Figure

7 Regulation of genes involved in synthesis of β-hydroxybutyrate. Panel A shows comparisons of the 1 h and 24 h time points only, panel B shows comparisons involving the 6 h time point. In a rat proximal tubule cell line β-hydroxybutyrate induced TGFβ expression [29]. Thus, a positive feedback of the two parameters can be hypothesized. TGFβ may mediate elevation of ketone bodies by exercise, as TGFβ application to murine brains mobilizes ketone Inhibitors,research,lifescience,medical bodies [30], while inhibition of TGFβ by an antibody [31] reduces it. 2.11. Creatine Synthesis Guanidinoacetate methyltransferase (Gamt), the final step in creatine synthesis, shows the rare pattern, up-regulation in untreated hepatocytes and down-regulation in TGFβ treated hepatocytes (see Figure 8A, second group of bars). Inhibitors,research,lifescience,medical The respective transcript changes are moderate (+0.67,−1.56), but Selleckchem GABA Receptor inhibitor statistically highly significant (p < 0.011, p < 0.033). This fact is especially remarkable, as there is endogenous TGFβ production (see Section 2.13) in untreated cultured hepatocytes. Apparently, there is a threshold switch, which suppresses the effect of moderate TGFβ levels to Gamt. Figure 8 (A) Regulation of creatine Inhibitors,research,lifescience,medical synthesis and of some solitude genes; (B) Regulation

of selected genes encoding TGFβ, its receptors and related proteins. The penultimate step, glycine amidinotransferase (Gatm), shows only a slight up-regulation in both experiments (see Inhibitors,research,lifescience,medical Figure 8A, first group of bars). The absolute expression is also low, but as creatine is known to be exported by hepatocytes and glycine amidinotransferase is essential for this function, we assume that sufficient RNA is present in the cell to synthesize glycine amidinotransferase. Apparently, this seems to be the case, where low affinity of the chip’s probes lead to a low luminescence. The low deviation in the three repeats supports this assumption. It can be concluded that creatine synthesis is sensitive to TGFβ. Creatine supplementation prevents NAFLD in rat [32]. Thus, down-regulation of Gamt by TGFβ and a decrease in internal creatine production will possibly increase fat accumulation in hepatocytes.

aminophylline Inhibitors,research,lifescience,medical This result is in concordance with the finding in pig livers (Figure 2 in [1]), in which there is a strong creatine excretion into the serum of control livers (with elevated TGFβ levels) that does not occur when TGFβ is inhibited. As ornithine is a byproduct of Gatm, creatine synthesis is coupled to reactions of the urea cycle (see Supplementary file 6 for these reactions and Section 2.7). As urea synthesis is the function with a much higher reaction flux in hepatocytes, it is not feasible to associate transcript changes of enzymes such as arginase to creatine synthesis. 2.12. Solitude Genes with a Remarkable Pattern In this subsection, genes with a remarkable regulation not accompanied by a similar pattern of other genes belonging to the same functional context are considered.