The nuclear receptor liver X receptor [LXR] is activated by endogenous oxidized derivatives of cholesterol. It constitutes a critical receptor in the regulation of various physiological functions related to the development of metabolic and cardiovascular diseases, such as atherosclerosis and diabetes, as well as various other disorders. Both isoforms of LXR, LXRα [NR1H3] and LXRβ [NR1H2], form heterodimers with the isoforms of the retinoid X receptor [RXR], which then regulate the gene expression by binding to DNA sequences associated with target genes. LXR acts as a cholesterol sensor in response to an increased concentration of cholesterol in cells and induces the transcription of genes that protect cells from cholesterol overload. LXRs play numerous roles in controlling cholesterol homeostasis via their actions on bile acid synthesis and metabolism/excretion, reverse cholesterol transport and cholesterol absorption/excretion in the intestines. Therefore, these receptors show great potential as pharmacological targets for anti-atherosclerotic activities. Recent discoveries have also emphasized the important involvement of LXRs in the pathogenesis of diabetes, Alzheimer’s disease, inflammation, adrenal steroid synthesis, skin aging and male fertility. However, LXR activation has also been shown to stimulate lipogenesis via sterol regulatory element binding protein-1c, leading to liver steatosis and hypertriglyceridemia. This review summarizes recent scientific discoveries and the biological actions of LXR with a special focus on the involvement of this type of receptor in important diseases and conditions.
Aim: The lipoprotein-associated phospholipase A2(Lp-PLA2) level has been shown to be associated with the risk of clinical cardiovascular events. We aimed to investigate whether Lp-PLA2 is associated with the progression of subclinical atherosclerosis in the general population. Methods: The degree of carotid plaque and the maximal intima-media thickness(IMT) were measured twice over a 5-year interval in 913 participants 45 to 74 years of age at baseline in a cohort study. The associations between the plasma Lp-PLA2 activity and the progression of carotid plaque and changes in the IMT level were assessed according to sex after adjusting for traditional risk factors and the high-sensitivity C-reactive protein(hsCRP) level. Results: During the 5-year follow-up period, the progression of plaque was observed in 58.5% of men and 48.3% of women. The median maximal IMT level increased by 0.12 mm in men and 0.09 mm in women per year. The progression of plaque and changes in the IMT level increased according to the quartile of the Lp-PLA2 activity in men(p＜0.05 for trend), but not women. Following adjustment for traditional risk factors and the hsCRP level, the odds ratio for plaque progression associated with an increase in the Lp-PLA2 activity of one standard deviation was 1.28(95% CI=1.09-1.49, p=0.043) in men and 0.92(95% CI=0.78-1.08, p=0.273) in women. The regression coefficient for IMT progression was 0.003(p=0.004) in men and −0.001(p=0.166) in women after adjusting for the other factors. Conclusions: The Lp-PLA2 level is associated with the progression of subclinical atherosclerosis in men. Lp-PLA2 may play an important role in the pathogenesis of atherosclerosis and be a potential target for the early prevention of cardiovascular disease.
Aim: The clustering of metabolic abnormalities occurs not only due to abdominal obesity but also other etiologies. We investigated the contribution of visceral fat accumulation and the circulating adiponectin level to the clustering of metabolic abnormalities in a Japanese population. Methods: We used the data for 1,989 Japanese employees to perform a structural equation modeling analysis. According to the concept of metabolic syndrome, we developed a multiple indicator multiple cause (MIMIC) model and investigated to what extent measurements of the visceral fat area (VFA) and circulating adiponectin levels explain the morbidity of clustering of metabolic abnormalities, represented as a latent variable termed “risk clustering.” The following clinically measurable parameters were set as the phenotypes of the risk clustering: systolic blood pressure and glucose, high-density lipoprotein cholesterol, triglyceride, uric acid and alanine aminotransferase levels. Results: The mean age of the subjects was 46±11 years, and 72% of the participants were men. A VFA of ≥100 cm2 was observed in 32% of the subjects. The squared multiple correlation R2 of the risk clustering was as high as 0.73, indicating that the measurements of the VFA and adiponectin levels explained 73% of the variance in the risk clustering. The R2 between the risk clustering and metabolic parameters ranged from 0.14 to 0.54, thus indicating that these metabolic parameters reflectedthe development of morbidity of the risk clustering in the body within a range of 14% to 54%. Conclusions: The measurements of the VFA and adiponectin level makes a considerable contributionto the risk clustering.
Aim: To evaluate progression of arteriosclerosis using cardio-ankle vascular index(CAVI) and carotid duplex ultrasonography(DUS) in young and adolescent patients considered to be at risk of cardiovascular disease. Methods: We evaluated the progression of arteriosclerosis using CAVI and carotid DUS in 240 young and adolescent patients. Dyslipidemia(DL), hypertension(HT), and diabetes mellitus(DM) were major cardiovascular risk factors. Patients were divided to 4 groups according to number of risk factors. Results: In terms of risk factors, CAVI and CAVI difference(CAVI-D) were elevated only in the HT group(p=0.0290, p=0.0243 vs. no risk respectively). CAVI-D was positively associated with diastolic blood pressure(DBP). Mean IMT was positively associated with LDL-C or systolic blood pressure, and negatively with HDL-C. Plaque score was associated with LDL-C or DBP. In patients with the 3 risk factors, CAVI, CAVI-D and mean intima-media thickness(IMT) were significantly higher than in those without risk(p=0.0009, p=0.0042 and p=0.0151 respectively), and CAVI and CAVID were higher than in those with 1 risk(p=0.0204 and p=0.0231). Carotid plaque develops from around 30 years of age in Japan. Despite numbers of risk factors, there were no differences in CAVI, CAVI-D, mean IMT or plaque score between smoker and non-smoker groups. Conclusion: In conclusion, an increase in the number of risk factors also results in progression of arteriosclerosis in young and adolescent patients. HT was the most important risk factor for arteriosclerosis in these patients.
Aim: The present study evaluated the effects of pioglitazone treatment on the incidence of primary cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke. Methods: A prospective, multicenter, randomized, open label, comparative study was conducted among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction. Results: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol. The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and 10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary outcome was not significant between the two groups(1.8% per year). Conclusions: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two years of pioglitazone treatment did not produce any statistically significant reductions in the rate of primary cardiovascular events.
Aims: The association between a low ankle brachial index(ABI) and mortality and vascular morbidity in Japanese individuals with diabetes and the independence of this association from other risk factors have not yet been examined in the primary care setting among a large number of patients. Methods: An observational prospective cohort study was performed among 3,004 Japanese individuals(2,598 patients with diabetes) to examine all-cause death and cardiovascular disease(CVD) in relation to low ABI(＜0.9) values and other risk factors. Results: Low ABI values were found in 127 subjects(4.2%) and was associated with smoking, diabetes, hypertension, pulse pressure, glycosylated hemoglobin A1C, lipid profiles, glomerular filtration rate, uric acid and prevalent CVD at baseline. Over 13,242 person-years, 93 deaths and 117 cases of CVD occurred. In a multivariate Cox regression analysis, the hazard ratio for low-normal ABI values was 3.97(95% CI, 2.29 to 6.88) for all-cause death and 2.86(95% CI, 1.83-4.49) for fatal and non-fatal CVD and all-cause death. Similar hazard ratios were found when the subjects were confined to those with diabetes. All risk analyses indicated that age, a low ABI, diabetes, a history of CVD and smoking remained significantly and independently predictive of CVD and all-cause death. Conclusions: A low ABI exhibits significant cross-sectional associations with conventional risk factors and further more with the glomerular filtration rate, uric acid level and presence of prevalent CVD at baseline, and a low ABI independently predicts subsequent death and cardiovascular events. These findings support the concept that a low ABI is an integrated marker of an excess risk of death and cardiovascular events, independent of conventional risk factors.
Aim: The commonly observed relationship between increased visceral adiposity and metabolic abnormalities may be partly mediated by a concomitant increase in liver fat content. We evaluated the independent association between the level of alanine aminotransferase (ALT) as a surrogate marker of the liver fat content and the incidence of metabolic abnormalities after adjusting for the amount of visceral adipose tissue (AT). Methods: The subjects included 1,118 Japanese individuals (44% women) who underwent computed tomography to assess the amount of visceral AT on medical checkups. Cross-sectional associations between the serum ALT, visceral AT and metabolic risk factors were examined. Results: The ALT level and visceral AT were found to show a significant correlation(r=0.41 in men and r=0.36 in women, p＜0.001). In a multivariable linear regression analysis, the ALT level and visceral AT were found to be independently associated with blood pressure in men and triglycerides and 2-hour post-challenge glucose in both genders(p＜0.01), whereas only visceral AT was found to be associated with HDL-cholesterol(p＜0.01). When the participants were classified into four subgroups based on the 75th percentiles of ALT and visceral AT, the low ALT/high-visceral AT group, but not the high-ALT/low-visceral AT group, had a significantly higher odds ratio for low HDL-cholesterol among both genders(p＜0.05) and for hypertriglyceridemia in men only(p＜0.05). Meanwhile, the high-ALT/low-visceral AT group, but ot the low-ALT/high-visceral AT group, had a significantly higher odds ratio for IGT among women(p＜0.05). Conclusions: Although the ALT level and visceral AT were found to be independently associated with most metabolic risk factors, visceral AT had a dominant association with dyslipidemia in both genders, while the ALT level appeared to have a closer association with IGT in women.
Aim: The medical management of patients with chronic kidney disease(CKD) has changed within the past 20 years. We speculate that this change has resulted in a decrease in the prevalence of atherosclerotic cardiovascular disease in patients with CKD. The aim of the present study was to analyze changes in the prevalence of coronary artery disease(CAD) in patients newly started on hemodialysis, as well as trends in clinical factors and medications over the past two decades. Methods: This single-center cross-sectional study examined data for 315 consecutive patients starting hemodialysis(age, 64±12 years; men, 73%; diabetic nephropathy, 57%) between January 1993 and December 2010. All patients were routinely screened for CAD within three months of starting hemodialysis, regardless of whether ischemic heart disease was suspected. The patients were categorized into six groups based on the date of the initial dialysis session in order to compare the historical prevalence of unidentified CAD(uCAD) in association with the clinical factors. In addition, we performed a subgroup analysis among 222 patients without known cardiac disease. Results: The prevalence of uCAD gradually declined from 69% to 25% over 18 years(p＜0.001 for trend). The mean high-density lipoprotein cholesterol(HDL-C) concentration increased(p＜0.001 for trend), while the median C-reactive protein(CRP) level decreased over time. In parallel with these trends, the proportion of statin users significantly increased over time(p＜0.001 for trend). The use of erythropoiesis-stimulating agents(ESAs) and renin angiotensin aldosterone system inhibitors(RAS-Is) also increased during the same period(both p＜0.001 for trend). A univariate logistic regression analysis identified a significant association between the prevalence of uCAD and the use of ESAs(OR: 0.565, p=0.016) or RAS-Is(OR: 0.501, p=0.004). In addition, a lower BMI, lower HDL-Clevel and higher CRP level were found to be closely associated with uCAD, independent of confounding variables. The findings for the new dialysis patients without cardiac disease were similar. Conclusions: The prevalence of uCAD in patients with end-stage kidney disease has remarkably decreased over the past two decades. Major improvements in the medical management of CKD may modify the prevalence of coronary atherosclerosis.
Aim: The prognoses of symptomatic and asymptomatic intracranial atherosclerotic stenosis(ICAS) differ. Understanding the underlying pathomechanisms and predictors of progression or regression may help to clarify the differences. We herein attempted to compare the course and predictors of symptomatic ICAS to those of coexisting asymptomatic ICAS. Methods: This was a post-hoc analysis of the ‘Trials of Cilostazol in Symptomatic intracranial arterial stenosis-2(TOSS-2)’ study, which recruited patients with acute symptomatic ICAS receiving intensive medical treatment. Changes in the status of ICAS were classified as being indicative of regression, progression or no changes. Univariate and multivariate ordinal regression analyses were performed to identify predictors of symptomatic and asymptomatic ICAS based on clinical, laboratory and radiologic data. Results: Of the 409 patients, symptomatic ICAS demonstrated regression in 110(27%) cases and progression in 52(13%) cases. Among these patients, 250(61.1%) had asymptomatic ICAS, which regressed in 38(15%) cases and progressed in 16(6%) cases. Severe baseline stenosis, a high highdensity lipoprotein(HDL) cholesterol level and the use of cilostazol were found to be independently associated with a favorable course of symptomatic ICAS(p＜0.001, p=0.005 and p=0.038, respectively). Regarding asymptomatic ICAS, severe stenosis, the use of angiotensin receptor antagonists and a low fasting glucose level were associated with a favorable course(p＜0.001, p=0.011 and p=0.007, respectively). Conclusions: Changes in atherosclerosis are more dynamic in patients with symptomatic ICAS, and the predictors of symptomatic and asymptomatic ICAS differ. In this study, changes in the status of symptomatic ICAS were associated with the level of HDL cholesterol, which is known to affect the regression of atherosclerosis and vascular remodeling.
Aim: Small intestine-derived chylomicrons and chylomicron remnants, which are predominant in patients with postprandial hypertriglyceridemia, chylomicron syndrome and/or familial dyslipidemia, carry one molecule of apolipoprotein B-48(apo B-48) per lipoprotein particle. We investigated the reference interval for the apo B-48 concentration. Methods: We studied 516 individuals who provided written informed consent and confirmed that they were not taking any medications. BMI, waist circumference, blood pressure and the fasting serum concentrations of LDL-C, triglyceride(TG), HDL-C and apo B-48 were measured. The Apo B-48 concentrations were compared according to sex, a pre- or postmenopausal status, dyslipidemia(LDL-C ≥140 mg/dL, TG ≥150 mg/dL, HDL-C ＜40 mg/dL), metabolic syndrome(MetS) and the number of risk factors. Results: The fasting apo B-48 concentrations(mean±SD) were significantly higher in men than in women(3.8±3.3 μg/mL vs 2.4±1.9 μg/mL, p＜0.001), subjects with a BMI of ≥25 kg/m2 versus a BMI of ＜25 kg/m2 (4.4±3.7 μg/mL vs 2.8±2.4 μg/mL, p＜0.001) and those with versus without MetS(6.5±4.3 μg/mL vs 3.0±2.6 μg/mL, p＜0.001). High apo B-48 concentrations were also observed in correlation with the number of risk factors for the MetS. The upper reference limit of apo B-48 was estimated to be 5.7 μg/mL among the 332 patients with normolipidemia, excluding those exhibiting a mean value above ±2.58 standard deviations(SDs), as the mean and range of mean ±1.96 SD were calculated to be 2.04 μg/mL(reference value) and 0.74 to 5.65 μg/mL(reference interval), respectively. Conclusions: Based on our study of normolipidemic patients, the upper reference limit for the fasting apo B-48 concentration is estimated to be 5.7 μg/mL.