Figure 1. Resistin signaling pathway.
Resistin is a cysteine-rich secreted protein present in plasma and belongs to resistin-like molecules (RELMs), also known as members of the family of FIZZs (found in inflammatory zone). Rodent resistin is secreted exclusively by adipocytes; whereas human resistin is expressed primarily in peripheral blood mononuclear cells and is increased in expression upon differentiation into macrophages. Recent studies have shown that resistin acts on insulin signaling pathways to induce insulin resistance, and acts on vascular endothelial cells and smooth muscle cells to affect cell function, suggesting that resistin may be involved in vascular lesions.
Resistin is rich in cysteine residues and consists of 108 amino acid residues with a full length of 476 base pairs. The relative molecular mass is 12.5×103. The gene coding region is located on chromosome 19p13. The resistin, anti-receptor-like molecules α (RELM-α), RELM-β, and RELM-γ belong to the RELMs family. The mouse has a high degree of homology with the human resistin gene fragment. Patel et al. first reported the general structure of resistin using X-ray crystallization technology and identified two different rat resistin cycle states: a lamanyh molecular mass (HMW) hexamers and low molecular mass monomer forms. The latter is considered to have a higher biological activity against hepatic insulin dysfunction in vivo. Several different high molecular mass subtypes have recently been demonstrated in human serum resistin. Different isomers have different biological activities in muscle and liver tissues, especially in obesity and insulin resistance models.
Resistin signaling pathway
Resistin signaling pathway cascade
There have been several reports on resistin receptors, but no studies have been able to strongly demonstrate the presence of resistin-specific receptors.
TLR4: studies have confirmed that Toll-like receptors (TLRs) are pattern recognition receptors (PRRs). TLRs are transmembrane proteins that recognize the pathogen-associated molecular pattern (PAMP) and then transmit information to the cell and trigger an inflammatory response. TLR4 is an important and well-studied member of the TLRs. Resistin- TLR4 partial signal transduction pathway: binding of resistin to TLR4-MD2 complex, causing TLR4 structural changes and transfer to cells, activation of JNK and P38 via the adaptor protein MyD88, activated JNK and P38 mediating inflammation. CAP1 adenylate cyclase-associated protein (CAP): Human CAP1 is an Actin-binding protein consisting of 475 amino acid residues consisting of a carboxy-terminal, dysfunctional amino terminus that binds to actin and a central proline-rich domain. CAP1 is thought to be predominantly present in the cytoplasm, but recent studies have shown that CAP1 is present on the surface of THP-1 cell membranes. In yeast, CAP1 can be combined with adenylate cyclase (AC) to promote AC activation. Lee et al. stimulated THP-1 cells with resistin and found that resistin significantly increased the level of cellular cAMP, activated PKA and NF-κB, and then up-regulated the levels of inflammatory cytokines such as IL-6, TNF-α and IL-1B; PKA inhibitors blocked resistin-induced NF-κB activation and cytokine expression; while silencing cap1 gene inhibited the effects of resistin on cAMP, PKA, NF-κB and cytokine expression; co-immunoprecipitation experiments demonstrated resistin and CAP1 binds to each other and the binding site is the SH3 structure in the CAP1-rich proline domain.
The expression of resistin is affected by various factors such as age, gender, nutritional status, hormones, local factors and drugs. The level of resistin mRNA increases during pregnancy, especially during the second trimester. Infants have the highest levels of resistin within 45 days of birth and decrease with age. Dietary restriction can reduce the expression of resistin mRNA in adipose tissue of female rats and pregnant rats. In obese mice induced by high-fat diet, with the increase of body mass and elevated blood glucose, obesity and insulin resistance will appear one after another, and serum resistin levels will also increase. Resistin gene expression may be regulated by a protein kinase A-dependent pathway. Rajala et al. reported that there is no necessary relationship between the expression of resistin mRNA and protein expression. The information on resistin gene expression needs further study. The regulation of insulin on resistin is still controversial. The expression of resistin mRNA was significantly down-regulated when a certain concentration of insulin was administered to 3T3-L1 cells cultured in vitro. However, in diabetic rats induced by diabetic obese rats and streptozotocin, the expression of resistin in adipose tissue was decreased. After insulin administration, the expression of resistin was significantly increased. It was found that insulin can increase the secretion of resistin in a concentration-dependent manner. Endothelin 1 significantly reduces the secretion of resistin and inhibits the secretion of insulin-stimulated resistin. Androgen up-regulates the expression of resistin mRNA. Both glucocorticoids and thyroxine regulate fat cell metabolism and insulin sensitivity. They can be used as potential regulators of resistin gene expression. Tumor necrosis factor α negatively regulates the expression of resistin, and this negative regulation is time- and dose-dependent. The oxidase proliferator-activated receptor gamma plays a direct role in the regulation of resistin expression and rosiglitazone (an oxidase-proliferator-activated receptor gamma agonist) can reduce resistin mRNA and protein levels. Isoproterenol inhibits the expression of the resistin gene, and propranolol has the opposite effect, and phentolamine has no effect on resistin expression.
Relationship with disease
Atherosclerosis is known to be a chronic inflammatory response involving a range of specific cells and molecules. Two recent studies have shown that there are resistin concentrations in atherosclerotic plaques in humans and mice; as lesions develop, macrophage infiltration increases, and resistin expression increases; early onset coronary heart disease patient’s serum resistin levels were significantly increased. It suggests that the resistin secreted by macrophages may play a role in the pathogenesis of atherosclerosis.
Studies suggest that resistin, in addition to its involvement in metabolic regulation, also plays a role in immune regulation and may be involved in inflammatory responses. The cascade effect of inflammation can cause high resistine. Inflammatory factor tumor necrosis affects the expression of resistin by interleukin-6 and IL-1β. Recently, resistin has been proposed as a novel feature of pro-inflammatory molecules, and resistin and aprosin may act as markers for pro-inflammatory responses.
Jiang S, Park D W, Tadie J M, et al. Human Resistin Promotes Neutrophil Proinflammatory Activation and Neutrophil Extracellular Trap Formation and Increases Severity of Acute Lung Injury. Journal of Immunology. 2014, 192(10):4795.
Razvi S S, Richards J B, Malik F, et al. Resistin deficiency in mice has no effect on pulmonary responses induced by acute ozone exposure. Ajp Lung Cellular & Molecular Physiology. 2015, 309(10): 00270.
Eliasmiró M, Mendesbraz M, Cereijo R, et al. Resistin and visfatin in steatotic and non-steatotic livers in the setting of partial hepatectomy under ischemia-reperfusion. Journal of Hepatology. 2014, 60(1):87-95.
Ikeda Y, Tsuchiya H, Hama S, et al. Resistin regulates the expression of plasminogen activator inhibitor-1 in 3T3-L1 adipocytes. Biochem Biophys Res Commun. 2014, 448(2):129-133.
Hu Q, Tan H, Irwin D M. Evolution of the Vertebrate Resistin Gene Family. Plos One. 2015, 10(6): 0130
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