Elsevier

Life Sciences

Volume 108, Issue 2, 17 July 2014, Pages 88-93
Life Sciences

The role of phosphatidylcholine and deoxycholic acid in inflammation

https://doi.org/10.1016/j.lfs.2014.05.013Get rights and content

Abstract

Aims

Phosphatidylcholine with deoxycholic acid (PC/DA) is widely used to reduce localized fat deposits with mild adverse effects. We previously demonstrated that PC induces lipolysis with mild PMN infiltration, while DA induces adipose tissue damage. Therefore, the aim of this study was to extend our understanding of the pro-inflammatory responses of PC, DA, and PC/DA.

Main methods

We evaluated the level of edema and polymononuclear (PMN) infiltration by histopathological examination. Myeloperoxidase (MPO) activity was analyzed using an MPO activity assay kit. Levels of inflammatory cytokines (IL-1β and IL-6) and PGE2 were measured by ELISA.

Key findings

A low and high dose of PC failed to induce an inflammatory response, whereas DA led to an intense inflammatory response in a dose dependent manner. Combined PC/DA treatment resulted in a mild inflammatory response that was notably less severe than higher DA. Together, these results demonstrated that DA plays a role in inflammation caused by combined PC/DA. Histopathological examination and measurement of MPO activity indicated that DA was the primary cause of edema and PMN infiltration. Further, increased levels of cytokines (IL-1β and IL-6) and PGE2 demonstrated that DA might directly induce inflammation, whereas PC alone has no effect on inflammation.

Significance

These results indicate that DA rather than PC is responsible for inflammation, and that PC may not aggravate inflammatory responses induced by DA. Thus, the results of this study suggest that the adverse effects of PC/DA during localized fat treatment may be solely due to DA.

Introduction

Surgical procedures such as liposuction and dermolipectomy were developed to remove localized fat deposits and to improve medical and cosmetic aspects of patients (Hexsel et al., 2003). However, in addition to the risks associated with surgery, these procedures are accompanied by discomfort and anguish (Rotunda et al., 2005). As a result, phosphatidylcholine with deoxycholic acid (PC/DA) emerged as a nonsurgical alternative for fat removal and treatment of obesity by melting cell membranes (Rotunda et al., 2004). Since then, PC has been highlighted as a safe, low cost, easy to apply, and efficacious alternative to achieve reduction of small localized fat deposits on the face and body (Hexsel et al., 2003). Because of its effective, efficient, and low-risk features, PC/DA is now used to treat obesity more frequently than previous techniques such as liposuction and dermolipectomy (Noh and Heo, 2012).

PC/DA consists of 93% lipid phosphatidylcholine (PC) dissolved in bile salt and 2.4% deoxycholic acid (DA) (Klein et al., 2009). PC is the main constituent of soy beans, is well known to inhibit fatty acid accumulation, and is used as a treatment for myocardial ischemia, cerebrovascular disease, dementia, and fatty liver-induced liver dysfunction (Noh and Heo, 2012). The mechanism of action of injectable PC/DA has not been fully elucidated; however, several mechanisms have been proposed, including emulsification and transport of triglycerides from fat cells, cell membrane lysis, and lipase activity. As a principal component of intravenous PC/DA, DA is known to enhance the aqueous solubility of phosphatidylcholine, and may also facilitate clinical fat reduction on its own. However, DA induces nonspecific cell lysis and necrosis of fat and muscle after tissue incubation, as well as diminishes membrane integrity and cell viability (Schuller-Petrovic et al., 2008). Further, exposure of cultured cells to high concentrations of DA (42 mM) results in rapid cell death due to membrane disruption (Rotunda et al., 2004, Rotunda et al., 2005, Schuller-Petrovic et al., 2008, Thuangtong et al., 2010).

The profile of side effects of subcutaneously injected PC/DA has been well documented as the prevalence of PC/DA injections has increased. Acute side effects of PC/DA include edema, erythema, and burning, all of which disappear within hours. Additional side effects of PC/DA include tenderness, ecchymoses, and paresthesia, which resolve in a span of a few days to weeks. Most patients tolerate these adverse effects well; however, some unusually severe and prolonged events have been reported (Palmer et al., 2006). The side effects were predominantly induced by an inflammatory reaction at treatment site or by mechanical trauma after injection (Salti et al., 2008). Rotunda and Kolodney established that PC/DA injection on human fat may cause vacuolization of adipocytes and acute inflammation, and ascertained that there is the histological evidence of adipocyte wall disruption, focal inflammation and collagen deposition (Rotunda and Kolodney, 2006). In some cases, long-term effects including nodularity have been reported to persist for several weeks (Schuller-Petrovic et al., 2008) due to removal of destroyed fat cells by macrophages and subsequent inflammatory response (Mahmud and Crutchfield, 2012). Despite these reports, the systemic effects of PC/DA are not fully understood (Ablon and Rotunda, 2004, Gupta et al., 2009, Rotunda and Kolodney, 2006), meaning that the administering physician, following significant consultation with the patient, is responsible for any adverse effects (Hasengschwandtner, 2005).

We previously demonstrated that there are significant differences between PC and DA with respect to their effects on adipose tissue. Specifically, we reported that PC induces weight loss due to destruction of adipose tissue, while DA induces tissue damage without achieving weight loss (Won et al., 2013). Further, we performed gene expression analysis and found that pro-inflammatory cytokines and chemokines are greatly elevated in PC or DA-injected adipose tissue. Although microscopic observation supports PC induced lipolysis with mild PMN infiltration, DA treatment does not induce lipolysis but does facilitate a greater level of PMN infiltration. Thus, in the present study, we aimed to determine whether PC or DA is responsible for the primary adverse effects seen with PC/DA by examining the pro-inflammatory responses in paw tissue treated with PC and DA alone or in combination.

Section snippets

Animals

Male Sprague–Dawley rats (6-week-old, 170–200 g) were purchased from Nara Biotechnology (Seoul, Republic of Korea) and housed in a constant temperature (22 ± 2°C) animal room on a 12 h–12 h light/dark cycle with free access to food and water. Before the experiment, all 36 rats were randomly split into nine groups of four rats for subplantar injection. The experimental protocol was approved by the Institutional Animal Care and Use Committee of Chung-Ang University.

Chemicals

PC (phospholipon 90G, Lipoid GmbH)

Effect of subplantar injection on rat paws

The effects of PC, DA, and PC/DA treatment on hind paws are summarized in Table 1. The thickness of paws treated with DA showed a noticeable time-dependent development of paw edema within 1 h, and swelling in paws treated with PC/DA also steadily increased up to 4 h after treatment. However, in the PC group, paw volume remained nearly the same compared to that of saline-treated paws. In particular, Fig. 1A–D clearly depicts the marked difference between PC and DA, and PC/DA on paw swelling.

Histopathologic examination

The

Discussion

Following the introduction of PC with DA as a treatment for xanthelasma in 1988 at the 5th International Congress of Mesotherapy in Paris, France (Nedvidkova et al., 2004), PC/DA has been used in the treatment of mental disturbances as well as hepatic and cardiac disorders induced by medication, alcohol, pollution, viruses, and toxins (Hexsel et al., 2005). A number of studies have recently demonstrated that PC/DA contributes to a decrease in the volume of adipose tissue (Klein et al., 2009,

Conclusion

In summary, our results determined that DA might be the major cause of adverse effect in PC/DA. Our experimental results showed that DA provokes a significantly greater level of edema and PMN infiltration compared with PC/DA, while PC has little effect on inflammation. Furthermore, treatment with DA, but not PC, resulted in a maximal increase in MPO activity and levels of cytokines and PGE2. Taken together, our findings suggest that DA is responsible for PC/DA-induced inflammation, and that PC

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This research was supported by the Department of Convergenc Medicine and Pharmaceutical Biosciences Research Scholarship Grants, Chung-Ang University in 2014.

References (21)

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