人单核细胞趋化蛋白-1 （MCP-1）是心血管疾病和代谢综合征生物学标示物
Monocyte chemoattractant protein 1 in obesity and insulin resistance
This study identifies monocyte chemoattractant protein 1 (MCP-1) as an insulin-responsive gene. It also shows that insulin induces substantial expression and secretion of MCP-1 both
in vitro in insulin-resistant (IR) 3T3-L1 adipocytes and
in vivo in IR obese mice (
ob/
ob). Thus, MCP-1 resembles other previously described genes (e.g.,
PAI-1 and
SREBP-1c) that remain sensitive to insulin in IR states. The hyperinsulinemia that frequently accompanies obesity and insulin resistance may therefore contribute to the altered expression of these and other genes in insulin target tissues.
In vivo studies also demonstrate that MCP-1 is overexpressed in obese mice compared with their lean controls, and that white adipose tissue is a major source of MCP-1. The elevated MCP-1 may alter adipocyte function because addition of MCP-1 to differentiated adipocytes
in vitro decreases insulin-stimulated glucose uptake and the expression of several adipogenic genes (
LpL, adipsin, GLUT-4, aP2, β3-adrenergic receptor, and peroxisome proliferator-activated receptor γ). These results suggest that elevated MCP-1 may induce adipocyte dedifferentiation and contribute to pathologies associated with hyperinsulinemia and obesity, including type II diabetes.
Peter Sartipy and David J. Loskutoff. Proc Natl Acad Sci U S A. 2003 June 10; 100(12): 7265–7270.
Effect of insulin on MCP-1 gene expression in vitro. Mature adipocytes were incubated without insulin (Ctrl) or with 1,000 nM insulin (Ins) for 3 h. (A) MCP-1 mRNA levels were determined in normal (N) and IR 3T3-L1 adipocytes by using real-time RT-PCR and normalized to the expression of 18S rRNA. The data are expressed as relative mRNA level compared with the average expression level in normal cells incubated without insulin (=1). (Inset) The effect of TNF-α on insulin-stimulated glucose uptake was analyzed in mature 3T3-L1 adipocytes incubated without (C) or with 3 ng/ml TNF-α for 3 days. Insulin-stimulated 3H-2-deoxyglucose uptake was determined, and the data are expressed as percentage of the control (i.e., cells incubated without TNF-α). The error bars represent the SE (n = 5); ***, P < 0.0001 relative to control cells. (B) Secretion of MCP-1 protein from normal (N) and IR 3T3-L1 adipocytes was determined in conditioned media by using ELISA. Differentiated adipocytes were treated as described in A. The data were normalized to total cell protein. The error bars represent the SE (n = 3); **, P < 0.01 and ***, P < 0.001 relative to control cells.
Proc Natl Acad Sci U S A. 2003 June 10; 100(12): 7265–7270.
MCP-1 gene expression in vivo.(A) Basal levels of MCP-1 mRNA were determined in s.c. adipose tissue from sex- and age-matched WT and ob/ob mice by using real-time RT-PCR. The data are normalized to the expression of 18S rRNA and are expressed as relative mRNA level compared with the average expression in WT mice (=1). The error bars represent the SE (n = 6); ***, P < 0.0001. (B) Basal levels of MCP-1 mRNA were determined in different tissues from ob/ob mice by using real-time RT-PCR. The data are normalized to the expression of 18S rRNA and are expressed as relative mRNA levels compared with the average expression in s.c. adipose tissue (=1). The error bars represent the SE (n = 4); a, P < 0.001 in adipose tissue vs. liver, kidney, and lung.
Proc Natl Acad Sci U S A. 2003 June 10; 100(12): 7265–7270.
Monocyte chemoattractant protein (MCP)-1 levels (pg/mL) in serum of patients with myocardial infarction (MI,
n = 64), ischemic stroke (IS,
n = 40), and healthy, control subjects (
n = 40). The data are expressed as whisker box plots; the box represents the 25–75th percentiles, the median is indicated by a bar across the box, the whiskers on each box represent the 10–90th percentiles.
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P < .002 when comparing with the control group.
A. Arakelyan et al. Mediators Inflamm. 2005 August 14; 2005(3): 175–179.
MCP-1 levels in children with ILD. MCP-1 levels in bronchoalveolar lavage fluid (BALF) of children with interstitial lung diseases (ILD) and healthy controls are shown at the (A) protein and at the (B) mRNA level. (C) MCP-1 levels in BALF of ILD children with and without pulmonary fibrosis. Pulmonary fibrosis was assessed by computed tomography according to [36,37]. (D) MCP-1 levels in ILD children related to ILD disease severity according to the criteria of Fan [33]. 1 = asymptomatic, no desaturation; 2 = symptomatic but normoxic (> 90%) under all conditions; 3 = symptomatic with desaturation during sleep or exercise; 4 = symptomatic with desaturation at rest; MCP-1 protein levels were quantified in BALF by a multiplex, particle-based assay (Bio-Rad Laboratories, Minneapolis, USA) as described previously [42]. MCP-1 mRNA levels were quantified in BALF cells by Real time RT-PCR using SYBR green and the iCycler iQ detection system (Biorad, Hercules, CA, USA) and were normalized to GAPDH. Median values are shown by horizontal bars. Differences between the patient groups were tested with the Mann-Whitney U test; * p < 0.05, *** p < 0.001; Children with systemic corticosteroid therapy are shown as grey circles. P: Pulmonary alveolar proteinosis; S: Sarcoidosis; † symbolize children who died due to respiratory failure. Dominik Hartl et al. Respir Res. 2005; 6(1): 93.
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