (0.2mg/kg) every other day for 3 weeks. To elucidate the molecular basis of Sparcl1-mediated NASH progression, we conducted RNA-Sequencing analysis for differentially expressed genes using the livers of chronic recombinant Sparcl1 protein or saline- treated mice.

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A weekly alternating diet between caloric restriction and medium fat protects the liver from NAFLD in middle aged C57BL/6J mice

Project description:SCOPE: We investigated whether a novel dietary intervention consisting of an every-other-week calorie-restricted diet could prevent nonalcoholic fatty liver disease (NAFLD) development induced by a medium-fat (MF) diet. METHODS AND RESULTS: Nine-week-old male C57BL/6J mice received either a (i) control (C), (ii) 30E% calorie restricted (CR), (iii) MF (25E% fat), or (iv) intermittent (INT) diet, a diet alternating weekly between 40E% CR and an ad libitum MF diet until sacrifice at the age of 12 months. The metabolic, morphological, and molecular features of NAFLD were examined. The INT diet resulted in healthy metabolic and morphological features as displayed by the continuous CR diet: glucose tolerant, low hepatic triglyceride content, low plasma alanine aminotransferase. In contrast, the C- and MF-exposed mice with high body weight developed signs of NAFLD. However, the gene expression profiles of INT-exposed mice differed to those of CR-exposed mice and showed to be more similar with those of C- and MF-exposed mice with a comparable body weight. CONCLUSIONS: Our study reveals that the INT diet maintains metabolic health and reverses the adverse effects of the MF diet, thus effectively prevents the development of NAFLD in 12-month-old male C57BL/6J mice. Male C57Bl/6J mice were divided to 4 dietary intervention groups: Control (AIN-93W), 30% calorie restriction (CR; AIN-93W-CR), medium fat (MF; AIN-93W-MF; 25% energy from fat) and intermittent diet (INT; weekly alternating diet between AIN-93W-MF ad lib and 40% CR of AIN-93W). We performed various measurements on metabolic parameters and gene expression analysis on the liver. This entry represents the microarray data of the liver gene expression of each mouse.

2015-10-26 | E-GEOD-61233 | biostudies-arrayexpress

Obesity Disrupts the Pituitary-Hepatic UPR Communication Leading to NAFLD Progression (liver bulk RNA seq)

Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese mouse and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.

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Project description:Obesity alters circulating levels of pituitary hormones that govern hepatic immune-metabolic homeostasis, and dysregulation of which leads to NAFLD. Here, using diet induced obese and IRE1PKO mice, we uncovered an blunted unfolded protein response (UPR) but elevated inflammatory signatures in pituitary glands of obese mice. Mechanistically, we demonstrated that the pituitary IRE1alpha-XBP1 UPR branch is essential for protecting against pituitary endocrine defects and NAFLD progression in obesity.

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