Identification of promethin and PGLP as two novel up-regulated genes in PPARc1-induced adipogenic mouse liver SongtaoYu a , Navin Viswakarma a , Surinder K. Batra b , M. Sambasiva Rao a , Janardan K. Reddy a, * a Department of Pathology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA b Department of Biochemistry and Molecular Biology, University of Nebraska Medical School, Omaha, NB, USA Received 10 September 2004; accepted 27 September 2004 Available online 22 October 2004 Abstract Peroxisome proliferator-activated receptor (PPAR) isoforms, a, c and b/d, function as important lipid sensors as well as key regulators of energy homeostasis. PPARa plays a dynamic role in energy combustion by transcriptionally upregulating fatty acid oxidation systems prima- rily in liver, whereas PPARc functions as a regulator of adipogenesis and lipid storage. Overexpression of PPARc, using adenoviral expression approach, in PPARa deficient mouse liver results in hepatic steatosis with concurrent expression of adipocyte specific genes. In this study, to gain a global molecular understanding of PPARc1-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 PPARc-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 PPARc overexpres- sion. PGLP, which encodes a 38 kDa cytoplasmic membranous protein, is a low abundant transcript in normal liver, but induced dramatically following PPARc 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 PPARc-target genes should provide a basis for understanding the molecular mechanisms underly- ing energy storage and lipid homeostasis. © 2004 Elsevier SAS. All rights reserved. Keywords: PPARc; Promethin; PGLP; Adipokines; Adiponectin; Cidea; Hepatic steatosis; Gene expression profiling 1. Introduction Peroxisome proliferators constitute a structurally diverse group of chemicals that exert their biological effects by acti- vating a receptor designated as peroxisome proliferator- activated receptor a (PPARa), a member of the steroid nuclear receptor superfamily [1–6]. The PPAR subfamily consists of three members, PPARa, PPARc, and PPARb (also called d), which play a prominent role in lipid homeo- stasis with PPARa and PPARb involved in lipid combustion and PPARc-exerting a dominant function in energy (lipid) conservation [7–14]. Peroxisome proliferators enhance fatty acid oxidation and energy combustion by activating PPARa and this receptor increases the transcriptional activity of genes involved in peroxisomal, mitochondrial and microso- mal fatty acid oxidation systems in liver [1,15–17]. Absence of PPARa abrogates the pleiotropic responses, including the liver tumor development induced by peroxisome prolifera- tors [3,18,19]. Accordingly, PPARa functions as a sensor for xenobiotic peroxisome proliferators, as well as, for natural Abbreviations: Cidea, cell death-inducing DNA fragmentation factor a subunit-like effector A; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome porliferator response element(s). * Corresponding author. Tel.: +1-312-503-7948; fax: +1-312-503-8249. E-mail address: jkreddy@northwestern.edu (J.K. Reddy). Biochimie 86 (2004) 743–761 www.elsevier.com/locate/biochi 0300-9084/$ - see front matter © 2004 Elsevier SAS. All rights reserved. doi:10.1016/j.biochi.2004.09.015