p53-Mediated regulation of hepatic lipid metabolism: Forging links between metabolism, atherogenesis, and cancer
Authors: Sabrina A. Stratton, Michelle Craig Barton
Journal: Journal of Hepatology (2011)

p53, a novel regulator of lipid metabolism pathwaysJournal of HepatologyVol. 56Issue 3PreviewIn this study we aimed at characterizing the regulation of hepatic metabolic pathways by the p53 transcription factor. Full-Text PDF No discussion of cancer biology is complete without mention of tumor suppressor p53 and its stress-activated protection of the genome. A plethora of regulatory signaling impinges on p53 to either limit p53 protein levels, in the absence of stress signaling, or to rapidly induce protein levels and mediate cell cycle arrest or cell death in the face of threats to genome integrity [1Feng Z. Hu W. Rajagopal G. Levine A.J. The tumor suppressor p53: cancer and aging.Cell Cycle. 2008; 7: 842-847Crossref PubMed Scopus (92) Google Scholar, 2Lane D. Levine A. p53 research: the past thirty years and the next thirty years.Cold Spring Harb Perspect Biol. 2010; 2: a000893Crossref Scopus (321) Google Scholar]. Although reports of p53 regulation and functions in cellular surveillance add up to an astounding number, recent discoveries that illustrate functions of p53 in cellular metabolism reveal that much is left to learn [3Vousden K.H. Ryan K.M. p53 and metabolism.Nat Rev Cancer. 2009; 9: 691-700Crossref PubMed Scopus (766) Google Scholar, 4Vousden K.H. Alternative fuel – another role for p53 in the regulation of metabolism.Proc Natl Acad Sci U S A. 2010; 107: 7117-7118Crossref PubMed Scopus (38) Google Scholar]. The ability of the p53-null mouse to survive to adulthood with few apparent challenges to normal development casts a shadow over likely roles for p53 in normal, cellular homeostasis [[5]Donehower L.A. Harvey M. Slagle B.L. McArthur M.J. Montgomery Jr., C.A. Butel J.S. et al.Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours.Nature. 1992; 356: 215-221Crossref PubMed Scopus (4054) Google Scholar]. Early development of specific tumors, the profile of which is dependent on strain, is the most striking phenotype of p53−/− mice. However, closer examination of these mice reveals that all is not perfect during development, as female mice lacking p53 have diminished fecundity and a significant number exhibits exencephaly [[6]Sah V.P. Attardi L.D. Mulligan G.J. Williams B.O. Bronson R.T. Jacks T. A subset of p53-deficient embryos exhibit exencephaly.Nat Genet. 1995; 10: 175-180Crossref PubMed Scopus (499) Google Scholar]. Additionally, once other structurally similar members of the p53 family were uncovered, including p63, p73 and multiple isoforms of all p53 family members, complexity in their potential cross-talk or functional compensation was suspected. This was borne out by the altered profiles of tumors that develop in mice variously depleted in the family members; for example, p53+/−; p73+/− mice develop hepatocellular carcinoma (HCC) and other tumors never found in p53+/− or p53−/− mice [[7]Flores E.R. Sengupta S. Miller J.B. Newman J.J. Bronson R. Crowley D. et al.Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family.Cancer Cell. 2005; 7: 363-373Abstract Full Text Full Text PDF PubMed Scopus (425) Google Scholar]. Clearly, levels of p53 are carefully regulated during embryogenesis, as deletion of the primary negative regulator of p53 protein levels, Mdm2, leads to early embryonic lethality at implantation [8de Oca Luna R.M. Wagner D.S. Lozano G. Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53.Nature. 1995; 378: 206-208Crossref PubMed Scopus (1211) Google Scholar, 9de Rozieres S. Maya R. Oren M. Lozano G. The loss of mdm2 induces p53-mediated apoptosis.Oncogene. 2000; 19: 1691-1697Crossref PubMed Scopus (115) Google Scholar]. In this issue of the Journal of Hepatology, Rotter and colleagues broaden the scope of p53 regulatory functions in normal cellular homeostasis by uncovering p53-mediated transcription of specific genes that function in lipid metabolic pathways (Goldstein et al., this issue). The use of hepatic tissue and cells to uncover p53-mediated regulation in lipid metabolism is especially appropriate, as the liver is a key player in lipid intake, synthesis, processing and secretion [[10]Reddy J.K. Rao M.S. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation.Am J Physiol Gastrointest Liver Physiol. 2006; 290: G852-858Crossref PubMed Scopus (659) Google Scholar]. At first glance, the liver would not seem a likely site where p53 would have a major functional role. Unlike many other tissues, the liver is non-responsive to whole-body irradiation, showing no p53 activation or induction of protective apoptotic pathways [[11]Midgley C.A. Owens B. Briscoe C.V. Thomas D.B. Lane D.P. Hall P.A. Coupling between gamma irradiation, p53 induction and the apoptotic response depends upon cell type in vivo.J Cell Sci. 1995; 108: 1843-1848Crossref PubMed Google Scholar]. Specific mutations in the gene encoding p53 occur in HCC, but often arise relatively late during tumorigenesis or are secondarily induced as a result of environmental insults, such as adducts formed in the presence of aflatoxin poisoning [12Hsu I.C. Metcalf R.A. Sun T. Welsh J.A. Wang N.J. Harris C.C. Mutational hotspot in the p53 gene in human hepatocellular carcinomas.Nature. 1991; 350: 427-428Crossref PubMed Scopus (1412) Google Scholar, 13Bressac B. Kew M. Wands J. Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa.Nature. 1991; 350: 429-431Crossref PubMed Scopus (1241) Google Scholar]. However, dysfunction in p53, due to inactivation by proteins produced in hepatitis B or C infection, is likely causal in virus-associated HCC [[14]Murakami S. Hepatitis B virus X protein: structure, function and biology.Intervirology. 1999; 42: 81-99Crossref PubMed Scopus (140) Google Scholar]. More recent studies of genome wide expression patterns in human and mouse HCC suggest a signature of pathways associated with tumor development, among which p53 regulation and intersection are significant [[15]Tarocchi M. Hannivoort R. Hoshida Y. Lee U.E. Vetter D. Narla G. et al.Carcinogen-induced hepatic tumors in KLF6+/− mice recapitulate aggressive human hepatocellular carcinoma associated with p53 pathway deregulation.Hepatology. 2011; 54: 522-531Crossref PubMed Scopus (36) Google Scholar]. Goldstein et al. use a variety of platforms to assess hepatic functions for p53, not only in human hepatic tumor-derived, cultured cell lines but also in donor liver primary hepatocytes, mouse hepatocytes and embryonic fibroblasts. In an unbiased approach, microarray analysis of gene expression was carried out in human hepatoblastoma-derived HepG2 cells, engineered by retroviral introduction of shRNA targeting p53 or control shRNA, and further altered in p53 expression levels by exposure to the inhibitor Nutlin. The specific mechanism of Nutlin-mediated stability of p53, due to disruption of Mdm2-p53 interaction without exposure to DNA damaging agents or induction of genotoxic stress [[16]Vassilev L.T. Vu B.T. Graves B. Carvajal D. Podlaski F. Filipovic Z. et al.In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.Science. 2004; 303: 844-848Crossref PubMed Scopus (3825) Google Scholar], may have been critical in linking p53 to hepatic genes active in lipid metabolism; robust activation of early response genes, active in damage control or cell death, could potentially obscure expression of other p53-regulated genes. Over 300 genes were significantly activated in this study, of which 5% were associated with lipid metabolism. The group of genes, classified as lipid metabolic pathway genes, covers multiple aspects of lipid metabolism, including regulators of intracellular ceramide and fatty acids, systemic lipid absorption and lipoprotein metabolism. The authors performed detailed, in-depth analyses to show that p53 directly regulates specific genes from the larger number in this category: (1) phospholipid transfer protein (PLTP), which is secreted by the liver as an HDL-bound protein and is associated with atherogenesis [17Siggins S. Jauhiainen M. Olkkonen V.M. Tenhunen J. Ehnholm C. PLTP secreted by HepG2 cells resembles the high-activity PLTP form in human plasma.J Lipid Res. 2003; 44: 1698-1704Crossref PubMed Scopus (53) Google Scholar, 18Schlitt A. Blankenberg S. Bickel C. Lackner K.J. Heine G.H. Buerke M. et al.PLTP activity is a risk factor for subsequent cardiovascular events in CAD patients under statin therapy: the AtheroGene study.J Lipid Res. 2009; 50: 723-729Crossref PubMed Scopus (33) Google Scholar]. (2) Carboxyl ester lipase (CEL), an enzyme that hydrolyzes dietary triglycerides and ceramide, and promotes uptake of HDL-associated cholesteryl esters in the liver [[19]Howles P.N. Stemmerman G.N. Fenoglio-Preiser C.M. Hui D.Y. Carboxyl ester lipase activity in milk prevents fat-derived intestinal injury in neonatal mice.Am J Physiol. 1999; 277: G653-661PubMed Google Scholar]. (3) Adenosine triphosphate-binding cassette, subfamily A, member 12 (ABCA12), a member of the large ABC superfamily of ATP-dependent trans-membrane proteins, which functions in active transport of lipids across the cell membrane [[20]Stefkova J. Poledne R. Hubacek J.A. ATP-binding cassette (ABC) transporters in human metabolism and diseases.Physiol Res. 2004; 53: 235-243PubMed Google Scholar]. p53-mediated regulation of apolipoprotein levels in non-hepatic, cultured cells was previously reported in DNA damage-induced transcription of ApoB, which encodes the primary apolipoprotein responsible for cholesterol transport to tissues, and Apobec1, a cytidine deaminase that edits Apob and Nf1 mRNA [[21]Ashur-Fabian O. Har-Zahav A. Shaish A. Wiener Amram H. Margalit O. Weizer-Stern O. et al.ApoB and apobec1, two genes key to lipid metabolism, are transcriptionally regulated by p53.Cell Cycle. 2010; 9: 3761-3770Crossref PubMed Scopus (25) Google Scholar]. Previous links between p53, oxidative stress and metabolic regulation, as reviewed in depth by Vousden and colleagues [3Vousden K.H. Ryan K.M. p53 and metabolism.Nat Rev Cancer. 2009; 9: 691-700Crossref PubMed Scopus (766) Google Scholar, 4Vousden K.H. Alternative fuel – another role for p53 in the regulation of metabolism.Proc Natl Acad Sci U S A. 2010; 107: 7117-7118Crossref PubMed Scopus (38) Google Scholar], broadened the functions of p53 in tumor suppression. The metabolic demands of tumor growth and malignant progression may induce a switch to glycolysis, which p53 opposes by repressing glycolytic gene expression, activating TIGAR to slow glycolysis and preventing reactive oxidant accumulation [[22]Yeung S.J. Pan J. Lee M.H. Roles of p53, MYC and HIF-1 in regulating glycolysis – the seventh hallmark of cancer.Cell Mol Life Sci. 2008; 65: 3981-3999Crossref PubMed Scopus (400) Google Scholar]. Importantly, as shown in the current study of lipid metabolism genes, many of these functions of p53 in metabolic control occur during normal cellular growth and homeostasis, as well as in response to stress induction. With this report of p53-mediated control of specific genes in lipid metabolism, functions of p53 are further extended from tumor suppression to lipid-transfer control, cardiometabolic diseases and atherogenesis [[23]Mercer J. Figg N. Stoneman V. Braganza D. Bennett M.R. Endogenous p53 protects vascular smooth muscle cells from apoptosis and reduces atherosclerosis in ApoE knockout mice.Circ Res. 2005; 96: 667-674Crossref PubMed Scopus (143) Google Scholar]. Taken together with indirect regulation of inflammation, by virtue of p53-mediated suppression of NF-κB activation [[24]Ak P. Levine A.J. p53 and NF-kappaB: different strategies for responding to stress lead to a functional antagonism.Faseb J. 2010; 24: 3643-3652Crossref PubMed Scopus (152) Google Scholar], these p53-regulated pathways may add to the complex picture of p53 functions in aging [[25]Tyner S.D. Venkatachalam S. Choi J. Jones S. Ghebranious N. Igelmann H. et al.p53 mutant mice that display early ageing-associated phenotypes.Nature. 2002; 415: 45-53Crossref PubMed Scopus (1176) Google Scholar]. Premature signs of aging are also reported for TA-p63 deleted mice [[26]Su X. Chakravarti D. Cho M.S. Liu L. Gi Y.J. Lin Y.L. et al.TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs.Nature. 2010; 467: 986-990Crossref PubMed Scopus (367) Google Scholar], emphasizing that, while downstream targets of p53 are numerous, upstream regulation of p53 is complex, influenced by a large variety of homeostatic and stress-induced controls, and likely involves interactions among its family members and isoforms. These variables must be considered and further defined to fully assess or interpret the impact of p53 dysfunction, and to develop effective treatments of cancers, cardiometabolic diseases and likely others, yet to be discovered under the regulatory influence of p53. The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.