ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK

Abstract

ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome. ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome. With the rising prevalence of metabolic syndrome in the Western world (1Ford E.S. Giles W.H. Dietz W.H. Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey.JAMA. 2002; 287: 356-359Crossref PubMed Scopus (5748) Google Scholar), it is increasingly clear that chronic, low-grade inflammation serves as an important common denominator linking together visceral obesity, type 2 diabetes (T2D), and its vascular complications, including coronary artery disease (CAD) (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 3Rocha V.Z. Libby P. Obesity, inflammation, and atherosclerosis.Nat. Rev. Cardiol. 2009; 6: 399-409Crossref PubMed Scopus (651) Google Scholar). Although genetic and epidemiological data strongly indicate that therapeutic strategies designed to target inflammatory responses could be a viable approach to control various cardiometabolic risk factors (3Rocha V.Z. Libby P. Obesity, inflammation, and atherosclerosis.Nat. Rev. Cardiol. 2009; 6: 399-409Crossref PubMed Scopus (651) Google Scholar, 4Goyal R. Faizy A.F. Siddiqui S.S. Singhai M. Evaluation of TNF-alpha and IL-6 levels in obese and non-obese diabetics: pre- and postinsulin effects.N. Am. J. Med. Sci. 2012; 4: 180-184Crossref PubMed Scopus (94) Google Scholar–5Ridker P.M. Rifai N. Pfeffer M. Sacks F. Lepage S. Braunwald E. Elevation of tumor necrosis factor-alpha and increased risk of recurrent coronary events after myocardial infarction.Circulation. 2000; 101: 2149-2153Crossref PubMed Scopus (835) Google Scholar, 6Fernandez-Real J.M. Genetic predispositions to low-grade inflammation and type 2 diabetes.Diabetes Technol. Ther. 2006; 8: 55-66Crossref PubMed Scopus (26) Google Scholar, 7Davies R.W. Wells G.A. Stewart A.F. Erdmann J. Shah S.H. Ferguson J.F. Hall A.S. Anand S.S. Burnett M.S. Epstein S.E. et al.A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex.Circ Cardiovasc Genet. 2012; 5: 217-225Crossref PubMed Scopus (97) Google Scholar), results from recent clinical trials have been rather disappointing. Antibodies designed to selectively block tumor necrosis factor (TNF)α (etanersept), interleukin (IL)-1β (gevokizumab), or IL-1β receptor (anakinra) failed to improve insulin sensitivity and showed only mild and inconsistent benefits in plasma glucose levels and β-cell function, despite their efficacy in other inflammatory conditions (8Larsen C.M. Faulenbach M. Vaag A. Volund A. Ehses J.A. Seifert in type 2 diabetes J. Med. PubMed Scopus Google Scholar, S.E. 2 diabetes as an inflammatory Rev. PubMed Scopus Google S.E. to target inflammation in type 2 PubMed Scopus Google Scholar). clinical benefits of reducing risk of by anti-inflammatory mediators of inflammation have to be R. Anti-inflammatory for the treatment of atherosclerosis.Nat. Rev. PubMed Scopus Google Scholar). Although clinical efficacy and genetic and epidemiological data the of responses with metabolic in as to a inflammatory may clinical benefits to patients with cardiometabolic including and S.E. 2 diabetes as an inflammatory Rev. PubMed Scopus Google Scholar, S.E. to target inflammation in type 2 PubMed Scopus Google Scholar). ETC-1002 as is a novel investigational drug for the treatment of dyslipidemia and other cardiometabolic risk factors. effects of ETC-1002 on and glucose have been in models and have been linked to of AMP-activated protein kinase (AMPK) S. A.F. et protein kinase and for ETC-1002, a novel of and PubMed Scopus Google Scholar, A.F. M. novel ETC-1002, reduces and in a Scholar, A.F. ETC-1002 reduces and and control in J. a novel of plasma and in mouse by and Scholar). AMPK an therapeutic as it a in via glucose and as as proinflammatory AMP-activated protein an that of PubMed Scopus Google Scholar, A. J.M. AMP-activated protein kinase and on and Med. PubMed Scopus Google S. AMP-activated protein drug target to in and to 2012; PubMed Scopus Google Scholar). In clinical ETC-1002 not only but also significantly levels of C.M. M. J. ETC-1002 and other risk factors in with or Am. Cardiol. 2012; Google Scholar), an risk factor for and a clinical biomarker of inflammation and J. 2009; PubMed Scopus Google Scholar, to vascular events in and with 2009; PubMed Google Scholar). of AMPK been to inflammatory in and in vivo A. M. AMPK and responses in and 2010; PubMed Scopus Google Scholar, E. E. of AMPK attenuates proinflammatory activity and the of J. Physiol. Physiol. PubMed Scopus Google Scholar, R. M. P. A. J. E. R. et of AMP-activated protein kinase the in human PubMed Scopus Google Scholar, S. N. proinflammatory in a of AMP-activated protein PubMed Scopus Google M. M. N. an the production of tumor necrosis factor and factor by expression in human in Ther. 2010; PubMed Scopus Google Scholar), and including and have been with anti-inflammatory of AMPK A. J.M. AMP-activated protein kinase and on and Med. PubMed Scopus Google Scholar, J. of the kinase AMPK and in 2006; PubMed Scopus Google Scholar, AMP-activated protein kinase inflammation 2010; PubMed Scopus Google J. protein kinase macrophage to an anti-inflammatory PubMed Scopus Google Scholar). the of of the of protein kinases as JNK and been linked to anti-inflammatory M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar). in JNK phosphorylation been with the S. S. J. et AMPK reduces mouse adipose macrophage inflammation and insulin resistance in PubMed Scopus Google Scholar). that in primary human monocyte-derived macrophages ETC-1002 of a of proinflammatory that with the of AMPK and MAP kinase AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by inhibitory silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. 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These effects of AMPK in to of receptor and of proinflammatory by cells E. E. of AMPK attenuates proinflammatory activity and the of J. Physiol. Physiol. PubMed Scopus Google Scholar, M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar, S. S. J. et AMPK reduces mouse adipose macrophage inflammation and insulin resistance in PubMed Scopus Google Scholar). phosphorylation and of AMPK in primary human anti-inflammatory macrophages were with of in the or of of of proinflammatory cytokines and into with In levels of proinflammatory cytokines and the of In with a and consistent inflammatory as by a in the of a of proinflammatory and as and to be a of low-grade inflammation with metabolic (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 3Rocha V.Z. Libby P. Obesity, inflammation, and atherosclerosis.Nat. Rev. Cardiol. 2009; 6: 399-409Crossref PubMed Scopus (651) Google Scholar). in treatment with ETC-1002 strongly suppressed the release of and by in with inhibitory effects from to release of and by human in for were with of in the or of of of and in the by for with for as of the for were by and the expression of and mediators of vascular inflammation by in for were with of in the or of of of the and mediators of vascular inflammation in the by for were with and for as of the for were by and into inflammatory is by and novel in Med. PubMed Scopus Google Scholar, in 2012; PubMed Scopus Google Scholar), investigated the effects of ETC-1002 on the expression of and that to and and novel in Med. 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J. et AMPK reduces mouse adipose macrophage inflammation and insulin resistance in PubMed Scopus Google Scholar), human significantly reduced levels of and by and in AMPK phosphorylation coincided with increased phosphorylation of MAP kinases and JNK as by increased and JNK protein cells were with in the of ETC-1002, AMPK and phosphorylation increased to and JNK levels were by and treated with of ETC-1002 and by and of ETC-1002 kinase B1 is an kinase that and activates AMPK AMP-activated protein an that of PubMed Scopus Google Scholar, S. AMP-activated protein drug target to in and to 2012; PubMed Scopus Google Scholar, A. of and AMPK in responses to and PubMed Scopus Google Scholar, J. C.M. and of and Rev. 2012; PubMed Scopus Google Scholar). have that in is for AMPK S. A.F. et protein kinase and for ETC-1002, a novel of and PubMed Scopus Google Scholar). the of macrophage AMPK by ETC-1002 is also to protein levels and the effects of on AMPK phosphorylation and of human were with control or for by a or cells were treated with or ETC-1002, and AMPK phosphorylation as as production of proinflammatory cytokines were by Western and with a in protein with cells with and showed increased AMPK phosphorylation in to ETC-1002 treatment In AMPK phosphorylation in cells with consistent with anti-inflammatory effects of AMPK ETC-1002 release of IL-6 and by macrophages cells with not only to ETC-1002 treatment but also proinflammatory Thus, data that in primary human ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. of into adipose by into proinflammatory macrophages is a of chronic, low-grade inflammation with of visceral adipose (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, inflammatory properties of adipose macrophages diet-induced PubMed Scopus Google Scholar). ETC-1002 the of proinflammatory in the of ETC-1002 to in to thioglycollate-induced in in peritoneal increased after and and were treated with of ETC-1002 to into the peritoneal significantly reduced by and by in mouse peritoneal of the disease in of the of inflammation to by a of in peritoneal PubMed Scopus Google Scholar). In the of leukocytes in peritoneal reduced and indicating that ETC-1002 is to of and macrophages the and of inflammatory into inflammatory disease and macrophages a of not only cells to but also may control by soluble mediators of inflammation and inflammatory R. F. R. the control of macrophage 2012; PubMed Scopus Google Scholar, the and PubMed Scopus Google P. and by and its on and PubMed Scopus Google Scholar). inhibitory of ETC-1002 on homing in be to reduced expression of by human with on release of and into by ETC-1002 levels and were data indicate that of is to from reduced macrophage but is by have that in a mouse model of a treatment with ETC-1002 to as as to plasma glucose and insulin levels S. A.F. et protein kinase and for ETC-1002, a novel of and PubMed Scopus Google Scholar). adipose macrophages to a in responses and insulin resistance in (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, inflammatory properties of adipose macrophages diet-induced PubMed Scopus Google Scholar, J. J.M. of cells insulin sensitivity in obese insulin 8: PubMed Scopus Google Scholar), the of ETC-1002 on control be linked to reduced levels of adipose inflammation. were on and with or ETC-1002 for the of the visceral adipose from on with the epididymal mass significantly increased to a in fat-pad mass the of adipose inflammation, of epididymal were as vivo and IL-6 levels were in by for in of adipose by in IL-6 levels and consistent with the in anti-inflammatory effects of ETC-1002, IL-6 release reduced by in ETC-1002 properties of ETC-1002 were further in vivo as AMPK phosphorylation by restored in adipose of decreased phosphorylation of adipose JNK and in with reduced expression of macrophage-specific marker strongly the for in anti-inflammatory effects of ETC-1002 in vivo In the that in primary human ETC-1002 exerts anti-inflammatory effects consistent with LKB1-dependent of macrophage AMPK and the of in vivo, ETC-1002 attenuates homing into inflammatory adipose inflammation. In models of inflammation, AMPK by or as as been to anti-inflammatory effects A. M. AMPK and responses in and 2010; PubMed Scopus Google Scholar, E. E. of AMPK attenuates proinflammatory activity and the of J. Physiol. Physiol. PubMed Scopus Google Scholar, R. M. P. A. J. E. R. et of AMP-activated protein kinase the in human PubMed Scopus Google S. N. proinflammatory in a of AMP-activated protein PubMed Scopus Google Scholar), in diminished in target and reduced levels of and A. M. AMPK and responses in and 2010; PubMed Scopus Google Scholar, E. E. of AMPK attenuates proinflammatory activity and the of J. Physiol. Physiol. PubMed Scopus Google Scholar). to the anti-inflammatory effects with human of AMPK in macrophage or macrophages reduces expression of and M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar, S. S. J. et AMPK reduces mouse adipose macrophage inflammation and insulin resistance in PubMed Scopus Google Scholar). AMPK and the of responses have been in recent genetic or of AMP-activated protein kinase inflammation 2010; PubMed Scopus Google Scholar, J. protein kinase macrophage to an anti-inflammatory PubMed Scopus Google Scholar). genetic the for AMPK in macrophage in and in vivo S. S. J. et AMPK reduces mouse adipose macrophage inflammation and insulin resistance in PubMed Scopus Google Scholar). In the levels of to the AMPK and its anti-inflammatory is a kinase that and activates AMPK AMP-activated protein an that of PubMed Scopus Google Scholar, S. AMP-activated protein drug target to in and to 2012; PubMed Scopus Google Scholar, A. of and AMPK in responses to and PubMed Scopus Google Scholar, J. C.M. and of and Rev. 2012; PubMed Scopus Google Scholar). AMPK by as or or in to in as an kinase A. of and AMPK in responses to and PubMed Scopus Google Scholar, J. the tumor and kinases in the AMP-activated protein kinase PubMed Google Scholar). silencing of in macrophages is to of of macrophage expression to AMPK phosphorylation in cells and to of further that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via on the is that macrophages inflammatory as by increased expression of IL-6 and may of to for with treatment the is have that AMPK inflammatory in the events to effects including J. protein kinase macrophage to an anti-inflammatory PubMed Scopus Google Scholar), AMP-activated protein kinase inflammation 2010; PubMed Scopus Google Scholar), A. J.M. AMP-activated protein kinase and on and Med. PubMed Scopus Google Scholar), and M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar), have been to the anti-inflammatory effects that as a of AMPK the primary among on of proinflammatory and In model primary human AMPK by ETC-1002 as in the reduced phosphorylation of JNK and of JNK and phosphorylation been for AMPK in macrophage as as in human of AMPK responses in a M. M. N. an the production of tumor necrosis factor and factor by expression in human in Ther. 2010; PubMed Scopus Google Scholar, M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar). low-grade inflammation been as a major factor in obesity, and (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, 3Rocha V.Z. Libby P. Obesity, inflammation, and atherosclerosis.Nat. Rev. Cardiol. 2009; 6: 399-409Crossref PubMed Scopus (651) Google Scholar). with macrophage in adipose and vascular the expression of a of and that of into inflammatory of in inflammatory 4: PubMed Scopus Google Scholar, A. in the vascular inflammatory of 2010; PubMed Scopus Google Scholar). have that AMPK reduces expression of in as as in adipose of obese M. proinflammatory responses AMPK in J. Physiol. 2009; PubMed Scopus Google Scholar, S.S. J. S. et with and in 2012; PubMed Scopus Google Scholar). ETC-1002 also macrophage expression in it a inhibitory on an of and that important in vascular and adipose inflammation, including and (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, A. in the vascular inflammatory of 2010; PubMed Scopus Google Scholar). In to the of mediators of inflammation, ETC-1002 significantly expression of and in clinical plasma levels of and with an increased risk for the of events in S. of in and coronary and its to of coronary 2010; PubMed Scopus Google Scholar, J. in or PubMed Scopus Google Scholar). the of ETC-1002 to macrophage in in a mouse model of thioglycollate-induced in of ETC-1002 reduced and macrophage of homing to reduced and be of as release by macrophages or is that production of macrophage or in the of the macrophage may also indicate that of and release is to from effects of the In adipose and into macrophages that a proinflammatory and in a of to and as as (2Olefsky J.M. Glass C.K. Macrophages, inflammation, and insulin resistance.Annu. Rev. Physiol. 2010; 72: 219-246Crossref PubMed Scopus (1977) Google Scholar, inflammatory properties of adipose macrophages diet-induced PubMed Scopus Google Scholar, S. A. R. Glass C.K. 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Similarly, ETC-1002 adipose JNK phosphorylation in on and as by reduced expression of macrophage-specific marker 4F/80. adipose mass reduced in obese treated with ETC-1002 in with decreased IL-6 levels in of epididymal adipose inflammation coincided with increased AMPK phosphorylation and consistent with data that ETC-1002 reduces with plasma glucose and insulin levels in a mouse model of S. A.F. et protein kinase and for ETC-1002, a novel of and PubMed Scopus Google Scholar). and epidemiological data a for inflammation in metabolic have been to inflammatory clinical results for designed to selectively block or (8Larsen C.M. Faulenbach M. Vaag A. Volund A. Ehses J.A. Seifert in type 2 diabetes J. Med. PubMed Scopus Google Scholar, S.E. 2 diabetes as an inflammatory Rev. PubMed Scopus Google S.E. to target inflammation in type 2 PubMed Scopus Google Scholar). Similarly, clinical of anti-inflammatory mediators of inflammation, as and clinical benefits from to be R. 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Cardiol. 2012; Google Scholar), ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation with insulin resistance and vascular complications of metabolic J. of for of the AMP-activated protein kinase coronary artery disease 2 diet-induced interleukin liver kinase B1 major protein kinase monocyte-derived macrophage inhibitory type 2 diabetes tumor necrosis factor