CIDEC/FSP27 exacerbates obesity-related abdominal aortic aneurysm by promoting perivascular adipose tissue inflammation

Abstract

Abdominal aortic aneurysm (AAA) is strongly correlated with obesity, partially due to the abnormal expansion of abdominal perivascular adipose tissue (PVAT). Cell death-inducing DNA fragmentation factor-like effector C (CIDEC), also known as fat-specific protein 27 (FSP27) in rodents, is specifically expressed in adipose tissue where it mediates lipid droplet fusion and adipose tissue expansion. Whether and how CIDEC/FSP27 plays a role in AAA pathology remains elusive. Here, we show that FSP27 exacerbates obesity and angiotensin Ⅱ (Ang Ⅱ )-induced AAA progression. FSP27 deficiency in mice inhibited high-fat diet-induced PVAT expansion and inflammation. Both global and adipose tissue-specific FSP27 ablation significantly decreased obesity-related AAA incidence. Deficiency of FSP27 in adipocytes abrogated matrix metalloproteinase-12 (MMP12) expression in aortic tissues. Infiltrated macrophages, which partially colocalize with MMP12, were significantly decreased in the FSP27-deficient aorta. Mechanistically, knockdown of Fsp27 in 3T3-L1 adipocytes inhibited C-C motif chemokine ligand 2 (CCL2) expression and secretion through a c-Jun N-terminal kinase (JNK)-dependent pathway, thereby leading to reduced induction of macrophage migration, while Cidec overexpression rescued this effect. Overall, our study demonstrates that CIDEC/FSP27 in adipose tissue contributes to obesity-related AAA formation, at least in part, by enhancing PVAT inflammation and macrophage infiltration, thus shedding light on its significance as a key regulator in the context of obesity-related AAA.

Keywords

AAA / inflammation / PVAT / Cidec / CCL2

References

[1] Golledge J . Abdominal aortic aneurysm: update on pathogenesis and medical treatments. Nat Rev Cardiol 2019; 16: 225- 42.

[2] Anagnostakos J , Lal BK . Abdominal aortic aneurysms. Prog Cardiovasc Dis 2021; 65: 34- 43.

[3] Wang Z , You Y , Yin Z et al. Burden of aortic aneurysm and its attributable risk factors from 1990 to 2019: an analysis of the Global Burden of Disease Study 2019. Front Cardiovasc Med 2022; 9: 901225.

[4] Kent KC . Clinical practice. Abdominal aortic aneurysms. N Engl J Med 2014; 371: 2101- 8.

[5] Nordon IM , Hinchliffe RJ , Loftus IM et al. Pathophysiology and epidemiology of abdominal aortic aneurysms. Nat Rev Cardiol 2011; 8: 92- 102.

[6] Okrzeja J , Karwowska A , Blachnio-Zabielska A . The role of obesity, inflammation and sphingolipids in the development of an abdominal aortic aneurysm. Nutrients 2022; 14: 2438.

[7] Golledge J , Clancy P , Jamrozik K et al. Obesity, adipokines, and abdominal aortic aneurysm: health in men study. Circulation 2007; 116: 2275- 9.

[8] Sheng C , Liu T , Chen S et al. The neglected association between central obesity markers and abdominal aortic aneurysm presence: a systematic review and meta-analysis. Front Cardiovasc Med 2023; 10: 1044560.

[9] Stoll S , Sowah SA , Fink MA et al. Changes in aortic diameter induced by weight loss: the HELENA trial- whole-body MR imaging in a dietary intervention trial. Front Physiol 2022; 13: 976949.

[10] Cronin O , Walker PJ , Golledge J . The association of obesity with abdominal aortic aneurysm presence and growth. Atherosclerosis 2013; 226: 321- 7.

[11] Apoloni RC , Zerati AE , Wolosker N et al. Analysis of the correlation between central obesity and abdominal aortic diseases. Ann Vasc Surg 2019; 54: 176- 84.

[12] Rabben T , Mansoor SM , Bay D et al. Screening for abdominal aortic aneurysms and risk factors in 65-year-old men in Oslo, Norway. Vasc Health Risk Manag 2021; 17: 561- 70.

[13] Wang L , Djousse L , Song Y et al. Associations of diabetes and obesity with risk of abdominal aortic aneurysm in men. J Obes 2017; 2017: 3521649.

[14] Liu Y , Qian SW , Tang Y et al. The secretory function of adipose tissues in metabolic regulation. Life Metab. 2024; 3: loae003.

[15] Ye T , Zhang G , Liu H et al. Relationships between perivascular adipose tissue and abdominal aortic aneurysms. Front Endocrinol (Lausanne) 2021; 12: 704845.

[16] Rabkin SW . The role matrix metalloproteinases in the production of aortic aneurysm. Prog Mol Biol Transl Sci 2017; 147: 239- 65.

[17] Police SB , Thatcher SE , Charnigo R et al. Obesity promotes inflammation in periaortic adipose tissue and angiotensin II-induced abdominal aortic aneurysm formation. Arterioscler Thromb Vasc Biol 2009; 29: 1458- 64.

[18] Chen FJ , Yin Y , Chua BT et al. CIDE family proteins control lipid homeostasis and the development of metabolic diseases. Traffic 2020; 21: 94- 105.

[19] Xu L , Zhou L , Li P . CIDE proteins and lipid metabolism. Arterioscler Thromb Vasc Biol 2012; 32: 1094- 8.

[20] Lyu X , Wang J , Wang J et al. A gel-like condensation of Cidec generates lipid-permeable plates for lipid droplet fusion. Dev Cell 2021; 56: 2592- 606.e7.

[21] Gong J , Sun Z , Wu L et al. Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites. J Cell Biol 2011; 195: 953- 63.

[22] Puri V , Konda S , Ranjit S et al. Fat-specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J Biol Chem 2007; 282: 34213- 8.

[23] Nishino N , Tamori Y , Tateya S et al. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 2008; 118: 2808- 21.

[24] Zhou L , Park SY , Xu L et al. Insulin resistance and white adipose tissue inflammation are uncoupled in energetically challenged Fsp27-deficient mice. Nat Commun 2015; 6: 5949.

[25] Nishimoto Y , Nakajima S , Tateya S et al. Cell death-inducing DNA fragmentation factor A-like effector A and fat-specific protein 27β coordinately control lipid droplet size in brown adipocytes. J Biol Chem 2017; 292: 10824- 34.

[26] Longo GM , Buda SJ , Fiotta N et al. MMP-12 has a role in abdominal aortic aneurysms in mice. Surgery 2005; 137: 457- 62.

[27] Curci JA , Liao S , Huffman MD et al. Expression and localization of macrophage elastase (matrix metalloproteinase-12) in abdominal aortic aneurysms. J Clin Invest 1998; 102: 1900- 10.

[28] Biros E , Gabel G , Moran CS et al. Differential gene expression in human abdominal aortic aneurysm and aortic occlusive disease. Oncotarget 2015; 6: 12984- 96.

[29] Gao YJ , Zhang L , Samad OA et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 2009; 29: 4096- 108.

[30] Takahashi K , Yamaguchi S , Shimoyama T et al. JNK- and Iκ- Bdependent pathways regulate MCP-1 but not adiponectin release from artificially hypertrophied 3T3-L1 adipocytes preloaded with palmitate in vitro. Am J Physiol Endocrinol Metab 2008; 294: E898- 909.

[31] Mottillo EP , Shen XJ , Granneman JG . β3-adrenergic receptor induction of adipocyte inflammation requires lipolytic activation of stress kinases p38 and JNK. Biochim Biophys Acta 2010; 1801: 1048- 55.

[32] Stackelberg O , Bjorck M , Sadr-Azodi O et al. Obesity and abdominal aortic aneurysm. Br J Surg 2013; 100: 360- 6.

[33] Piacentini L , Werba JP , Bono E et al. Genome-wide expression profiling unveils autoimmune response signatures in the perivascular adipose tissue of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2019; 39: 237- 49.

[34] Meekel JP , Dias-Neto M , Bogunovic N et al. Inflammatory gene expression of human perivascular adipose tissue in abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2021; 61: 1008- 16.

[35] Piacentini L , Chiesa M , Colombo GI . Gene regulatory network analysis of perivascular adipose tissue of abdominal aortic aneurysm identifies master regulators of key pathogenetic pathways. Biomedicines 2020; 8: 288.

[36] Folkesson M , Vorkapic E , Gulbins E et al. Inflammatory cells, ceramides, and expression of proteases in perivascular adipose tissue adjacent to human abdominal aortic aneurysms. J Vasc Surg 2017; 65: 1171- 9.e1.

[37] Tanaka N , Takahashi S , Matsubara T et al. Adipocyte-specific disruption of fat-specific protein 27 causes hepatosteatosis and insulin resistance in high-fat diet-fed mice. J Biol Chem 2015; 290: 3092- 105.

[38] Aaron N , Zahr T , He Y et al. Acetylation of PPARγ in macrophages promotes visceral fat degeneration in obesity. Life Metab. 2022; 1: 258- 69.

[39] Russo S , Kwiatkowski M , Govorukhina N et al. Metainflammation and metabolic reprogramming of macrophages in diabetes and obesity: the importance of metabolites. Front Immunol 2021; 12: 746151.

[40] Marquez-Sanchez AC , Koltsova EK . Immune and inflammatory mechanisms of abdominal aortic aneurysm. Front Immunol 2022; 13: 989933.

[41] Yuan Z , Lu Y , Wei J et al. Abdominal aortic aneurysm: roles of inflammatory cells. Front Immunol 2020; 11: 609161.

[42] Raffort J , Lareyre F , Clement M et al. Monocytes and macrophages in abdominal aortic aneurysm. Nat Rev Cardiol 2017; 14: 457- 71.

[43] Koch AE , Kunkel SL , Pearce WH et al. Enhanced production of the chemotactic cytokines interleukin-8 and monocyte chemoattractant protein-1 in human abdominal aortic aneurysms. Am J Pathol 1993; 142: 1423- 31.

[44] Tieu BC , Lee C , Sun H et al. An adventitial IL-6/MCP1 amplification loop accelerates macrophage-mediated vascular inflammation leading to aortic dissection in mice. J Clin Invest 2009; 119: 3637- 51.

[45] de Waard V , Bot I , de Jager SC et al. Systemic MCP1/CCR2 blockade and leukocyte specific MCP1/CCR2 inhibition affect aortic aneurysm formation differently. Atherosclerosis 2010; 211: 84- 9.

[46] Ghigliotti G , Barisione C , Garibaldi S et al. Adipose tissue immune response: novel triggers and consequences for chronic inflammatory conditions. Inflammation 2014; 37: 1337- 53.

[47] Kanda H , Tateya S , Tamori Y et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006; 116: 1494- 505.

[48] Zhang W , Wang M , Wang E et al. Downregulation of RhoA/ROCK1/YAP/F-actin causing decreased aortic smooth muscle cell stiffness promotes aortic dissection formation. Life Metab. 2024; 3: loae022.

[49] Atkinson G , Bianco R , Di Gregoli K et al. The contribution of matrix metalloproteinases and their inhibitors to the development, progression, and rupture of abdominal aortic aneurysms. Front Cardiovasc Med 2023; 10: 1248561.

[50] Maguire EM , Pearce SWA , Xiao R et al. Matrix metalloproteinase in abdominal aortic aneurysm and aortic dissection. Pharmaceuticals (Basel) 2019; 12: 118.

[51] Lagente V , Le Quement C , Boichot E . Macrophage metalloelastase (MMP-12) as a target for inflammatory respiratory diseases. Expert Opin Ther Targets 2009; 13: 287- 95.

[52] Wang Y , Ait-Oufella H , Herbin O et al. TGF-β activity protects against inflammatory aortic aneurysm progression and complications in angiotensin II-infused mice. J Clin Invest 2010; 120: 422- 32.

[53] Salarian M , Ghim M , Toczek J et al. Homeostatic, noncanonical role of macrophage elastase in vascular integrity. Circ Res 2023; 132: 432- 48.

[54] Davis FM , Rateri DL , Daugherty A . Abdominal aortic aneurysm: novel mechanisms and therapies. Curr Opin Cardiol 2015; 30: 566- 73.

[55] Fraga-Silva RA , Trachet B , Stergiopulos N . Emerging pharmacological treatments to prevent abdominal aortic aneurysm growth and rupture. Curr Pharm Des 2015; 21: 4000- 6.

[56] Chen JY , Wu YP , Li CY et al. PPARγ activation improves the microenvironment of perivascular adipose tissue and attenuates aortic stiffening in obesity. J Biomed Sci 2021; 28: 22.

[57] Sommer N , Roumane A , Han W et al. Gene therapy restores adipose tissue and metabolic health in a pre-clinical mouse model of lipodystrophy. Mol Ther Methods Clin Dev 2022; 27: 206- 16.

[58] Toh SY , Gong J , Du G et al. Up-regulation of mitochondrial activity and acquirement of brown adipose tissue-like property in the white adipose tissue of Fsp27 deficient mice. PLoS One 2008; 3: e2890.

[59] Qian H , Chen Y , Nian Z et al. HDAC6-mediated acetylation of lipid droplet-binding protein CIDEC regulates fat-induced lipid storage. J Clin Invest 2017; 127: 1353- 69.

RIGHTS & PERMISSIONS

2024 The Author(s). Published by Oxford University Press on behalf of Higher Education Press.