Clusterin (23. Clusterin in Circulation)

Atherosclerosis and Diabetes

By combining a sandwich ELISA assay and immunoblotting analysis a measurable increase of clusterin serum levels with age in males was demonstrated and provide evidence that, as compared to healthy donors, the serum clusterin amount increases significantly in diabetic type II patients and in patients suffering from either a developing coronary heart disease, or myocardial infarction. The highest serum clusterin levels were found during myocardial infarction but no correlation was observed with the number of vessels with documented atherosclerotic damage. Clusterin accumulation in serum is probably coupled to a generalized stress mediated induction mechanism that is specifically related to certain diseases; moreover these data raise the possibility that elevated clusterin levels in serum may represent a strong indication of vascular damage ^Ref .

Serum clusterin was 52.8+/-0.8 microg/mL (mean+/-SEM; range, 36.0 84.3 microg/mL; n=92) in healthy Japanese men, and 49.3+/-0.5 microg/ ml (34.5–72.8; n=241) in healthy Japanese women. Multiple regression of these data and results from 67 men with coronary heart disease (CHD) showed that clusterin concentration was unrelated to age, sex or body mass index, but was positively related to serum PON1 (p<0.001) and apo B (p<0.02) concentrations. In women, it was also positively related to blood glucose (p<0.02). After adjusting for its associations with covariates, serum clusterin averaged 5.4 microg/ml lower in CHD men than in controls (p<0.003). Type 2 diabetics had higher clusterin concentrations (men, 83.1+/-3.4 microg/ ml, n=64; women, 64.0+/-2.3 microg/mL, n=46) than healthy men and women (p<0.001). In these type 2 diabetics, clusterin concentration was unrelated to PON1 concentration, but was positively related to blood glucose (p<0.01). After adjustment for its relation to blood glucose, the mean clusterin concentration was similar in diabetics and healthy subjects. These findings suggest that clusterin may be anti-atherogenic in humans, and that its concentration is raised by type 2 diabetes ^Ref .

Liver Cirrhosis

Clusterin and vitronectin were quantified in serum from patients suffering from alcoholic liver cirrhosis (n = 83), and in serum-free culture supernatants from the hepatoma cell line HepG2. The median clusterin concentration was 0.20 g/l in cirrhosis and 0.37 g/l in the controls, whereas corresponding vitronectin values were 0.19 and 0.26 g/l, respectively. The concentration of both proteins showed significant correlation (p < 0.0001) with disease severity and with established plasma markers of hepatic synthetic function, such as albumin and prothrombin complex. The clusterin level, but not the vitronectin level, correlated with survival (p = 0.005). The rates of synthesis of clusterin, vitronectin and C3 from HepG2 cells were 0.02, 0.21 and 1.9 microgram­s/10(6) cells/24 h, respectively. It is concluded that clusterin (as vitronectin and C3) is mainly produced in the liver and may be a useful marker in the evaluation of severity of liver disease and prognosis of patients with alcoholic cirrhosis ^Ref .

Alcohol Consumption

(1)The sialylation index of clusterin (moles sialic acid per mole clusterin protein) in rats administered ethanol for 4, 6, and 8 weeks and a gradual withdrawal and a follow-up abstinence for 1, 2, and 4 weeks; and (2) enzymatic activities of hepatic sialyltransferase and plasma sialidase during the same periods of alcohol treatment and abstinence in rats were determined. Although no significant differences in the clusterin sialylation index between rats of the control and ethanol groups were found at the 4th week of alcohol treatment, a highly significant loss of 24% (p < 0.001) and 44% (p < 0.001) was found after 6 and 8 weeks, respectively, of alcohol feeding of these animals. Furthermore, a significant recovery of 38% (p < 0.001), 78% (p < 0.001), 84% (p < 0.001) and 96% (p < 0.001) in the sialylation index of clusterin were found, respectively, during withdrawal and 1, 2, and 4 weeks of subsequent alcohol abstinence in these animals. These changes in the sialic acid content of clusterin were accompanied by a similar pattern of changes in the enzyme activities of hepatic sialyltransferase and plasma sialidase in animals undergoing chronic ethanol treatment, withdrawal, and abstinence periods.the analysis of the sialylation index of clusterin seems to be a simple and feasible method to use to evaluate the extent of ethanol exposure ^Ref . Chronic alcohol consumption impairs the hepatic sialylation of a number of glycoproteins by specifically down-regulating Gal-beta-1,4GlcNAc alpha2,6sialyl­transferase mRNA. It was found that chronic ethanol consumption markedly inhibits hepatic sialylation of clusterin. Because the sialic-acid index of Apo J (SIJ; moles of sialic acid per mole of Apo J protein) is approximately seven times more than that for transferrin (28 vs. 4), it was evaluated whether plasma SIJ would be an even more sensitive marker for chronic ethanol consumption than CDT in both rats and human subjects. The method involved immunoaffinity purification of plasma HDL-Apo J, followed by its sialic acid determination. It was found that chronic ethanol feeding resulted in loss of sialic acid residues of plasma HDL-Apo J in rats. This loss of sialic acid was positively correlated with both amount and duration of ethanol treatment. In human subjects, an intake of about 60 g of alcohol for 30 days led to almost 50% (P <.01) depletion of sialic acid from plasma HDL-Apo J. Further, it was established that there was a positive correlation of alteration in SIJ with alcohol consumption, detoxification, abstinence, and relapse in human alcohol-dependent patients (sensitivity, 90%-92%). In addition, plasma SIJ was decreased by 50%-57% (P <.01) in both male and female alcohol-dependent subjects. It was suggest that plasma SIJ can be used as a viable marker for early detection of chronic alcohol consumption in human beings ^Ref .

Systemic Lupus Erythematosus

The levels of serum clusterin were measured by ELISA in 80 patients with SLE (76 female, 4 male). Clinical and serological information was gathered on 115 visits. Overall disease activity scores were determined using the systemic lupus Activity Measure-revised. Serum clusterin levels were significantly decreased in patients with SLE and correlated inversely with disease activity (p < 0.00001). Low clusterin levels were significantly associated with skin ulcers (p < 0.0001), loss of hair (p = 0.002), proteinuria (p = 0.018), low platelet count (p = 0.03), and arthritis (p < 0.0001). The clusterin levels did not correlate with either systemic complement consumption, as measured by C3 or C4, or with prednisone use. A highly significant correlation was observed between low levels of serum clusterin and a number of SLE disease features.this deficiency of clusterin could directly or indirectly affect the disease process. Individuals lacking sufficient amounts of clusterin systemically likely have poor control of antibody mediated inflammation at sites of apoptosis where autoantigens are exposed ^Ref .

Peeclampsia

Immunoassays showed that clusterin levels in the 80 preeclamptic women were significantly higher than those in the 80 controls (mean +/- SD; 1.62 +/- 0.46 times reference level in preeclamptic women vs. 1.30 +/- 0.46 times reference level in controls, P < 0.001) ^Ref .

Prostate Cancer

The average clusterin level in serum was reported to be 101+/-42 microg/ml (n=96). There was no correlation to age or serum cholesterol levels. Analysis of serum clusterin levels in patients with newly diagnosed prostate cancer (n=5), hormone responsive tumors (n=5), and hormone refractory disease (n=5), demonstrated that no significant changes in serum clusterin levels accompany the progression of prostatic disease, or response to hormone therapy ^Ref .

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