Characterization of the Mouse and Human Monoacylglycerol O-Acyltransferase 1 (Mogat1) Promoter in Human Kidney Proximal Tubule and Rat Liver Cells

Abstract

Monoacylglycerol acyltransferase 1 (Mogat1) catalyzes the conversion of monoacylglycerols (MAG) to diacylglycerols (DAG), the precursor of several physiologically important lipids such as phosphatidylcholine, phosphatidylethanolamine and triacylglycerol (TAG). Expression of Mogat1 is tissue restricted and it is highly expressed in the kidney, stomach and adipose tissue but minimally in the normal adult liver. To understand the transcriptional regulation of Mogat1, we characterized the mouse and human Mogat1 promoters in human kidney proximal tubule-2 (HK-2) cells. In-silico analysis revealed several peroxisome proliferator response element (PPRE) binding sites in the promoters of both human and mouse Mogat1. These sites responded to all three peroxisome proliferator activated receptor (PPAR) isoforms such that their respective agonist or antagonist activated or inhibited the expression of Mogat1. PPRE site mutagenesis revealed that sites located at -592 and -2518 are very effective in decreasing luciferase reporter gene activity. Chromatin immunoprecipitation (ChIP) assay using PPARα antibody further confirmed the occupancy of these sites by PPARα. While these assays revealed the core promoter elements necessary for Mogat1 expression, there are additional elements required to regulate its tissue specific expression. Chromosome conformation capture (3C) assay revealed additional cis-elements located ~10–15 kb upstream which interact with the core promoter. These chromosomal regions are responsive to both PPARα agonist and antagonist.

Hippocampal PPARα is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice

“…The immunofluorescence results indicated that chronic stress induced global changes of hippocampal PPARα distribution. As a nuclear receptor, PPARα has the main physiological function of modulating the transcriptional activities of some genes, including those for Glut1, CREB, Mogat1 and HO‐1, by binding PPREs (Roy et al ., ; Sankella et al ., ; Wu et al ., ; You et al ., ). Among these genes, CREB is well known to participate in depression (Blendy, ; Gass and Riva, ; Krishnan and Nestler, ).…”

Hepatic monoacylglycerol acyltransferase 1 is induced by prolonged food deprivation to modulate the hepatic fasting response

“…Whereas previous work has shown that PPAR is an important regulator of Mogat1 expression in steatotic liver, in this study we show using whole-body PPAR-null mice that this member of the PPAR family controls Mogat1 expression in nonsteatotic fed liver and the induction of Mogat1 that occurs with fasting. In fact, many genes regulating triglyceride metabolism, including Gpat1 and Dgat1, are directly regulated by PPAR activation (24)(25)(26)(27). Previous work has shown that chromatin in the Mogat1 promoter is occupied by PPAR and directly responds to this nuclear receptor (27).…”

“…In fact, many genes regulating triglyceride metabolism, including Gpat1 and Dgat1, are directly regulated by PPAR activation (24)(25)(26)(27). Previous work has shown that chromatin in the Mogat1 promoter is occupied by PPAR and directly responds to this nuclear receptor (27). In addition, the induction in Mogat1 expression by either fenofibrates or fasting is abolished in hepatocyte-specific PPAR-knockout mice (28).…”

Epigenetic programming at the Mogat1 locus may link neonatal overnutrition with long‐term hepatic steatosis and insulin resistance

“…Up-regulation of Mogat1 might be attributed to an increased level of upstream transcription factors, including the peroxisome proliferator-activated receptors a and g (PPARA, PPARG) (30,31). However, protein content and mRNA levels were similar among groups at 2 wk and 6 mo of age (Supplemental Fig.…”