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. 2009 Apr 1;4(2):231-243.
doi: 10.2217/clp.09.2.

Guardian of corpulence: a hypothesis on p53 signaling in the fat cell

Merlijn Bazuine  1 , Karin G Stenkula, Maggie Cam, Mathilde Arroyo, Samuel W Cushman
Affiliations

Guardian of corpulence: a hypothesis on p53 signaling in the fat cell

Merlijn Bazuine et al. Clin Lipidol. .

Abstract

Adipocytes provide an organism with fuel in times of caloric deficit, and are an important type of endocrine cell in the maintenance of metabolic homeostasis. In addition, as a lipid-sink, adipocytes serve an equally important role in the protection of organs from the damaging effects of ectopic lipid deposition. For the organism, it is of vital importance to maintain adipocyte viability, yet the fat depot is a demanding extracellular environment with high levels of interstitial free fatty acids and associated lipotoxic effects. These surroundings are less than beneficial for the overall health of any resident cell, adipocyte and preadipocyte alike. In this review, we discuss the process of adipogenesis and the potential involvement of the p53 tumor-suppressor protein in alleviating some of the cellular stress experienced by these cells. In particular, we discuss p53-mediated mechanisms that prevent damage caused by reactive oxygen species and the effects of lipotoxicity. We also suggest the potential for two p53 target genes, START domain-containing protein 4 (StARD4) and oxysterol-binding protein (OSBP), with the concomitant synthesis of the signaling molecule oxysterol, to participate in adipogenesis.

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Conflict of interest statement

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Figures

Figure 1
Figure 1. Stages in the adipogenic conversion process
The insert depicts a typical example of the distribution between the small and large adipocytes we observe in an organism. Initial pluripotent stem cells are committed to the mesenchymal lineage. Subsequent differentiation steps lead to loss of potency and the ability to divide in the formation of a fully committed preadipocyte cell. Upon initiation of adipogenesis these cells accumulate small lipid droplets in the perinuclear region and undergo marked alterations in cellular morphology and transcriptional activity. Ultimately, these small lipid droplets engorge themselves with lipids and become enlarged, fully lipid-laden adipocytes. The cytoplasm and nucleus of these rounded cells are squeezed by the enormous lipid droplet into a narrow area just underneath the plasma membrane. The relative position of several key transcription factors involved in adipogenic conversion (PCAF/GCN5, C/EBP-β, SREBP, PPAR-γ and C/EBP-α) is depicted at the relative position of their action during adipogenesis. The red shaded area and arrow indicate the time wherein we postulate p53 to be active in the manner described in the text. It is of interest to note that in the initiation phase of adipogenesis in the 3T3-L1 cell line, after the contact-inhibited cell-cycle arrest and clonal expansion phase, a large amount of cells are lost owing to apoptosis. Indicative of an involvement of p53-signaling pathways as this may be, it is at present unclear if these stages in 3T3-L1 adipogenesis (a semi-transformed cell-line) accurately reflect the process of adipogenesis in vivo. C/EBP: CCAAT/enhancer-binding protein; GCN5: General control nonderepressible; PCAF: p300/CREB-binding protein associated factor; SREBP: Sterol regulatory element-binding protein.
Figure 2
Figure 2. The underlying hypothesis on the role of p53 in adipogenesis
Exposure to free fatty acids in the interstitial fluid will activate p53 through lipotoxic stress and ROS-induced cellular damage. Is the level of p53-activation too high and persistent? The tumor-suppressor p53 will eventually induce apoptosis, leading to loss of the cell. Is the level of p53 activation too low? There will not have been an effect of this ‘guardian’ at all and the cell will ultimately succumb to the damage induced by reactive oxygen radicals and lipotoxic effects. Only when the level of p53 activation is ‘just right’, will it confer protection to the small adipocytes by the induction of reactive oxygen-scavenging genes and possibly even by enhancing the lipogenic capacity of these cells. Thereby, p53 activation, when properly controlled, will ensure the clearance of lipotoxic stress, protecting not just the cell, but once again the organism as a whole. However, it is worthy to note for consideration, that in our present-day society ‘just right’ may have shifted considerably from our original evolutionary settings. ROS: Reactive oxygen species.
Figure 3
Figure 3. Negative- and positive-feedback loops involved in p53 signaling
Negative- (closed arrow –•) and positive- (open arrow →) feedback loops involved in p53 signaling are highlighted and the manner in which they intertwine to synchronize regulation of the cell cycle with the regulation of protein synthesis. Indicated are classical components of the p53-mediated cell-cycle arrest pathway: Mdm2, Mdm4 and the p53-effector p21waf1; essential components of the metabolic fuel-sensing pathway: AMPK and mTORC; and the recently positioned sestrins, as discussed in the text. mTORC: Mammalian target of rapamycin complex.
Figure 4
Figure 4. Potential involvement of p53 activity in adipogenesis, as hypothesized in the text
Free fatty acid-mediated lipotoxity and associated oxidative stress and cholesterol-overload with associated ER stress can both induce p53 activation. Several recently identified transcriptional targets of p53, such as PCAF, StARD4 and OSBP, impinge on known components of the transcriptional machinery governing adipogenic conversion. In particular, StARD4 is of interest as it contributes to the synthesis of oxysterol. This powerful signaling molecule can mediate paracrine signaling and acts on a known, but enigmatic component of adipogenesis, the LXR receptors. The net increase in lipogenic activity and the genesis of the lipid droplet in these cells will subsequently provide a sink for the excessive amounts of free fatty acids and cholesterol (represented by curved arrows) governed by the aP2 fatty acid transporter and the ACAT mediator of cholesterol esterification. This ultimately leads to removal of the stresses that initiated p53-activation and termination of the p53-signal (prior to the initiation of apoptotic processes). It is noteworthy that the respective position of StARD4, OSBP and PCAF is only due to diagrammatic constraints: either lipotoxicity or ER-stress can induce these transcriptional targets of p53 through the activation of p53-mediated transcription. A detailed description of this model and its respective components can be found in the text along with accompanying references. ACAT: Acyl-coenzyme A:cholesterol acyl-transferase; C/EBP: CCAAT/enhancer-binding protein; ER: Endoplasmic reticulum; LXR: Liver X receptor; OSBP: Oxysterol-binding protein; PCAF: p300/CREB-binding protein associated factor; SREBP: Sterol regulatory element-binding protein.
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