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Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury.

ABSTRACT: Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alterations and immune cell activation. Women are at a higher risk than men for developing alcohol induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat composition are well known. However, it is still unclear if alcohol-induced adipose tissue inflammation occurs in a sex-dependent manner. Here we have employed the clinically relevant NIAAA model of chronic-binge alcohol consumption to investigate this sexual dimorphism. We report that female mice have greater liver injury than male mice despite lower alcohol consumption. Chronic-binge alcohol induces adipose tissue inflammation in vivo in female mice, which is illustrated by increased expression of TNF?, IL-6, and CCL2, compared to only IL-6 induction in male adipose tissue. Further, macrophage activation markers such as CD68 as well as the pro-inflammatory activation markers CD11b and CD11c were higher in female adipose tissue. Interestingly, alcohol induced expression of TLR2, 3, 4, and 9 in female but not male adipose tissue, without affecting the TLR adaptor, MyD88. Higher trends of serum endotoxin in female mice may likely contribute to adipose tissue inflammation. In vitro chronic alcohol-mediated sensitization of macrophages to endotoxin is independent of sex. In summary, we demonstrate for the first time that there is a sexual dimorphism in alcohol-induced adipose tissue inflammation and female mice exhibit a higher degree of inflammation than male mice.

SUBMITTER: Fulham MA

PROVIDER: S-EPMC5053524 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury.

Fulham Melissa A MA Mandrekar Pranoti P

PloS one 20161006 10

Alcoholic liver disease occurs due to chronic, heavy drinking and is driven both by metabolic alterations and immune cell activation. Women are at a higher risk than men for developing alcohol induced liver injury and this dimorphism is reflected in animal models of alcoholic liver disease. The importance of adipose tissue in alcoholic liver disease is emerging. Chronic alcohol consumption causes adipose tissue inflammation, which can influence liver injury. Sex differences in body fat compositi ...[more]

PMID: 27711160

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Project description:Purpose: To conduct a transcriptomic study of gene oscillations in mouse liver by RNA sequencing of total RNA samples from 6 different time points across the day. Specific interest is to see whether sex is a factor in large scale gene oscillations under ad-libitum control conditions and in response to caloric restriction diet, since caloric restriction was previously reported to affect gene oscillation Methods: Total RNA was isolated from 20 mg mouse liver tissue using mini spin column QIAGEN RNeasy Mini Kit (Ref #74104, Lot#163035346, Hilden, Germany) according to the manufacturer’s protocol. Sample purity was checked on Nano Drop 2000 (Thermo Fisher Scientific, Waltham, MA, USA) with 260/280 ratio ≥ 2.0 and 260/230 ratio ≥ 2.0 for every sample. Each sample used for the analysis had RNA integrity number > 7. The RNA sequencing was performed by Novogene Corporation Inc (Sacramento, CA, USA). After sample quality control, non-directional – polyA enrichment library was prepared using NEBNext Ultra™ II RNA Library Prep Kit for Illumina, and 50M reads (150bp, paired end) per sample were generated on Illumina NovaSeq 6000 platform. RNA-seq reads were mapped to the mouse protein coding genes (Ensembl: Mus_musculus; GRCm38) using Bowtie allowing up to 2-mismatches. The gene expected read counts and Transcripts Per Million (TPM) were estimated by RSEM (v1.2.3). The TPMs were further normalized by EBSeq R package to correct potential batch effect. Results: We have performed RNA sequencing analysis of mouse livers on Ad-libitum and timed Caloric Restriction diet across 6 time points in 24h. The results of subsequent JTK_Cycle analysis (R package) revealed that circadian rhythms in total RNA liver transcriptome are different between sexes of mice in both the number of oscillating genes and phase under ad-libitum diet. Caloric restriction increased the number of oscillating genes in both sexes and resulted in a larger overlap of rhythmic transcriptome between sexes, but did not eliminate the difference completely. The response of transcriptome to caloric restriction in terms of gain or loss of rhythm in gene expression profiles was also different between sexes. Additionally, we have shown that the lack of data stratification by sex might result in the failure to detect rhythmic changes in expression of some genes. Conclusions: Our study represents the first systematic analysis of the effect of sex on circadian rhythms of liver transcriptome under ad libitum and caloric restriction diets. We have shown that sex based differences exist in rhythmic transcriptome, as well as in the response of rhythmic transcriptome to diet. We are providing the data useful for both circadian and metabolic researchers and point out the gene candidates which may not be identified as rhythmic, if the data is not stratified by sex. With the help of GO analysis we have concluded that sex also influences the preference towards different processes to be regulated in rhythmic manner on transcriptional level - fatty acid metabolism and protein transport in males vs nucleic acid metabolism and RNA processing in females on ad-libitum diet. On calorie-restricted diet nucleic acid metabolism and RNA processing were enriched in males vs protein transport and signal transduction in females on calorie-restricted diet. These findings highlight a complex interaction of sex and diet in their effect on circadian rhythms in liver gene expression. All of the data from sequenced RNA samples from MALE liver were previously uploaded with the GSE211975 dataset. The current dataset only contains RNA-seq samples from FEMALE liver.

Dataset Information

Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury.

Publications

Sexual Dimorphism in Alcohol Induced Adipose Inflammation Relates to Liver Injury.

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