Dataset Information

Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.

ABSTRACT: Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevation of serum markers of insulin resistance, including increases in total cholesterol, low-density lipoproteins, high-density lipoproteins, phospholipids, and glucose. The development of NAFLD was associated with overexpression of the critical fatty acid uptake and de novo lipogenesis genes Pparg, Mogat1, Cd36, Acaab1, Fabp2, and Gdf15 in male and female mice. The expression of Pparg, Mogat1, and Cd36 was positively correlated with liver triglycerides in male mice, and Mogat1 and Cd36 expression were positively correlated with liver triglycerides in female mice. Our results indicate the value of CC mice in combination with HF/HS diet-induced alterations as an approach to study the susceptibility and interindividual variabilities in the pathogenesis of nonalcoholic fatty liver and early nonalcoholic steatohepatitis at the population level, uncovering of susceptible and resistant cohorts, and identifying sex-specific molecular determinants of disease susceptibility.

SUBMITTER: de Conti A

PROVIDER: S-EPMC7552439 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.

de Conti Aline A Tryndyak Volodymyr V Willett Rose A RA Borowa-Mazgaj Barbara B Watson Anna A Patton Ralph R Khare Sangeeta S Muskhelishvili Levan L Olson Greg R GR Avigan Mark I MI Cerniglia Carl E CE Ross Sharon A SA Sanyal Arun J AJ Beland Frederick A FA Rusyn Ivan I Pogribny Igor P IP

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20200418 6

Interindividual variability and sexual dimorphisms in the development of nonalcoholic fatty liver disease (NAFLD) are still poorly understood. In the present study, male and female strains of Collaborative Cross (CC) mice were fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks to investigate interindividual- and sex-specific variations in the development of NAFLD. The severity of liver steatosis varied between sexes and individual strains and was accompanied by an elevat ...[more]

PMID: 32304142

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Project description:Identification of molecular determinants of the inter-individual and sex variability in the development of nonalcoholic fatty liver disease (NAFLD) is of great importance. Next-generation sequencing (NGS) derived transcriptome profiling (RNA-seq) is a powerful technique to investigate gene transcripts and gene variants for the systems-based analysis of molecular and cellular pathways. The goal of this study was to determine transcriptomic profiles in the livers of male and female Collaborative Cross (CC) mice fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks and to identify inter-individual- and sex-specific gene expression differences during the development of NAFLD. Liver mRNA profiles of 10 CC mouse strains (CC003/Unc, CC011/Unc, CC013/GeniUnc, CC019/TauUnc, CC032/GeniUnc, CC040/TauUnc, CC041/TauUnc, CC042/GeniUnc, CC043/GeniUnc, and CC060/Unc) fed an HF/HS diet were generated by deep sequencing, in triplicate, using Illumina NextSeq 500 NGS system. The sequence reads that passed quality filters were analyzed at the transcript level using TopHat followed by Cufflinks. The total number of differentially expressed genes identified by RNA-seq varied between sexes and individual mouse strains and correlated with the severity of liver steatosis. Pathway analysis of differentially expressed genes showed dysregulation of genes involved in lipid metabolism, cell proliferation and death, inflammation, and fibrogenesis pathways in the livers of males and females CC mice. The RNA-seq data were validated and confirmed by qRT-PCR analysis of 27 selected genes associated with lipid metabolism and fibrogenesis using TaqMan assays. Our results show that RNA-seq based transcriptome analysis offers a comprehensive, quantitative, and qualitative evaluation of whole-genome expression that can be used for the identification of unique genes associated with the inter-individual and sex differences in susceptibility to NAFLD at the population level.

Project description:The pathological progression of nonalcoholic fatty liver disease (NAFLD) is driven by multiple factors, and nonalcoholic steatohepatitis (NASH) represents its progressive form. In our previous studies, we found that bicyclol had beneficial effects on NAFLD/NASH. Here we aim to investigate the underlying molecular mechanisms of the bicyclol effect on NAFLD/NASH induced by high-fat diet (HFD) feeding. A mice model of NAFLD/NASH induced by HFD-feeding for 8 weeks was used. As a pretreatment, bicyclol (200 mg/kg) was given to mice by oral gavage twice daily. Hematoxylin and eosin (H&E) stains were processed to evaluate hepatic steatosis, and hepatic fibrous hyperplasia was assessed by Masson staining. Biochemistry analyses were used to measure serum aminotransferase, serum lipids, and lipids in liver tissues. Proteomics and bioinformatics analyses were performed to identify the signaling pathways and target proteins. The real-time RT-PCR and Western blot analyses were performed to verify the proteomics data. As a result, bicyclol had a markedly protective effect against NAFLD/NASH by suppressing the increase of serum aminotransferase, hepatic lipid accumulation and alleviating histopathological changes in liver tissues. Proteomics analyses showed that bicyclol remarkably restored major pathways related to immunological responses and metabolic processes altered by HFD feeding. Consistent with our previous results, bicyclol significantly inhibited inflammation and oxidative stress pathway related indexes (SAA1, GSTM1 and RDH11). Furthermore, the beneficial effects of bicyclol were closely associated with the signaling pathways of bile acid metabolism (NPC1, SLCOLA4 and UGT1A1), cytochrome P450-mediated metabolism (CYP2C54, CYP2C70 and CYP3A25), biological processes such as metal ion metabolism (Ceruloplasmin and Metallothionein-1), angiogenesis (ALDH1A1) and immunological responses (IFI204 and IFIT3). These findings suggested that bicyclol is a potential preventive agent for NAFLD/NASH by targeting multiple mechanisms in future clinical investigations.

Project description:Gypenosides (GP), extracted from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino, have been used to treat metabolic disorders, including lipid metabolism disorders and diabetes. Although recent studies have confirmed their beneficial effects in nonalcoholic fatty liver disease (NAFLD), the underlying therapeutic mechanism remains unclear. In this study, we explored the protective mechanism of GP against NAFLD in mice and provided new insights into the prevention and treatment of NAFLD. Male C57BL6/J mice were divided into three experimental groups: normal diet, high-fat diet (HFD), and GP groups. The mice were fed an HFD for 16 weeks to establish an NAFLD model and then treated with GP for 22 weeks. The transcriptome and proteome of the mice livers were profiled using RNA sequencing and high-resolution mass spectrometry, respectively. The results showed that GP decreased serum lipid levels, liver index, and liver fat accumulation in mice. Principal component and heatmap analyses indicated that GP significantly modulated the changes in the expression of genes associated with HFD-induced NAFLD. The 164 differentially expressed genes recovered using GP were enriched in fatty acid and steroid metabolism pathways. Further results showed that GP reduced fatty acid synthesis by downregulating the expression of Srebf1, Fasn, Acss2, Acly, Acaca, Fads1, and Elovl6; modulated glycerolipid metabolism by inducing the expression of Mgll; promoted fatty acid transportation and degradation by inducing the expression of Slc27a1, Cpt1a, and Ehhadh; and reduced hepatic cholesterol synthesis by downregulating the expression of Tm7sf2, Ebp, Sc5d, Lss, Fdft1, Cyp51, Nsdhl, Pmvk, Mvd, Fdps, and Dhcr7. The proteomic data further indicated that GP decreased the protein expression levels of ACACA, ACLY, ACSS2, TM7SF2, EBP, FDFT1, NSDHL, PMVK, MVD, FDPS, and DHCR7 and increased those of MGLL, SLC27A1, and EHHADH. In conclusion, GP can regulate the key genes involved in hepatic lipid metabolism in NAFLD mice, providing initial evidence for the mechanisms underlying the therapeutic effect of GP in NAFLD.

Dataset Information

Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.

Publications

Characterization of the variability in the extent of nonalcoholic fatty liver induced by a high-fat diet in the genetically diverse Collaborative Cross mouse model.

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