Trans-10, cis-12-conjugated linoleic acid alters hepatic gene expression in a polygenic obese line of mice displaying hepatic lipidosis

Department of Animal Science, North Carolina State University, Raleigh, NC 27695, USA.
The Journal of nutritional biochemistry (Impact Factor: 3.79). 10/2009; 21(9):848-55. DOI: 10.1016/j.jnutbio.2009.06.013
Source: PubMed


The trans-10, cis-12 isomer of conjugated linoleic acid (CLA) causes a rapid reduction of body and adipose mass in mice. In addition to changes in adipose tissue, numerous studies have reported alterations in hepatic lipid metabolism. Livers of CLA-fed mice gain mass, partly due to lipid accumulation; however, the precise molecular mechanisms are unknown. To elucidate these mechanisms, we examined fatty acid composition and gene expression profiles of livers from a polygenic obese line of mice fed 1% trans-10, cis-12-CLA for 14 days. Analysis of gene expression data led to the identification of 1393 genes differentially expressed in the liver of CLA-fed male mice at a nominal P value of .01, and 775 were considered significant using a false discovery rate (FDR) threshold of .05. While surprisingly few genes in lipid metabolism were impacted, pathway analysis found that protein kinase A (PKA) and cyclic adenosine monophosphate (cAMP) pathways signaling pathways were affected by CLA treatment and 98 of the 775 genes were found to be regulated by hepatocyte nuclear factor 4alpha, a transcription factor important in controlling liver metabolic status.

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    • "The exact mechanism through which this isomer influences oocyte lipid metabolism remains elusive. Nevertheless, the t10, c12 CLA appears to affect the PKA signal transduction pathway, and thus the cAMP cascade of reactions [67] (Figure 4). On the other hand, an increase in lipolysis and in cytosolic perilipin associated with smaller LD was identified in human adipocytes cultured in the presence of this CLA isomer [68]. "
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    ABSTRACT: Oocyte intracellular lipids are mainly stored in lipid droplets (LD) providing energy for proper growth and development. Lipids are also important signalling molecules involved in the regulatory mechanisms of maturation and hence in oocyte competence acquisition. Recent studies show that LD are highly dynamic organelles. They change their shape, volume, and location within the ooplasm as well as their interaction with other organelles during the maturation process. The droplets high lipid content has been correlated with impaired oocyte developmental competence and low cryosurvival. Yet the underlying mechanisms are not fully understood. In particular, the lipid-rich pig oocyte might be an excellent model to understand the role of lipids and fatty acid metabolism during the mammalian oocyte maturation and their implications on subsequent monospermic fertilization and preimplantation embryo development. The possibility of using chemical molecules to modulate the lipid content of oocytes and embryos to improve cryopreservation as well as its biological effects during development is here described. Furthermore, these principles of lipid content modulation may be applied not only to germ cells and embryo cryopreservation in livestock production but also to biomedical fundamental research.
    Mediators of Inflammation 03/2014; 2014(2):692067. DOI:10.1155/2014/692067 · 3.24 Impact Factor
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    • "The effects of dietary trans-10, cis-12-CLA on lipid metabolism in adipose and liver have been examined previously [2] [3]. Gene expression profiling studies in rodent adipose [2] [4], liver [5] [6] [7], and macrophages [8] have been conducted to help elucidate the molecular mechanisms elicited by trans-10, cis-12-CLA. In adipose and liver, trans-10, cis-12-CLA reduces adipogenesis, increases hepatic steatosis, and leads to insulin resistance, hyperinsulinemia, and inflammation [3] [9]. "
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    ABSTRACT: Exogenous trans-10, cis-12-CLA (CLA) reduces lipid synthesis in murine adipose and mammary (MG) tissues. However, genomewide alterations in MG and liver (LIV) associated with dietary CLA during lactation remain unknown. We fed mice (n = 5/diet) control or control + trans-10, cis-12-CLA (37 mg/day) between d 6 and d 10 postpartum. The 35,302 annotated murine exonic evidence-based oligo (MEEBO) microarray and quantitative RT-PCR were used for transcript profiling. Milk fat concentration was 44% lower on d 10 versus d 6 due to CLA. The CLA diet resulted in differential expression of 1,496 genes. Bioinformatics analyses underscored that a major effect of CLA on MG encompassed alterations in cellular signaling pathways and phospholipid species biosynthesis. Dietary CLA induced genes related to ER stress (Xbp1), apoptosis (Bcl2), and inflammation (Orm1, Saa2, and Cp). It also induced marked inhibition of PPAR γ signaling, including downregulation of Pparg and Srebf1 and several lipogenic target genes (Scd, Fasn, and Gpam). In LIV, CLA induced hepatic steatosis probably through perturbations in the mitochondrial functions and induction of ER stress. Overall, results from this study underscored the role of PPAR γ signaling on mammary lipogenic target regulation. The proinflammatory effect due to CLA could be related to inhibition of PPAR γ signaling.
    05/2013; 2013(9):890343. DOI:10.1155/2013/890343
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    • "Despite the clear deleterious effects observed in rodents, the European Food Safety authority after an evaluation of the available data concluded that consumption of 3.5 g CLA (or 4.5 g product/d) from a commercial product containing equal proportions of trans-10, cis-12-CLA and cis-9, trans- 11-CLA was not deleterious to health [14]. However, at the molecular level, hepatic steatosis in rodents due to trans-10, cis-12-CLA at ≥0.5% of the diet has been linked to alterations in the expression of genes associated with energy expenditure , apoptosis, fatty acid oxidation, lipolysis, differentiation, and lipogenesis [1] [15]. Therefore, it is likely that sustained supplementation of the above amount, which is much greater Table 1: Summary of the changes in liver mass, liver TG, and adipose tissue mass observed in previous mouse studies feeding different levels of trans-10, cis-12-CLA compared with feeding linoleic acid (LA) or oleic acid (as canola oil). "
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    ABSTRACT: Dietary trans-10, cis-12-conjugated linoleic acid (trans-10, cis-12-CLA) fed to obese and nonobese rodents reduces body fat but leads to greater liver mass due to steatosis. The molecular mechanisms accompanying such responses remain largely unknown. Our study investigated the effects of chronic low trans-10, cis-12-CLA supplementation on hepatic expression of 39 genes related to metabolism, inflammation, and stress in growing mice. Feeding a diet supplemented with 0.3% trans-10, cis-12-CLA (wt/wt basis) for 6 weeks increased liver mass and concentration of long-chain fatty acids (LCFAs) in liver, while adipose tissue mass decreased markedly. These changes were accompanied by greater expression of genes involved in LCFA uptake (Cd36), lipogenesis, and triacylglycerol synthesis (Acaca, Gpam, Scd, Pck1, Plin2). Expression of these genes was in line with upregulation of the lipogenic transcription factor Srebf1. Unlike previous studies where higher >0.50% of the diet) doses of trans-10, cis-12-CLA were fed, we found greater expression of genes associated with VLDL assembly/secretion (Mttp, Cideb), ketogenesis (Hmgcs2, Bdh1), and LCFA oxidation (Acox1, Pdk4) in response to trans-10, cis-12-CLA. Dietary CLA, however, did not affect inflammation- and stress-related genes. Results suggested that a chronic low dose of dietary CLA increases liver mass and lipid accumulation due to activation of lipogenesis and insufficient induction of LCFA oxidation and VLDL assembly/secretion.
    09/2012; 2012(11):571281. DOI:10.1155/2012/571281
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