p53, a novel regulator of lipid metabolism pathways.
OBJECTIVE
In this study we aimed at characterizing the regulation of hepatic metabolic pathways by the p53 transcription factor.


METHODS
Analysis of gene expression following alteration of p53 status in several human- and mouse-derived cells using microarray analysis, quantitative real-time PCR, chromatin immunoprecipitation, and reporter gene assays. A functional assay was performed to determine lipid transfer activity.


RESULTS
We identified a novel role for the p53 protein in regulating lipid and lipoprotein metabolism, a process not yet conceived as related to p53, which is known mainly for its tumor suppressive functions. We revealed a group of 341 genes whose expression was induced by p53 in the liver-derived cell line HepG2. Twenty of these genes encode proteins involved in many aspects of lipid homeostasis. The mode of regulation of three representative genes (Pltp, Abca12, and Cel) was further characterized. In addition to HepG2, the genes were induced following activation of p53 in human primary hepatic cells isolated from liver donors. p53-dependent regulation of these genes was evident in other cell types namely Hep3B cells, mouse hepatocytes, and fibroblasts. Furthermore, p53 was found to bind to the genes' promoters in designated p53 responsive elements and thereby increase transcription. Importantly, p53 augmented the activity of secreted PLTP, which plays a major role in lipoprotein biology and atherosclerosis pathology.


CONCLUSIONS
These findings expose another facet of p53 functions unrelated to tumor suppression and render it a novel regulator of hepatic lipid metabolism and consequently of systemic lipid homeostasis and atherosclerosis development.
Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel. ido.goldshtein@weizmann.ac.il
Ido
I
Goldstein
Osnat
O
Ezra
Noa
N
Rivlin
Alina
A
Molchadsky
Shalom
S
Madar
Naomi
N
Goldfinger
Varda
V
Rotter
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000378:metabolism; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D020869:Gene Expression Profiling; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism / Q000502:physiology*; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D046228:Microarray Analysis; D049294:Phospholipid Transfer Proteins / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
C473801:ABCA12 protein, human; D018528:ATP-Binding Cassette Transporters; C493430:PLTP protein, human; D049294:Phospholipid Transfer Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C054621:CEL protein, human; D008049:Lipase