Unraveling Lipid Metabolism with Microarrays
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Lipophilic statins, including atorvastatin, may exert significant antiproliferative and proapoptotic effects in breast cancer as demonstrated in both clinical trials and cell models. However, heterogeneity in treatment response still remains a noteworthy challenge to be addressed. In this regard, we previously proposed a multigene signature including genes involved in cholesterol biosynthesis, which were dysregulated upon atorvastatin treatment and was shown to predict statin responsiveness in breast cancer BC cell lines and primary tumors.
To further delineate the molecular mechanisms underlying this variability, we sought to characterize the differential statin-induced effects on intracellular lipid regulation observed in BC cell lines based on their sensitivity to atorvastatin treatment.
Under complete culture conditions, atorvastatin-induced decrease in cell proliferation was inversely correlated to a progressive accumulation of neutral lipids in lipid droplets LDs in the insensitive cells following 72 hours treatment. Transcriptional profiling of genes involved in lipid metabolism using microarrays and validated by qRT-PCR ruled out the likelihood that atorvastatin treatment altered lipid uptake and export mechanisms in sensitive cells in the presence of exogenous lipid supply. Nevertheless, gene ontology analysis indicated that an induction of cell stress responses was likely associated to atorvastatin sensitivity.
Significant deregulation of genes involved in the fatty acid metabolic process, including biosynthesis of monounsaturated fatty acids MUFAs , and cholesterol biosynthesis were instead linked to atorvastatin insensitivity. Accordingly, we found that the magnitude of the induction of the mRNAs of stearoyl-CoA desaturase SCD , the key effector in MUFAs metabolism, and 3-hydroxymethylglutaryl-CoA reductase HMGCR , the established target of statins, were consistently lower in sensitive cells compared to the insensitive counterpart in response to atorvastatin treatment.
Therefore, we suggest that the ability to significantly increase the number of stored neutral lipids in response to statin treatment may likely confer a proliferative advantage to BC cells. Our results also identified MUFAs metabolism as an attractive pathway to be further investigated in view of finding promising biomarkers for unraveling the molecular basis of statin sensitivity in breast cancer.
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Atorvastatin insensitivity is associated with increased lipid droplets accumulation and fatty acid metabolism in breast cancer cells [abstract]. NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. Consumption of foods containing flavonoids is associated with a reduced risk of cardiovascular diseases CVD , possibly by lipid-lowering effects. On the other hand, for one of these flavonoids, quercetin, also genotoxicity was shown especially in in vitro bioassays.
Therefore, the first aim of this thesis was to identify mechanisms underlying potential beneficial health effects of flavonoids. The focus was on hepatic lipid metabolism and circulating lipids and a molecular and physiological approach was used. Secondly, we aimed to study the potential in vivo genotoxic effects of quercetin by transcriptome analyses in liver and small intestine, since these represent the tissues of first contact exposed to relatively high levels upon oral intake of flavonoids.
Circulating lipids are important CVD-related risk markers, which are in general determined with commercially available enzyme-based assays. However, the usual enzyme in these assays, peroxidase, has previously been reported to be inhibited by flavonoids. Therefore, we have studied in chapter 2 whether these assays can adequately be used in flavonoid research.
We observed that various flavonoid aglycones interfere with peroxidase used in triglycerides TG and free fatty acids FFA enzymatic assays, reporting incorrect lower TG and FFA levels than actually present. Furthermore, addition of metabolites such as isorhamnetin or quercetinO-glucuronide, the major metabolite of quercetin in human and rat plasma, to murine serum also resulted in a significant reduction of the detected TG levels, while a trend was seen towards reduced FFA levels.
It can be concluded that when applying these biochemical assays, vigilance is needed and alternative analytical methods assessing FFA or TG levels should preferably be applied for studying the biological effects of flavonoids on TG and FFA levels. In chapter 3 mechanistic and physiological effects of quercetin on hepatic lipid metabolism were studied. Gas chromatography and 1H-NMR were used to quantitatively measure serum lipid profiles. Whole genome microarray analysis of liver tissue was used to identify potential mechanisms underlying altered circulating lipid levels by quercetin supplementation.
Body weight, energy intake and hepatic lipid accumulation did not differ significantly between the quercetin and the control group.
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Two relevant regulators, cytochrome P oxidoreductase Por , rate limiting for cytochrome P activities and the transcription factor constitutive androstane receptor Car ; official symbol Nr1i3 were also up- regulated in the quercetin-fed mice. We concluded that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, which may contribute to potential beneficial effects of quercetin on CVD.
The set-up of the experiment was the same as in chapter 3, with the exception of the background diet that was used, which was different in fat content and composition.
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Berger, and M. Narayanan, N. Narayanan, and B. Narayanan, O. Geoffrey, and D. Xiao, M. Kruhoffer, P. Bendix Jeppesen, A. Reziwanggu, T. Orntoft, and K. Rondinone and J.
Unraveling Lipid Metabolism with Micorarrays
Grainger, D. Mosedale, E. Holmes, and J. Rubinstein, S.