Cigarette smoking induces insulin resistance: Partly via ASP–C5L2 pathway?

Bioscience Hypotheses (2009) 2, 267e269

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Cigarette smoking induces insulin resistance: Partly via ASPeC5L2 pathway?* Wenlong Li, Rutai Hui* Key Laboratory for Clinical Cardiovascular Genetics, Ministry of Education & Sino-German Laboratory for Molecular Medicine, Cardiovascular Institute & Fu Wai Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, 167 Beilishilu, Beijing 100037, PR China Received 6 April 2009; accepted 15 April 2009

KEYWORDS Smoke; Insulin resistance; Acylation-stimulating protein

Abstract Smoking is one of the main risk factors for cardiovascular disease. The smokers exhibit different degrees of insulin resistance. The pathway of acylation-stimulating protein (ASP) and its specific receptor, C5a-like receptor 2 (C5L2), involves in the effective clearance of plasma glucose and triglyceride. ASP and insulin play similar but distinct roles in adipose metabolism. High level of ASP is indicative of ASP resistance and insulin resistance. Low level of ASP indicates increased insulin sensitivity. We proposed that the abnormality of ASPeC5L2 pathway contributes to insulin resistance in smokers. ª 2009 Elsevier Ltd. All rights reserved.

Introduction Smoking is one of the main risk factors for coronary heart disease(CHD), stroke and sudden cardiac death [1,2], both in active smokers and passive smokers [3]. In 2000, 1.69 million residents worldwide dead of CHD caused by smoking [4]. By 2020, smoking will cause 8.4 million deaths and will be the largest health problem (http://www.who.int/tobacco/). In China, there are 350 million active smokers and 540 million passive smokers, and caused one million deaths each year by smoking annually (www.chinacdc.net.cn). It has been shown that smoking cession dramatically reduces the risk of

coronary events within 3 years [5]. However, smoking cession is hard for smokers [6]. Smoking contains more than 2000 chemical materials, including nicotine, polycyclic aromatic hydrocarbons, trace metal ions, pro-oxidants and reactive oxygen species [7]. High insulin concentrations and different degrees of insulin resistance have been found in smokers [8,9]. In contrast, smoking cessation would significantly increase the insulin sensitivity [10]. Many mechanisms have been proposed to explain the effects of smoking on glucose metabolism, but none has been satisfactory.

Hypothesis * This article was supported by The National High-tech Research and Development Program of China (No. 2006AA02A406). * Corresponding author. Tel.:þ86 10 8839 8154; fax:þ86 10 6833 1730. E-mail addresses: [email protected], [email protected] (R. Hui).

Acylation-stimulating protein (ASP), identical to C3adesArg, is a cleavage product of complement C3, mediated through the interaction of complement factors B and adipsin [11]. ASP increases postprandial triglyceride (TG) clearance and

1756-2392/$ - see front matter ª 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bihy.2009.04.008

268 glucose uptake. Complement 5a receptor like receptor (C5L2) is the specific receptor of ASP. In humans, ASP increases significantly in obesity and obesity related disease [12,13]. Smoking activates complement system and may increase ASP level [14]. We hypothesized that the abnormality of ASPeC5L2 pathway contributes to the insulin resistance in smokers. First, smoking activates the complement system and induces high expression of ASP (ASP resistance). Second, high level of ASP stimulates insulin secretion (insulin resistance). Third, smoking suppresses the activation of C5L2 (blocking ASPeC5L2 interaction). Finally, the clearance of plasma glucose and TG delays in smokers.

ASPeC5L2 and insulin resistance There are two forms of adipose tissue in human: brown and white. White adipocytes actively regulate the pathways for energy homeostasis, by producing amount of secretary proteins which namely adipocytokines [15]. These adipocytokines include ASP, adiponectin, resistin, interleukin-6 and tumor necrosis factor-a. The amount of brown adipose tissue is very small in adult human beings. ASP stimulates postprandial TG clearance and adipose TG synthesis in three separate aspects [12,16]. First, ASP increases the translocation of Glut1, Glut3 and Glut4, from an intracellular vesicle to the plasma membrane in adipocytes, fibroblast cells and muscle cells [17e19]. Although Glut3 and Glut1 play minor role in glucose transportation, Glut4 is the predominant glucose transporter. Glucose transportation acts as the rate-controlling step in healthy subjects [20], this results in an increase in the maximal rate of entry of glucose into cells, as well as the intracellular availability of glucose. Second, ASP increases the rate of free fatty acid (FFA) trapping and re-esterification [17]. ASP enhances the activity of diacylglycerol acyltransferase, the key enzyme catalyzing the final and committed step in the synthesis of TG [21]. Finally, ASP inhibits the hormonesensitive lipase in cells via stimulation of phosphodieaterase, and inhibits lipolysis of TG and release rate of FFA in adipose tissue [22]. Thus, both ASP and insulin markedly increase glucose uptake and TG synthesis, while their effects are independent and additive [19,22]. The decrease of ASP level affects the storage of adipocyte TG mass, but increases the sensitivity of adipose tissue towards ASP [23]. The clearance of postprandial TG and FFA significant delays in ASP-/- mice, meanwhile, the insulin  glucose product decreases significantly (30e40%), implying increased insulin sensitivity [24]. A positive feedback loop between ASP and insulin has been identified. ASP dose-dependently augments glucose-stimulated insulin secretion through a direct activation on the islet beta cells [25]. Insulin stimulates increased ASP production from adipocytes [26]. The high levels of ASP are indicative of ASP resistance [27,28], just as high levels of insulin indicate insulin resistance. Increased level of ASP has been found to associate with insulin resistance [29], furthermore, endurance exercise can reduce baseline ASP levels and increase both ASP sensitivity and insulin sensitivity [30]. Thus, serum level of ASP has been considered as an important marker of ASP sensitivity and insulin sensitivity. Low ASP level

W. Li, R. Hui increases insulin sensitivity and high ASP level decreases insulin sensitivity. C5L2, a G protein-coupled 7-transmembrane domain complement 5a receptor like receptor, has been found to bind ASP specifically and stably [31]. ASP initiates a cascade of activation, phosphorylation and translocation of C5L2 in vivo and in vitro [32]. Differentiated adipocytes express more C5L2 than undifferentiated adipocytes, fibroblast cells or muscle cells [33]. The level of C5L2 mRNA, cellsurface protein and ASP binding are significantly increased by insulin and thiazolidinedione, but decreased by tumor necrosis factor-a, which overexpressed after smoking [34,35]. High expression of C5L2 significantly increases ASP response [32], while down regulation of C5L2 decreases ASP response correlate [32,36]. In vivo, C5L2-neutralizing antibodies effectively delay TG clearance and decreases TG mass in adipose tissue [37]. A missense mutation (G968T) in C5L2 gene, resulting Ser323Ile substitution in the carboxyl terminal region, significantly increases levels of plasma glucose, TG and ASP [38]. Taken together, ASPeC5L2 pathway plays key role in energy storage. In addition, lipoprotein lipase (LPL) is an important enzyme which hydrolyzes circulating lipoproteins and releases FFA. ASP increases in situ LPL activity to increase TG mass in adipose, while decreases LPL activity to increase utilization of FFA in muscle. In contrast, blocking of ASPeC5L2 interaction inhibits LPL activity in adipose tissue, but increases the LPL activity and TG mass in muscle [37]. However, the increased muscle TG mass is associated with lipotoxicity, especially in obese diabetic subjects [39].

Conclusion and evaluation The ASPeC5L2 pathway plays key role in glucose disposal and FFA clearance, and the abnormality of ASPeC5L2 pathway would contribute to the insulin resistance in smokers. The level of ASP can be detected by ELISA. The decreased expression of C5L2 mRNA and protein could be detected by real time PCR and Weston blot, respectively. The phosphorylation of C5L2 could be measured by specific antibodies. Thus, we can detect the level of ASP in smokers to indicate insulin resistance. As low level of ASP increases insulin sensitivity, medicines would be used to downregulate the expression of ASP. The suppression of C5L2 can be relieved by thiazolidinedione treatment. Taken together, rectification of abnormality of ASPeC5L2 pathway would be helpful to decrease insulin resistance in smokers.

Conflict of interest We declare that we have no financial and personal relationships with other people or organizations that can inappropriately influence our work, there is no professional or other personal interest of any nature or kind in any product, service and/or company that could be construed as influencing the position presented in, or the review of, the manuscript entitled ‘‘Cigarette smoking induces insulin resistance: partly via ASPeC5L2 pathway?’’

Cigarette smoking induces insulin resistance

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