Scholarly article on topic 'Resolution of inflammation in obesity-induced liver disease'

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Academic research paper on topic "Resolution of inflammation in obesity-induced liver disease"

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IN INFLAMMATION

Resolution of inflammation in obesity-induced liver disease

Bibiana Rius, Cristina López-Vicario, Ana González-Périz, Eva Morán-Salvador, Verónica García-Alonso, Joan Clària and Esther Titos

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Frontiers in Immunology

1664-3224

Mini Review Article

02 Jul 2012

31 Jul 2012

31 Jul 2012

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Rius B, Lopez-vicario C, Gonzalez-periz A, Moran-salvador E, Gara'a-alonso V, Claria J and Titos E(2012) Resolution of inflammation in obesity-induced liver disease. 3:257. doi:10.3389/fimmu.2012.00257

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© 2012 Rius, Lopez-vicario, Gonzalez-periz, Moran-salvador, Gara'a-alonso, Claria and Titos. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

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1 Resolution of inflammation in obesity-induced liver disease

4 Bibiana Rius1, Cristina López-Vicario1, Ana González-Périz1'2, Eva Morán-Salvador1,

1 12 3 * 12

5 Verónica García-Alonso , Joan Clària ' ' ' and Esther Titos '

7 1Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centre Esther

8 Koplowitz, IDIBAPS, Barcelona Spain

9 2CIBERehd, Barcelona, Spain

10 3Department of Physiological Sciences I, University of Barcelona, Barcelona, Spain

18 Word Count: 2998

20 Number of Figures: 2

26 *Correspondence:

28 Joan Clària

29 Department of Biochemistry and Molecular Genetics

30 Hospital Clínic

31 Villarroel 170

32 Barcelona 08036

33 Spain

34 jclaria@clinic.ub.es

38 Running Title: Resolution of obesity-induced inflammation

39 Abstract

41 Low-grade inflammation in adipose tissue is recognized as a critical event in the development

42 of obesity-related co-morbidities. This chronic inflammation is powerfully augmented through

43 the infiltration of macrophages, which together with adipocytes, perpetuate a vicious cycle of

44 inflammatory cell recruitment and secretion of free fatty acids and deleterious adipokines that

45 predispose to greater incidence of metabolic complications. In the last decade, many factors

46 have been identified to contribute to mounting unresolved inflammation in obese adipose

47 tissue. Among them, pro-inflammatory lipid mediators (i.e. leukotrienes) derived from the

48 omega-6 polyunsaturated arachidonic acid have been shown to play a prominent role. Of note,

49 the same lipid mediators that initially trigger the inflammatory response also signal its

50 termination by stimulating the formation of anti-inflammatory signals. Resolvins and

51 protectins derived from the omega-3 polyunsaturated docosahexaenoic and eicosapentaenoic

52 acids have emerged as a representative family of this novel class of autacoids with dual anti-

53 inflammatory and pro-resolving properties that act as "stop signals" of the inflammatory

54 response. This review discusses the participation of these endogenous autacoids in the

55 resolution of adipose tissue inflammation, with a special emphasis in the amelioration of

56 obesity-related metabolic dysfunctions, namely insulin resistance and non-alcoholic fatty liver

57 disease.

60 Keywords: Obesity, omega-6 fatty acids, eicosanoids, omega-3 fatty acids, resolvins, stromal-

61 vascular macrophages, Kupffer cells.

62 Resolution of inflammation. Circuits and chemical mediators.

64 Inflammation plays a vital role in host defense against invasive pathogens and tissue and

65 wound repair. Inflammation is part of the innate immune response and is initiated by a cascade

66 of signals in response to an infection or injury that leads to the recruitment of specialized

67 inflammatory cells, particularly neutrophils (PMN), into injured tissue to neutralize and

68 eliminate the injurious stimuli (Barton, 2008; Chen and Nunez, 2010). The innate immune

69 response not only acts as the first line of defense against an insult, but it also provides the

70 necessary signals to instruct the adaptive immune system for an effective response to deal with

71 the noxious agent. Although inflammation is important in eradication of pathogens,

72 unresolved, chronic inflammation that occurs when the offending agent is not removed or

73 contained is detrimental to the host, resulting in tissue damage, fibrosis and loss of function

74 (Barton, 2008; Chen and Nunez, 2010).

76 Since unresolved inflammation is detrimental to the host, higher organisms have evolved

77 protective mechanisms to ensure resolution of the inflammatory response in a specific time-

78 limited manner (Serhan, 2007). Once considered a mere passive process of dilution, resolution

79 is today envisioned as a highly-orchestrated process coordinated by a complex regulatory

80 network of cells and mediators. This novel insight offers the possibility to harness resolution

81 factors that clear inflammation and use them to ameliorate the pathologies associated with

82 chronic inflammation. This has the benefit to avoid any unwanted side-effect observed during

83 the long-term therapy with anti-inflammatory drugs such as cyclooxygenase (COX) inhibitors.

84 COX inhibitors, like aspirin (ASA) or ibuprofen, can cause gastrointestinal irritation and renal

85 damage when used in high doses (Wallace and Vong, 2008). Although at first glance selective

86 COX-2 inhibitors looked like to overcome NSAID toxicity on the gastrointestinal tract, COX-

87 2 inhibitors as Vioxx were later withdrawn from the market for their increased risk of

88 cardiovascular thrombotic events (Wallace and Vong, 2008). For this reason, the search for

89 novel targets and the identification of molecular circuits and chemical mediators involved in

90 resolution represent a priority in anti-inflammatory therapy.

92 Among the molecules that facilitate resolution, lipid mediators derived from the metabolism of

93 essential polyunsaturated fatty acids have attracted most attention. The first recognized family

94 of specialized pro-resolving mediators (SPM) was the lipoxins (LXs). LXs are conjugated

95 trihydroxytetraene-containing eicosanoids generated from endogenous sources of the omega-6

96 arachidonic acid (Serhan, 2002). A major route of transcellular LX biosynthesis is initiated by

97 15-lipoxygenase (15-LO) forming 15S-hydroxyeicosatetraenoic acid (15S-HETE), which is

98 rapidly converted to LXA4 by 5-LO (Figure 1) (Serhan et al., 1984). Another major route of

99 transcellular LX biosynthesis is the generation of 15-epi-LXs through a circuit initiated by

100 acetylation of COX-2 by ASA (Claria and Serhan, 1995). In this route, when ASA inhibits

101 prostaglandin (PG) formation in cells bearing a cytokine-induced COX-2, the resulting ASA-

102 acetylated COX-2 converts arachidonic acid into 15R-HETE. Subsequently, 15R-HETE is

103 transformed by 5-LO of activated neutrophils into 15-epi-LXs, which carry the carbon-15

104 alcohol in the R configuration, instead of the S as in the native LXs (Figure 1) (Claria and

105 Serhan, 1995). These SPM act as "stop-signals" for inflammation and inhibit leukocyte

106 chemotaxis, adhesion to and transmigration across endothelial monolayers in response to LTB4

107 (Serhan et al., 2008). LX stable analogs inhibit in vivo LTB4-induced leukocyte rolling,

108 adherence, margination and extravasation and when applied topically to mouse ears they

109 dramatically inhibit leukocyte infiltration and vascular permeability (Serhan et al., 2008).

Resolvins are the second family of SPM with recognized anti-inflammatory and pro-resolving properties. Resolvins are endogenous lipid mediators generated from the omega-3 docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids. They were initially identified using a lipidomics-based approach that combined liquid chromatography and tandem mass spectrometry within self-limited inflammatory exudates captured during the "spontaneous resolution" phase of acute inflammation (Serhan et al., 2000 and 2002). Resolvins are classified into D- and E-series in accordance with their biosynthetic precursor, either DHA or EPA, respectively. Schematically, resolvin biosynthesis is initiated by 15-LO which transforms endogenous sources of DHA into 17^-hydroxy-DHA which is further transformed by leukocyte 5-LO into resolvin (Rv) D1 and RvD2 (Figure 1) (Hong et al., 2003). Endothelial cells expressing COX-2 treated with aspirin also transform DHA into 17^-hydroxy-DHA which is further converted by 5-LO into 17,R-RvD1 (Figure 1) (Serhan et al., 2000 and 2002). DHA can also be metabolized into a dihydroxy-containing derivative via an intermediate epoxide that opens via hydrolysis and subsequent rearrangements to form protectin (PD) 1 (Figure 1) (Hong et al., 2003; Serhan et al., 2000 and 2002). Similarly, RvE1 biosynthesis is initiated when EPA is converted to 18-hydroperoxy-EPE by aspirin-treated COX-2 or through cytochrome P450 activity (Serhan et al., 2000; Haas-Stapleton et al., 2007). By transcellular biosynthesis, 18-hydroperoxy-EPE is transformed by 5-LO of neighboring leukocytes into RvE1 via a 5(6)epoxide intermediate (Figure 1) (Serhan et al., 2000 and 2002).

RvD1, RvD2, PD1 and RvE1 are potent SPM, which contrary to their metabolic substrates, DHA and EPA, exert their biological actions at the nanomolar range. Indeed, the potency of these SPM is notable with concentrations as low as 10 nM producing a fifty percent reduction in PMN transmigration. Two receptors (ALX/FPR2 and GPR32) have been shown to transmit RvD1 signals (Krishnamoorthy et al., 2010), whereas a G-protein coupled receptor (ChemR23) signals for RvE1 (Arita et al., 2005a). The full structural elucidation, stereochemical assignment and biological actions for these compounds were first completed in RvE1. RvE1 was readily shown to decrease PMN infiltration and T cell migration, reduce TNFa and IFNy secretion, inhibit chemokine formation and block IL-1-induced NF-kB activation (Bannenberg and Serhan, 2010; Schwab et al., 2007). RvE1 was also shown to stimulate macrophage phagocytosis of apoptotic PMN and to be a potent counter-regulator of L-selectin expression (Schwab et al., 2007; Dona et al., 2008). RvE1 displayed potent antiinflammatory actions in vivo, protecting mice against experimental periodontitis, colitis, peritonitis and brain ischemia-reperfusion (Arita et al., 2005b; Bannenberg and Serhan, 2010). A RvE1-initiated resolution program for allergic airway response was identified by Haworth et al (2008). Similarly, RvD1 and RvD2 were reported to reduce inflammatory pain, block IL-1P transcripts induced by TNFa in microglial cells and function as potent regulators limiting PMN infiltration into inflamed brain, skin and peritoneum (Sun et al., 2007; Hong et al., 2003). RvD2 in particular has been shown to be a potent endogenous regulator of excessive inflammatory responses in mice with microbial sepsis (Spite et al., 2009). Moreover, PD1 has been reported to exert protective actions in acute models of inflammation by blocking PMN migration and infiltration into the inflammatory site (Serhan et al., 2006). Finally, these SPM expedite the resolution process by paving the way for monocyte migration and their differentiation to phagocytosing macrophages, which remove dead cells (efferocytosis) and then terminate the inflammatory response by promoting macrophage efflux into lymphatics (Schif-Zuck et al., 2011).

161 Resolution of adipose tissue inflammation in obesity

163 Abdominal obesity and insulin resistance are the predominant underlying risk factors for the

164 metabolic syndrome and related co-morbidities such as type 2 diabetes, dyslipidemia and non-

165 alcoholic fatty liver disease (Elks and Francis, 2010). A wealth of evidence indicates that

166 metabolic disorders associated with obesity are initiated by the presence of a chronic "low-

167 grade" state of inflammation in the adipose tissue (Elks and Francis, 2010; Ferrante, 2007).

168 This "low-grade" inflammatory state is aggravated by the recruitment of inflammatory cells,

169 mainly macrophages in the adipose tissue (Elks and Francis, 2010; Ferrante, 2007). As a

170 consequence of this unresolved inflammatory response, the production of pro-inflammatory

171 adipokines (i.e. IL-6, TNFa and MCP-1) is increased while the secretion of adiponectin, an

172 anti-inflammatory and insulin-sensitizing adipokine, is reduced (Figure 2A) (Elks and

173 Francis, 2010; Ferrante, 2007). In addition to adipokines, the formation of pro- and anti-

174 inflammatory lipid mediators is also severely deregulated in obesity. Indeed, we have recently

175 demonstrated that the production of SPM (i.e. RvD1 and PD1 and the metabolic precursors

176 14-HDHA, 17-HDHA, 18-HEPE) is deficient in inflamed obese adipose tissue (Claria et al.,

177 2012). Whether the response to these mediators is also impaired and whether this SPM deficit

178 is a generalized property of obese tissues are open questions that need to be addressed.

180 Adipose tissue inflammation is also driven by the activation of classical pro-inflammatory

181 pathways such as arachidonate 5-LO. Indeed, over-expression of FLAP is a common finding

182 in adipose tissue of patients and animals with obesity and insulin resistance (Kaaman et al.,

183 2006; Horrillo et al., 2010). Moreover, linkage studies have identified 5-LO as a gene with

184 pleiotropic actions on adipose fat accumulation and pancreatic function (Mehrabian et al.,

185 2008). The ability of adipose tissue to generate 5-LO-derived products has recently been

186 challenged by Horrillo and collaborators. These authors have demonstrated the presence of all

187 enzymes necessary for the formation of 5-LO products (5-LO, FLAP, LTA4 hydrolase, and

188 LTC4 synthase) as well as all receptors involved in LT signaling (BLT1, BLT2, CysLT1, and

189 CysLT2) in adipose tissue of both lean and obese mice (Horrillo et al., 2010). Importantly,

190 adipose tissue samples from obese mice showed increased formation of 5-LO products, mainly

191 LTB4 (Horrillo et al., 2010). Similar findings have been reported in visceral adipose tissue

192 from obese Zucker rats (Chakrabarti et al., 2011). An important observation of the study by

193 Horrillo et al. was that LTB4 unequivocally triggered an inflammatory response in adipose

194 tissue by inducing the nuclear translocation of p50 and p65 subunits of NF-kB (Horrillo et al.,

195 2010). Secondary to LTB4-induced NF-kB activation, there was an enhanced release of MCP-

196 1 and IL-6, which directly connect adipose tissue inflammation with insulin resistance and

197 hepatic steatosis (Horrillo et al., 2010). The physiological consequences of these changes in

198 adipose tissue function were corroborated in vivo by observing that either pharmacological

199 inhibition of the 5-LO pathway or genetic deletion of Alox5, the gene coding for 5-LO,

200 alleviate insulin resistance and hepatic steatosis in obese animals (Horrillo et al., 2010;

201 Martínez-Clemente et al., 2010).

203 In sharp contrast to the pro-inflammatory actions for the most part of omega-6-derived

204 products, omega-3-derived lipid mediators act as "braking signals" of the persistent vicious

205 cycle leading to unremitting inflammation in obese adipose tissue. In 1989, Endres and

206 collaborators were the first to demonstrate anti-inflammatory properties of the omega-3 fatty

207 acids (Endres et al., 1989). Since then, supplementation of omega-3 fatty acids has proven to

208 exert overall benefits in obesity and metabolic syndrome. In a recent series of experiments,

209 González-Périz and coworkers have demonstrated that administration of an omega-3-enriched

210 diet to ob/ob mice, an experimental model of obesity and fatty liver disease, resulted in

increased adiponectin levels and reduced insulin resistance and hepatic steatosis (Gonzalez-Periz et al., 2009). These changes occurred in parallel with augmented formation of omegas-derived specialized pro-resolving mediators (SPM) in adipose tissue, while formation of the omega-6-derived products PGE2, 5-HETE and LTB4 was significantly inhibited (Gonzalez-Periz et al., 2009). Along these lines, intraperitoneal injection of nanogram doses of RvE1 elicited significant insulin-sensitizing effects by inducing adiponectin, GLUT-4 and IRS-1 expression in adipose tissue and conferred significant protection against hepatic steatosis (Gonzalez-Periz et al., 2009). Similarly, in leptin receptor-deficient (db/db) obese and diabetic mice, nanogram doses of RvD1 improved glucose tolerance, decreased fasting blood glucose, and increased insulin-stimulated Akt phosphorylation while reducing the formation of crownlike structures rich in inflammatory macrophages in adipose tissue (Hellmann et al., 2011). Recently, similar beneficial actions have been described for LXA4 in an experimental model of age-associated adipose inflammation (Borgeson et al., 2012).

Omega-3-derived mediators can also induce changes in the status of macrophage polarization toward a pro-resolution phenotype. Tissue macrophages are phenotypically heterogeneous and display an extensive receptor repertoire and a versatile biosynthetic capacity that confer them the plasticity to adapt to different tissue microenvironments (Gordon and Taylor, 2005). Macrophages are broadly characterized by their activation (polarization) state according to the M1/M2 classification system (Mantovani et al., 2007). In this classification, the M1 designation is reserved for classically activated macrophages following stimulation with IFNy and LPS, whereas the M2 designation is applied to the alternatively activated macrophages after in vitro stimulation with IL-4 and IL-13. M1 macrophages secrete high amounts of TNFa, IL-1P and IL-6, whereas M2 macrophages dampen pro-inflammatory cytokine levels and promote resolution of inflammation and tissue repair (Gordon and Taylor, 2005). M1/M2 macrophage polarization can be monitored by assessing the expression of selected markers. M1-associated markers include inducible nitric oxide synthase (iNOs) and classical proinflammatory mediators such as TNFa, IL-1P, IL-6 and MCP-1. In contrast, established M2 markers include scavenger, mannose (CD206) and galactose (Mgl-1) receptors, arginase 1, IL-10, chitinases Ym1 and Ym2 and resistin-like molecule (RELM)-a (Martinez et al., 2009).

In a recent study, Titos and collaborators have demonstrated that RvD1 consistently induced M2 polarization in adipose tissue macrophages (Titos et al., 2011). These investigators first noticed that DHA did not modify the total number of macrophages in obese adipose tissue, but markedly reduced the percentage of CD11bhigh/F4/80high expressing cells in parallel with the emergence of low-expressing CD11b/F4/80 macrophages, suggesting a phenotypic switch in macrophage polarization. Indeed, these investigators further demonstrated that DHA and RvD1 up-regulated a complete panel of M2 markers including IL-10, CD206, RELM-a and Ym1, and remarkably stimulated arginase 1 expression while promoting nonphlogystic macrophage phagocytosis and attenuating IFNy/LPS-induced Th1 cytokine secretion (Titos et al., 2011). These results were in agreement with those reported by Hellmann et al (2011), who showed the ability of RvD1 to improve insulin resistance in obese-diabetic mice, by reducing macrophage F4/80+CD11c+ cell accumulation and increasing the percentage of positive F4/80 cells expressing the M2 marker Mgl-1 in adipose tissue. The ability of resolvins to modify macrophage plasticity has also been demonstrated by Schif-Zuck S et al (2011), who reported that administration of RvD1 and RvE1 to peritonitis-affected mice enhanced the appearance of CD11blow macrophages by reducing the number of engulfment-related events required for macrophage deactivation and by reducing the ability of peritoneal macrophages to produce pro-inflammatory cytokines upon LPS stimulation. As the majority of macrophages that accumulate in obese adipose tissue are M1 inflammatory type, these findings are a strong

261 argument in favour of the pro-resolution actions of omega-3-derived mediators in obese

262 adipose tissue.

265 Resolution of obesity-induced steatohepatitis

267 Lipids, adipokines and other soluble factors released by inflamed adipose tissue have a direct

268 impact on other insulin-sensitive tissues, especially on the liver. In fact, both adipose and

269 hepatic tissues have immediate access to a vast network of blood vessels that implicate a direct

270 connection between these two tissues. This connection is exemplified by the observation that

271 the circulating fatty acid pool derived from fat is the primary contributor to hepatic steatosis,

272 the initial stage in non-alcoholic steatohepatitis (Donnelly et al., 2005). In this context,

273 adiponectin represents a paradigmatic example of the direct control of adipokines on liver

274 function. Adiponectin, which is an adipokine with potent anti-inflammatory and insulin-

275 sensitizing properties, is a hepatoprotective adipokine lowering hepatic steatosis and insulin

276 resistance and preventing liver fibrosis (Tilg, 2010). Importantly, adiponectin is able to up-

277 regulate the RvE1 receptor ChemR23 in primary human adipocytes, which expression is

278 seriously compromised in human and rodent fatty liver (Wanninger et al., 2012).

280 To better appreciate how adipose tissue influences hepatic inflammation and the progression

281 from steatosis to steatohepatitis, it is necessary to fully understand the complex cellular

282 architecture of the liver. The hepatic tissue is arranged in a peculiar fenestrated capillary

283 network known as the hepatic sinusoid (Wisse et al., 1996). The morphological features of the

284 hepatic sinusoid provide a unique environment where each single hepatocyte is in close

285 contact with other hepatocytes as well as with non-parenchymal sinusoidal liver cells,

286 including Kupffer cells, endothelial cells, and hepatic stellate cells (Wisse et al., 1996). In

287 terms of inflammation, Kupffer cells, the liver resident macrophages, play the most relevant

288 role and have been classically considered the major sinusoidal cell type involved in hepatic

289 eicosanoid formation (Decker, 1990). Indeed, Kupffer cells express COX-1, COX-2 and 5-LO

290 and generate relevant amounts of PGE2, PGI2, PGF2a, PGD2, LTB4 and LTC4/LTD4/LTE4

291 (Decker, 1990; Titos et al., 2000; Titos et al., 2003). These resident hepatic macrophages are also

292 able to generate LXA4 from endogenous sources of arachidonic acid or by transcellular

293 biosynthesis from 15S-HETE released by nearby 15-LO-containing hepatocytes (Claria and

294 Planaguma, 2005). Unlike LTB4 and PGE2, Kupffer cell-derived LXA4 down-regulates the

295 cytokine-chemokine axis in adjacent hepatocytes (Planaguma et al., 2002).

297 Liver tissue is also a rich source of omega-3-derived SPM, such as PD1 and its intermediate

298 precursor 17S-HDHA (Gonzalez-Periz et al., 2006). These SPM produced an amelioration of

299 necroinflammatory liver injury, an effect that was associated with a decrease in hepatic COX-

300 2 expression and PGE2 formation and reduced genotoxic DNA damage and oxidative stress in

301 isolated hepatocytes (Gonzalez-Periz et al., 2006). More important, these SPM reduced TNFa

302 release in macrophages, recognized as the predominant effector cells involved in the

303 inflammatory cascade leading to hepatocyte damage. A significant down-regulation of 5-LO

304 protein expression was also noticed in macrophages treated with 17S-HDHA and in liver

305 tissue from mice receiving DHA in the diet (Gonzalez-Periz et al., 2006). This is relevant

306 because the presence of an active 5-LO pathway in the liver is restricted to Kupffer cells and

307 its inhibition is linked to lower necroinflammatory liver injury and fibrosis (Titos et al., 2000,

308 2003 and 2005).

311 Summary

313 Obesity and the associated metabolic disorders are characterized by the presence of a chronic

314 "low-grade" inflammatory response in insulin sensitive tissues, in particular adipose tissue and

315 liver. The mechanisms explaining this observation are unknown but unremitting inflammation is

316 likely to be the consequence of an impaired resolution. Resolution of inflammation (the so-called,

317 "catabasis") is not a passive process that simply occurs when the stimulus disappears, but it is a

318 highly regulated process that requires the coordinated action of pro-resolution SPM. Among

319 these, in recent years we have witnessed an emergence of a number of SPM carrying both anti-

320 inflammatory and pro-resolution properties, namely lipoxins, resolvins and protectins. A

321 schematic representation of the actions of these lipid mediators on adipose tissue and liver cells is

322 shown in Figure 2B. In summation, these autacoids enhance inflamed adipose tissue catabasis

323 and provide powerful templates for the design of novel therapies to combat the progression of

324 metabolic complications associated with obesity.

327 ACKNOWLEDGEMENTS

329 Our laboratory is supported by grants from the Ministerio de Economía y Competitividad

330 (SAF 09/08767 and SAF 12/32789) and is a Consolidated Research Group recognized by the

331 Generalitat de Catalunya (2009SGR1484). CIBERehd is funded by the Instituto de Salud

332 Carlos III. This work was carried out at the Esther Koplowitz Centre.

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528 FIGURE LEGENDS

530 Figure 1. Biosynthesis of specialized pro-resolving mediators (SPM). During the process of

531 resolution of inflammation, the omega-6 fatty acid arachidonic acid (AA) is converted by 15532 lipoxygenase (15-LOX) to 15^-hydroxyeicosatetraenoic acid (15^-HETE), which is rapidly

533 converted to LXA^and LXB^by 5-LOX. Formation of 15-epi-LXA and 15-epi-LXB4 from 15^-

534 HETE can also occur after acetylation of cyclooxygenase-2 (COX-2) by aspirin (ASA).

535 Similarly, the omega-3 fatty acid eicosapentaenoic acid (EPA) is converted into 18536 hydroperoxy-EPE (18-HEPE) by aspirin-treated COX-2 or through cytochrome P450

537 (CYP450) and subsequently transformed by 5-LOX into 18S- or 18^-resolvin (Rv) E1. DHA

538 is converted into17-hydroxy-DHA (17-HDHA) by 15-LOX which subsequently is transformed

539 by 5-LOX into RvD1 and by epoxidation hydrolysis into protectin D1 (PD1), respectively.

540 Finally, DHA is transformed by 12-LOX into 14-hydroxy-DHA (14-HDHA) and by 5-LOX

541 into maresin 1 (MaR1).

543 Figure 2. (A) Schematic overview summarizing the cross-talk between macrophages and

544 adipocytes in obese adipose tissue. Obese adipose tissue shows a remarkable infiltration of

545 macrophages which form "crown-like" structures that surround necrotic adipocytes. This

546 recruited macrophages together with hypertrophy and/or hyperplasia of adipocytes produce an

547 aberrant release of pro-inflammatory adipokines (tumor necrosis factor (TNF) a, interleukin

548 (IL)-6, IL-1P and monocyte chemotactic protein-1 (MCP-1)) that leads to insulin resistance.

549 Unbalanced formation of pro-inflammatory leukotriene (LT) B4 and leptin accompanied by a

550 deficit in anti-inflammatory mediators (i.e. resolvin (Rv) D1, protectin (PD) 1 and

551 adiponectin) contributes to a state of unresolved inflammation in obese adipose tissue. (B)

552 Schematic representation of the protective actions of specialized omega-3-derived mediators

553 on liver and adipose tissue. Eicosapentaenoic acid (EPA) is converted into 18-hydroperoxy-

554 EPE (18-HEPE) and resolvin (Rv) E1, whereas DHA is converted into 17-hydroxy-DHA (17555 HDHA) and RvD1 and protectin D1 (PD1). In the liver, these specialized pro-resolving

556 mediators (SPM) protect hepatocytes from DNA damage and oxidative stress and dampen

557 inflammation by inhibiting TNFa, LTB4 and cyclooxygenase-2 (COX-2) in Kupffer cells. In

558 adipose tissue, SPM exert insulin sensitizing actions by up-regulating adiponectin, AMP-

559 activated protein kinase (AMPK), insulin receptor signaling 1 (IRS-1) and glucose transporter

560 (GLUT) 4 in adipocytes and promoting M2 polarization (arginase 1 (Arg1), IL-10, chitinase 3561 like 3 (Ym1), resistin-like molecule (RELM)-a and CD206) while inhibiting M1 markers 562 (TNFa, IL-6 and MCP-1) in macrophages.

Figure 2

^IL-6 ► Insulin Resistance tTNFa tlL-l|3 tMCP-1

tMCP-1 tTNFa

Macrophage Recruitment

Macrophage

sURvDl \|/PD1

sJ/Adiponectin

Adipocytes

Hepatocytes

iTiftflP™

Necroinflammation:

4/ DNA damage vj/ Oxidative Stress

Inflammation:

vl/TNFa

sH-TB4

sl/COX-2

EPA 18-HEPE

17-HDHA

RvDl PD1

Adipose Tissue

Adipocytes

Insulin resistance:

■TAdiponectin tAMPK tlRS-1 tGLUT-4

Macrophages

M2 polarization:

tArgl ^TNFa flL-10 vL-IL-6 -fYml sHVICP-1 tRELMa tCD206

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