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A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats.

ABSTRACT: We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (approximately 70%); detoxification, steroid, and sulfur metabolism (approximately 65%) as well as cell growth/proliferation and protein synthesis/transformation (approximately 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor alpha significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease.

SUBMITTER: Buque X

PROVIDER: S-EPMC2817580 | biostudies-literature | 2010 Mar

REPOSITORIES: biostudies-literature

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A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats.

Buqué Xabier X Martínez María José MJ Cano Ainara A Miquilena-Colina María E ME García-Monzón Carmelo C Aspichueta Patricia P Ochoa Begoña B

Journal of lipid research 20090924 3

We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steat ...[more]

PMID: 19783528

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Project description:BackgroundPatients with metabolic syndrome, who are characterized by co-existence of insulin resistance, hypertension, hyperlipidemia, and obesity, are also prone to develop non-alcoholic fatty liver disease (NAFLD). Although the prevalence and severity of NAFLD is significantly greater in men than women, the mechanisms by which gender modulates the pathogenesis of hepatic steatosis are poorly defined. The obese spontaneously hypertensive (SHROB) rats represent an attractive model of metabolic syndrome without overt type 2 diabetes. Although pathological manifestation caused by the absence of a functional leptin receptor has been extensively studied in SHROB rats, it is unknown whether these animals elicited sex-specific differences in the development of hepatic steatosis.MethodsWe compared hepatic pathology in male and female SHROB rats. Additionally, we examined key biochemical and molecular parameters of signaling pathways linked with hyperinsulinemia and hyperlipidemia. Finally, using methods of quantitative polymerase chain reaction (qPCR) and western blot analysis, we quantified expression of 45 genes related to lipid biosynthesis and metabolism in the livers of male and female SHROB rats.ResultsWe show that all SHROB rats developed hepatic steatosis that was accompanied by enhanced expression of SREBP1, SREBP2, ACC1, and FASN proteins. The livers of male rats also elicited higher induction of Pparg, Ppara, Slc2a4, Atox1, Skp1, Angptl3, and Pnpla3 mRNAs. In contrast, the livers of female SHROB rats elicited constitutively higher levels of phosphorylated JNK and AMPK and enhanced expression of Cd36.ConclusionBased on these data, we conclude that the severity of hepatic steatosis in male and female SHROB rats was mainly driven by increased de novo lipogenesis. Moreover, male and female SHROB rats also elicited differential severity of hepatic steatosis that was coupled with sex-specific differences in fatty acid transport and esterification.

Project description:To determine how soy protein isolate (SPI) ameliorated liver steatosis in male obese Zucker rats, we conducted global transcriptomic expression (RNAseq) analysis on liver samples of male rats fed either the SPI or a control casein (CAS)-based diet (n = 8 per group) for 16 weeks. Liver transcriptomics were analyzed using an Ilumina HiSeq system with 2 × 100 base pair paired-end reads method. Bioinformatics was conducted using Ingenuity Pathway Analysis (IPA) software (Qiagen, CA) with P < 0.05 and 1.3-fold differential expression cutoff values. Regression analysis between RNAseq data and targeted mRNA expression analysis of 12 top differentially expressed genes (from the IPA program) using quantitative PCR (qPCR) revealed a significant regression analysis (r 2 = 0.69, P = 0.0008). In addition, all qPCR values had qualitatively similar direction of up- or down-regulation compared to the RNAseq transcriptomic data. Diseases and function analyses that were based on differentially expressed target molecules in the dataset predicted that lipid metabolism would be enhanced whereas inflammation was predicted to be inhibited in SPI-fed compared to CAS-fed rats at 16 weeks. Combining upstream regulator and regulator effects functions in IPA facilitates the prediction of upstream regulators (e.g., transcription regulators) that could play important roles in attenuating or promoting liver steatosis due to SPI or CAS diets. Upstream regulators that were predicted to be activated (from expression of down-stream targets) linked to increased conversion of lipid and transport of lipid in SPI-fed rats included hepatocyte nuclear factor 4 alpha (HNF4A) and aryl hydrocarbon receptor (AHR). Upstream regulators that were predicted to be activated in CAS-fed rats linked to activation of phagocytosis and neutrophil chemotaxis included colony stimulating factor 2 and tumor necrosis factor. The results provide clear indication that long-term SPI-fed rats exhibited diminished inflammatory response and increased lipid transport in liver compared to CAS-fed rats that likely would contribute to reduced liver steatosis in this obese Zucker rat model.

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A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats.

Publications

A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats.

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