Identification of promethin and PGLP as two novel up-regulated genes in PPARγ1-induced adipogenic mouse liver

Peroxisome proliferator-activated receptor (PPAR) isoforms, α, γ and β/δ, function as important lipid sensors as well as key regulators of energy homeostasis. PPARα plays a dynamic role in energy combustion by transcriptionally upregulating fatty acid oxidation systems primarily in liver, whereas PPARγ functions as a regulator of adipogenesis and lipid storage. Overexpression of PPARγ, using adenoviral expression approach, in PPARα deficient mouse liver results in hepatic steatosis with concurrent expression of adipocyte specific genes. In this study, to gain a global molecular understanding of PPARγ1-induced gene expression in liver, we have analyzed gene expression profiles using the Affymetrix GeneChip mouse expression array set 430, that enables a comprehensive gene expression profiling with >39,000 transcripts. Microarray data analysis provided us with over 278 genes up-regulated fourfold or higher, and 121 genes down-regulated fourfold or higher in liver with PPARγ-induced hepatic adiposis. We have found 101 uncharacterized genes out of 278 up-regulated and 29 uncharacterized among the down-regulated gene categories, respectively. Of 177 functionally characterized candidate genes in the up-regulated category many appear to be involved in adipogenesis, lipid metabolism and signal transduction. To focus attention on the uncharacterized genes in the up-regulated category, we cloned the full-length cDNAs of two novel candidates, which we designated as promethin and PGLP. Promethin, a 15-kDa cytosolic protein, is not normally expressed in liver but induced robustly in liver with hepatic adiposis caused by PPARγ overexpression. PGLP, which encodes a 38:kDa cytoplasmic membranous protein, is a low abundant transcript in normal liver, but induced dramatically following PPARγ overexpression. The expression of these two genes was not increased in fatty livers induced by fasting or choline deficiency. The identification of these and other novel PPARγ-target genes should provide a basis for understanding the molecular mechanisms underlying energy storage and lipid homeostasis.