Clinical Significance of Serum 7-Ketocholesterol Concentrations in the Progression of Coronary Atherosclerosis

Hatori, Takashi; Takahashi, Mitsuru; Iizuka, Takuo; Shirai, Kohji

doi:10.5551/jat.no703

Cited by 30 publications

(14 citation statements)

References 54 publications

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“…Niemann-Pick type C (NP-C) disease is a rare, autosomalrecessive disorder resulting from homozygous or compound heterozygous NPC1 mutations and is clinically characterized by progressive neurological deterioration and liver/spleen enlargement due to abnormal sequestration of unesterified cholesterol and glycosphingolipids within the late endosome/lysosome compartments (18). Although the biological parents of NP-C patients carrying one mutant NPC1 allele are considered to be physiologically normal, we and others have recently shown that these apparently healthy carriers of heterozygous NPC1 mutation (NPC1 +/2 ) have increased plasma bile acid A (a glycine-conjugated 3b,5a,6b-trihydroxycholanic acid) (19) and 7-ketocholesterol (20), an oxidized lipid involved in atherosclerosis progression (21,22), indicating the potential detrimental effects of heterozygous NPC1 mutation on cardiometabolic functions. To date, no studies have directly and systematically investigated NPC1 mutations and their functional consequences in the pathogenesis of human obesity in the available literature.…”

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confidence: 99%

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity

et al. 2017

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Some Shanghai Clinical Center f a role of Niemann-Pick type C1 () for obesity traits. However, whether the loss-of-function mutations in cause adiposity in humans remains unknown. We recruited 25 probands with rare autosomal-recessive Niemann-Pick type C (NP-C) disease and their parents in assessment of the effect of heterozygous mutations on adiposity. We found that male carriers had a significantly higher BMI than matched control subjects or the whole population-based control subjects. Consistently, male mice had increased fat storage while eating a high-fat diet. We further conducted an in-depth assessment of rare variants in the gene in young, severely obese subjects and lean control subjects and identified 17 rare nonsynonymous/frameshift variants in (minor allele frequency<1%) that were significantly associated with an increased risk of obesity (3.40% vs. 0.73%, respectively, in obese patients and control subjects, = 0.0008, odds ratio = 4.8, 95% CI 1.7-13.2), indicating that rare variants were enriched in young, morbidly obese Chinese subjects. Importantly, participants carrying rare variants with severely damaged cholesterol-transporting ability had more fat accumulation than those with mild/no damage rare variants. In summary, rare loss-of-function mutations were identified as being associated with human adiposity with a high penetrance, providing potential therapeutic interventions for obesity in addition to the role of in the familial NP-C disease.

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confidence: 99%

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity

et al. 2017

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“…Concentrations of 7-ketocholesterol up to 10 M are found in macrophage-derived foam cells of atherosclerotic plaques and in cataract lenses, probably as a result of excessive autooxidation [133][134][135][136]. Importantly, in patients with coronary artery disease, significantly elevated serum 7-ketocholesterol levels compared with control subjects (19 ng/ml versus 32 ng/ml (48 nM versus 80 nM)) were observed [137]. Serum 7-ketocholesterol levels strongly correlated with the presence of acute myocardial infarction, the number of affected blood vessels and high sensitive C-reactive protein concentrations, suggesting a close association between elevated serum 7-ketocholesterol and the progression of coronary atherosclerosis and inflammation.…”

Section: Role Of 11␤-hsd1 In the Metabolism Of 7-ketocholesterolmentioning

confidence: 99%

The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations

Odermatt

Nashev

2010

The Journal of Steroid Biochemistry and Molecular Biology

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“…Exercise stress test (effort test) is a noninvasive test, this provides a great advantage, but it is necessary to increase the accuracy of the test because the specificity of the test is low and its evaluation is subjective (4, 5). Oxysterols have been implicated in the formation and progression of atherosclerotic plaques (6, 7). 7-ketocholesterol (7-KC), 7ß-hydroxycholesterol (7ß-OHC), beta-isomers of epoxide, 27-hydroxycholesterol (27-OHC) and cholestane-3β,5α,6β-triol (C-triol) have been shown to increase in plasma and/or atherosclerotic plaque in various studies (8, 9, 10, 11, 12).…”

Section: Introductionmentioning

confidence: 99%

The effect of effort test on the levels of ischemia modified albumin, 7-ketocholesterol and cholestan-3β , 5α , 6β -triol and their role in the diagnosis of coronary artery disease

Keles

Samadi

İşikhan

et al. 2019

Journal of Medical Biochemistry

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Summary Background Oxysterols have been shown to play a role in plaque formation while ischemia modified albumin (IMA) is widely accepted as an acute marker for ischemia. The effort test is one of the methods used to identify the presence of coronary artery disease. Thus, there may be a relationship between effort test result and the levels of IMA, 7-ketocholesterol (7-KC) and cholestane-3β,5α,6β-triol (C-triol). Methods Thirty patients who underwent effort test and 30 healthy subjects were included in the study. IMA levels were determined with the albumin-cobalt binding test, 7-KC and C-triol levels were determined with LC-MS/MS. Among the patients, two subgroups were identified according to the results of the effort test, group 1 consisted of patients with a positive effort test (n = 12), and group 2 consisted of patients who had a negative effort test (n = 18). Results 7-KC levels of patients were significantly higher compared to healthy subjects (39.87 ± 2.13 ng/mL, 20.26 ± 1.35 ng/mL; p=0.001). In patients, post-test 7-KC levels were significantly lower than pre-test levels (post-test vs. pre-test: 37.73 ± 2.44 ng/mL vs. 41.07 ± 2.18 ng/mL; p<0.001). There was a significant difference in post-test 7-KC levels among all study groups (negative, positive and healthy: 37.73 ± 2.44 ng/mL, 39.87 ± 2.13 ng/mL, 20.26 ± 1.35 ng/mL, respectively). There was no significant difference in IMA levels. Conclusions Patients with positive effort test had significantly higher levels of 7-KC. Additionally, after the effort test, the 7-KC value was reduced. 7-KC is a biomarker of oxidative damage and its value or changes before and after the effort test may be used as a biomarker in the diagnosis and follow-up of coronary artery disease.

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Clinical Significance of Serum 7-Ketocholesterol Concentrations in the Progression of Coronary Atherosclerosis

Cited by 30 publications

References 54 publications

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity

Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity

The glucocorticoid-activating enzyme 11β-hydroxysteroid dehydrogenase type 1 has broad substrate specificity: Physiological and toxicological considerations

The effect of effort test on the levels of ischemia modified albumin, 7-ketocholesterol and cholestan-3β , 5α , 6β -triol and their role in the diagnosis of coronary artery disease

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