Project description:Pyrroloquinoline quinone (PQQ) is a naturally occurring compound and known to improve growth and reproductive performance when added to diets of PQQ-deprived rodents. To understand its mechanism action, changes in hepatic gene expression were measured in rats fed diets with or without added PQQ. Gene expression changes for PQQ supplemented (EC50 ~ 3 nmol PQQ/Kg diet) or deficient rats were assayed by expression microarray analysis and compared to those for known transcriptional regulators (epicatechin; Epi; dexamethasone, Dex; clofibrate, Clo; phenobarbital, Pb). Two principal expression clusters were observed; one for Dex and another for Pb, Epi, Clo, and PQQ. Within the latter, a PQQ subcluster containing a unique group of genes for cell signaling and transport functions. Next, short and long term PQQ depletion and repletion protocols (48 or 36 h, respectively) were performed, leading to changes in hepatic gene expression for both time periods. Of the ~10,000 genes and ESTs analyzed, 4.7% of the transcripts were sensitive to changes in PQQ dietary status. PQQ deprivation generally caused down regulation of genes associated with mitochondriogenesis, cell differentiation, and immune function. These gene expression changes provide the basis for most of the previously published functional observations associated with PQQ deficiency and PQQ administered in pharmacological amounts. To assess PQQ’s potential functions, we used gene expression profiling through microarray technology as part of a comprehensive approach to identify potential pathways and mechanisms. Given that the systemic effects of PQQ deprivation are influenced at levels of dietary intake in the micromolar range, highly purified diets were used to reduce expression from other bioactive factors and xenobiotics, such as those found in typical rodent chow diets. To establish if the changes in gene expression in response to PQQ exposure will follow a similar pattern as other xenobiotics, the responses to PQQ exposure were contrasted with those from exposure to epicatechin (Epi), dexamethasone (Dex), clofibrate (Clo), or phenobarbital (Pb). Dietary conditions were also chosen to clarify the response to short- and longer-term PQQ deprivation. A goal was to determine if specific changes in dietary protocol or patterns could be used to identify genes important to the function of PQQ. Because it has been observed that mitochondrial-related functions are influenced by PQQ, we hypothesized that changes in genes important to fatty acid and amino acid metabolism and mitochondrial function would be likewise affected by dietary levels of PQQ. The overall study was carried out using two experiments. In this specific experiment, the gene expression profiles of Sprague Dawley (SD) rats treated with different xenobiotics were compared to the gene expression profile of PQQ treated SD rats.

Project description:A series of two color gene expression profiles obtained using Agilent 44K expression microarrays was used to examine sex-dependent and growth hormone-dependent differences in gene expression in rat liver. This series is comprised of pools of RNA prepared from untreated male and female rat liver, hypophysectomized (‘Hypox’) male and female rat liver, and from livers of Hypox male rats treated with either a single injection of growth hormone and then killed 30, 60, or 90 min later, or from livers of Hypox male rats treated with two growth hormone injections spaced 3 or 4 hr apart and killed 30 min after the second injection. The pools were paired to generate the following 6 direct microarray comparisons: 1) untreated male liver vs. untreated female liver; 2) Hypox male liver vs. untreated male liver; 3) Hypox female liver vs. untreated female liver; 4) Hypox male liver vs. Hypox female liver; 5) Hypox male liver + 1 growth hormone injection vs. Hypox male liver; and 6) Hypox male liver + 2 growth hormone injections vs. Hypox male liver. A comparison of untreated male liver and untreated female liver liver gene expression profiles showed that of the genes that showed significant expression differences in at least one of the 6 data sets, 25% were sex-specific. Moreover, sex specificity was lost for 88% of the male-specific genes and 94% of the female-specific genes following hypophysectomy. 25-31% of the sex-specific genes whose expression is altered by hypophysectomy responded to short-term growth hormone treatment in hypox male liver. 18-19% of the sex-specific genes whose expression decreased following hypophysectomy were up-regulated after either one or two growth hormone injections. Finally, growth hormone suppressed 24-36% of the sex-specific genes whose expression was up-regulated following hypophysectomy, indicating that growth hormone acts via both positive and negative regulatory mechanisms to establish and maintain the sex specificity of liver gene expression. For full details, see V. Wauthier and D.J. Waxman, Molecular Endocrinology (2008)

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Rattus norvegicus

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