PPP2R5C knockdown leads to SREBP-1 and ChREBP activation.

Abstract

<p><b>(A)</b> PPP2R5C knockdown leads to upregulation of genes enriched for PPARA and SREBP-1 targets. Genes either up- or down-regulated upon PPP2R5C knockdown in mouse primary hepatocytes were analyzed using TFactS software [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005561#pgen.1005561.ref037" target="_blank">37</a>] to identify transcription factors putatively misregulated upon PPP2R5C knockdown. FDR (False Discovery Rate) rate was controlled using the Benjamini-Hochberg procedure. <b>(B-C)</b> Expression of bona-fide SREBP-1 target genes is increased upon PPP2R5C knockdown in primary hepatocytes in culture (B) or in mouse liver in vivo (C). PPP2R5C was knocked-down in mouse primary hepatocytes using adenovirus and in vivo using adeno-associated virus as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005561#pgen.1005561.g002" target="_blank">Fig 2</a>. SREBP-1 target genes quantified by Q-RT-PCR, normalized to TBP. <b>(D)</b> Upon PPP2R5C knockdown in liver, SREBP-1 protein levels are elevated. <b>(E)</b> Expression of ChREBP target genes is increased upon PPP2R5C knockdown in mouse liver in vivo. PPP2R5C was knocked-down in vivo using adeno-associated virus as in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005561#pgen.1005561.g002" target="_blank">Fig 2</a>. ChREBP target genes quantified by Q-RT-PCR, normalized to TBP. <b>(F)</b> Graphical representation of the metabolic changes induced upon PPP2R5C knockdown in mouse liver. Livers with reduced PPP2R5C have increased glucose uptake, increased TAG synthesis, and increased VLDL secretion. Error bars: std. dev. *p-value<0.05, **p-value<0.01, ***p-value<0.001 by student t-test (B-C,E) (n = 4 for mouse primary hepatocytes, and 5 or 6 for mouse liver).</p