Associations of Serum Uric Acid with Endogenous Cholesterol Synthesis Indices in Men with High Cardiometabolic Risk

Abstract

Background:

Patients with metabolic syndrome (MetS) have increased endogenous synthesis of cholesterol, together with lower level of intestinal cholesterol absorption. However, less is known about how individual metabolic disturbances linked to MetS correlate with dysregulated cholesterol homeostasis.

Methods:

We consecutively examined 178 probands (91 women/87 men) characterized by the presence of one or two components of MetS (group with an increased cardiometabolic risk [CMR]) and 42 healthy controls (24 men/18 women) of similar age, as well. In all probands, the surrogate markers for cholesterol biosynthesis (lathosterol) and absorption (campesterol and β-sitosterol) were measured by capillary gas chromatography. In CMR group, we performed multivariate regression analysis to assess the dependence of the parameters of cholesterol biosynthesis/absorption on components of MetS including serum uric acid (SUA), apolipoprotein B (apoB), and age.

Results:

In CMR group, higher lathosterol to total plasma cholesterol (TC) ratio (LCR) was influenced by gender (P = 0.05, analysis of covariance [ANCOVA] for age), whereas ratios of campesterol (β-sitosterol, respectively) to TC were lower in CMR group (P < 0.001 and P = 0.002, ANCOVA for age). In men, LCR was positively associated with SUA, apoB, and hypertension (all P < 0.05). Lathosterol to campesterol or β-sitosterol ratios were highly dependent on SUA (both P < 0.01), the former being dependent also on apoB (P < 0.01). In women, these parameters were only weakly dependent on SUA.

Conclusions:

These results show that the concentration of SUA in men of CMR group is associated with the indices of de novo cholesterol biosynthesis. This association is probably influenced by interaction of arterial hypertension and apoB levels with cholesterol homeostasis.

Introduction

Cardiometabolic or metabolic syndrome (MetS) is one of the most important health concerns among highly developed countries in North America and Europe¹ and also in developing countries. The prevalence of MetS in middle-aged individuals is now ∼30%, but it is predicted that this value will increase to 50% by 2035.² Cardiometabolic syndrome is a non-random cluster of cardiovascular (CV) risk factors (RFs) connected with insulin resistance (IR) and abdominal distribution of adipose tissue. Individual components of MetS (dyslipidemia, hypertension, IR, hypercoagulable states, oxidative stress, and low-grade inflammation) meet the criteria of independent RF for coronary heart disease and its equivalents (NCEP 2002).³ This research focuses on the importance of clinical states that are considered as associated features of MetS and also were identified as RFs of cardiovascular diseases (CVDs), such as nonalcoholic fatty liver disease,⁴ obstructive sleep apnea,⁵ changed intestinal microbiome,⁶ or hyperuricemia.^7
–9 Plasma uric concentrations were positively associated with IR, obesity, type 2 diabetes mellitus, hypertension, and chronic kidney disease.¹⁰ Moreover, the highest quintiles of serum uric acid (SUA) concentration were linked with increased CV mortality in both men and women,¹¹ but the causality in the relationship between SUA and CVD has not been elucidated up to now.¹² One possible mechanism could stem from association of uric acid and lipid metabolism. Uric acid metabolism is linked with fructose and excessive fat storage,⁹ and with hypertriglyceridemia.¹³ Intestinal uric acid exporter, ABCG2, is also capable to transfer several types of sterol molecules including steroid hormones or bile acids and its function is dependent on cholesterol content in membranes.¹⁴

The dysregulated cholesterol homeostasis is a known metabolic feature of MetS. The patients with MetS have increased endogenous synthesis of cholesterol.^15

–18 Increased cholesterol biosynthesis is often documented by plasma higher concentrations of cholesterol precursors, such as desmosterol and lathosterol.¹⁵ Plant analogues of cholesterol, phytosterols, are consumed in the diet together with cholesterol, the most abundant phytosterols being campesterol and β-sitosterol. Their plasma concentration can serve in plasma as surrogate markers for both exogenous (dietary) and biliary cholesterol absorption, which is usually lower in patients with MetS.¹⁶

The aim of the study was to explore the associations between selected CV RFs, linked to MetS [triacylglycerols (TAG), waist, high-density lipoprotein cholesterol (HDL-C), glucose, uric acid, waist, visceral adiposity index, HOMA index of IR (HOMA-IR), and presence of hypertension], and surrogate markers of cholesterol biosynthesis/absorption in individuals with high cardiometabolic risk (CMR).

Materials and Methods

Subjects

We consecutively examined the patients with some form(s) of metabolic disease linked to increased CMR [dyslipidemia, obesity, arterial hypertension, and impaired fasting glycemia (IFG)] from the Lipid and Diabetes Outpatient Department of the 4th Department of Internal Medicine at the General Teaching Hospital in Prague between 2011 and 2017.

We enrolled in the study only the individuals with only one or two components of MetS classified according to the criteria of the International Diabetic Federation (IDF, 2009).¹⁹ This group (204 patients) was denominated as the CMR group and from these, 26 individuals were excluded for incomplete data.

The exclusion criteria for the study were as follows: history of diabetes mellitus (DM), CVD, hepatic and/or renal disease, excessive alcohol consumption (>30 grams/day), hypothyroidism, recent infection, malignancies, treatment with antihyperlipidemic or antidiabetic medications, inhibitors of xanthinoxidase, supplementation with polyunsaturated fatty acids and/or antioxidants, unstable body weight, and hormone replacement therapy. Among the CMR group, obesity was present in 125, IFG in 19, and dyslipidemia in 68 individuals. Arterial hypertension was treated in 91 patients; of these, 50 were given angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor type 1 blockers, with the remaining subjects treated by a combination of ACE inhibitors and calcium channel blockers.

Furthermore, 42 healthy controls (CON) were recruited at the same time from the clinic staff along with other healthy volunteers. Both groups had a similar distribution of gender, age, smokers [yes/no/ex-smoker 4/36/2 in CON vs. 33/140/5 in CMR, χ ² test (Yates' correction) = 1.308, P = 0.520; and consumption of alcohol (no/<1 glass day/1–2 glasses day/2–3 glasses day) 5/29/7/1 in CON vs. 47/106/20/5 in CMR, χ ² test (Yates' correction) = 3.367, P = 0.338]. The study protocol was approved by the Joint Ethics Committee of the General University Hospital and the 1st Medical Faculty of Charles University in Prague (decision no. 3311/2011). Each participant signed the informed consent form, thus assenting to participate in the study before enrolment. Basic clinical, anthropometrical, and biochemical characteristics are summarized in the Table 1.

Table 1.

Basic Clinical, Anthropometric, and Biochemical Data

	CON		CMR group^a		P ANCOVA
	Men	Women	Men	Women	Group	Sex
Number of cases	24	18	91	87	0.494^b
Age (years)^c	52.2 ± 12.6	53.4 ± 10.8	52.5 ± 11.7	55.4 ± 10.1	n.a.	n.a.
Body mass (kg)^c	72.2 ± 9.2	64.4 ± 8.9	87.2 ± 15.1	73.7 ± 11.1	<0.001	<0.001
Body mass index (kg/m²)^c	23.7 ± 3.3	23.5 ± 3.0	27.4 ± 3.9	27.5 ± 4.3	<0.001	0.940
Waist circumference (cm)^c	85.1 ± 6.4	74.3 ± 5.5	97.5 ± 10.8	89.8 ± 11.1	<0.001	<0.001
BP-systolic (mmHg)^c	120 ± 9	121 ± 8	132 ± 16	128 ± 13	<0.001	0.477
BP-diastolic (mmHg)^c	78 ± 5	76 ± 6	84 ± 10	82 ± 9	<0.001	0.308
Body fat (% of body weight)^c	24.4 ± 5.6	31.6 ± 4.5	28.0 ± 6.3	39.5 ± 5.8	<0.001	<0.001
Uric acid (μmol/L)^c	308 ± 72	232 ± 58	360 ± 74	268 ± 60	<0.001	<0.001
Glucose (mmol/L)^c	4.78 ± 0.43	4.83 ± 0.39	5.20 ± 1.19	4.91 ± 0.56	0.065	0.482
Insulin (mU/L)^d	4.9 [3.1–8.7]	7.8 [6.1–10.1]	8.7 [6.0–12.0]	7.8 [5.9–11.1]	0.003	0.107
HOMA-IR^d,e	1.0 [0.7–2.0]	1.7 [1.2–2.3]	2.0 [1.4–2.8]	1.7 [1.2–2.6]	0.002	0.166
Conjugated dienes in LDL (μmol/L)^c	48.8 ± 14.7	49.1 ± 13.2	60.8 ± 19.1	61.1 ± 18.7	<0.001	0.786
hsCRP (mg/L)^d	0.5 [0.6–4.2]	1.1 [0.8–1.4]	1.1 [2.1–4.2]	2.1 [0.7–4.1]	0.123	0.746
Total cholesterol (mmol/L)^c	5.13 ± 0.71	5.91 ± 1.16	5.83 ± 1.46	6.03 ± 1.20	0.081	0.015
Triacylglycerols (mmol/L)^d	0.92 [0.74–1.13]	0.90 [0.83–1.06]	1.52 [1.11–2.45]	1.25 [0.96–1.61]	<0.001	0.141
HDL-C (mmol/L)^c	1.52 ± 0.25	1.78 ± 0.29	1.36 ± 0.34	1.69 ± 0.41	0.0134	<0.001
Free fatty acids (mmol/L)^d	0.40 [0.27–0.62]	0.44 [0.30–0.55]	0.42 [0.31–0.56]	0.59 [0.40–0.76]	0.044	0.088
apoB (g/L)^d	0.97 ± 0.21	1.09 ± 0.26	1.26 ± 0.38	1.20 ± 0.31	<0.001	0.636
Visceral adiposity index^d,f	0.90 [0.73–1.16]	1.03 [0.96–1.20]	1.58 [1.12–2.54]	1.52 [1.21–2.06]	<0.001	0.698
Lathosterol/TC (μmol/mmol)^d	1.12 [0.73–1.46]	0.84 [0.67–1.08]	1.24 [0.87–1.76]	1.08 [0.78–1.42]	0.089	0.048
Campesterol/TC (μmol/mmol)^d	2.31 [1.66–2.99]	1.99 [1.65–2.81]	1.77 [1.28–2.22]	1.59 [1.10–2.12]	<0.001	0.818
β-sitosterol/TC (μmol/mmol)^d	1.78 [1.57–2.36]	2.00 [1.66–2.86]	1.39 [1.05–2.18]	1.40 [1.01–2.09]	0.002	0.543

One or two components of metabolic syndrome present: waist >94 (resp. 80) cm in M (resp. F), TAG >1.70 mmol/L; HDL-C <1.00 (resp. 1.30) mmol/L in M (resp. F); BP >130/85 mmHg (or antihypertensive treatment), fs glucose ≥ 5.60 mmol/L.

χ ² test; P—Significance after age adjustment: (ANCOVA).

Average ± SD.

Median [25th–75th percentile].

Index HOMA = glucose(mmol/L) × insulin(mU/L)/22.5.

Visceral adiposity index = {waist circumference/[39.68 + (1.88 × BMI)] × (TAG/1.03)} for men, = {waist circumference/[36.58 + (1.89 × BMI)] × (TAG/0.81)} for women.

ANCOVA, analysis of covariance; apoB, apolipoprotein B; CMR, cardiometabolic risk; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, HOMA index of IR; hsCRP, high-sensitivity C-reactive protein; IR, insulin resistance; LDL, low-density lipoprotein; n.a., not applicable; TAG, triacylglycerols; TC, total plasma cholesterol.

Data collection

Anthropometrical data were assessed in all included persons by the recommended procedures.²⁰ Body fat was calculated according to Durnin and Womersley²¹ using the sum of four skinfolds. Insulin sensitivity was estimated using the equation for HOMA index²² and visceral adiposity index was calculated according to modified formula by Krajcoviechova et al.²³

Blood samples were collected after overnight fasting. Concentration of basic biochemical parameters (lipids and glucose) were measured using standard enzymatic-colorimetric methods based on commercial kits by Roche Diagnostics GmbH, Mannheim, Germany [total plasma cholesterol (TC), TAG: CHOD-PAP and GPO-PAP; HDL-C: direct homogeneous test with PEG-modified enzymes; glucose: dehydrogenase method; uric acid: uricase peroxidase method], and by Beckman Coulter, Inc., Ireland (apoB: immunonephelometric method). Immunoreactive insulin was determined by the radioimmunoassay method using double monoclonal antibodies (Insulin IRMA; Imunotech, Prague, Czech Republic). Concentrations of conjugated dienes (CD) in precipitated low-density lipoproteins (LDLs) were determined spectrophotometrically.²⁴ The noncholesterol sterols (lathosterol, campesterol, and β-sitosterol) were measured by capillary gas chromatography as previously published^25,26 in nonsaponifiable part of plasma as acetates; the identity of compounds was confirmed by LC-MS/MS method.²⁷

Statistical evaluation

Continuous variables are expressed as mean ± standard deviation or median (interquartile range) according to the normal distribution of the variable. Categorical variables are expressed as the number of cases. The normal distribution of the continuous variables was tested by Shapiro–Wilk test. To compare categorical variables, Pearson's χ ² test was applied. Comparison of continuous variables among groups was carried out by analysis of variance (ANOVA) test and analysis of covariance (ANCOVA) test adjusted for age. Two-sided tests were utilized and a type I error significance level of 0.05 was considered. In CMR group, we estimated group sizes for regression analysis with number of independent variables = 10, ρ ² = 0.15, for α = 0.05 at 1−β = 0.70 as n > 90. The data were statistically evaluated with the help of the R software, version 3.2.1 (R Development Core Team 2015).²⁸

We performed multivariate regression analysis to assess the dependence of the parameters of cholesterol biosynthesis on independent variables: TAG, HDL-C, glucose, HOMA-IR, waist circumference, visceral adiposity index, uric acid, apolipoprotein B (apoB), presence of arterial hypertension, and age. The dependent variables with significant deviation from normal distribution were transformed by the Box–Cox transformation.

Results

Table 1 shows basic clinical and anthropometrical data of the subjects divided into the CON group and the high CMR group further stratified according to gender. Although we did not prove the effect of age by ANOVA (P = 0.10), between-group comparisons were performed after adjustment for age. The group at high CMR exhibits higher systolic and diastolic blood pressure, waist circumference, and body mass (percentage of fat mass and visceral adiposity index) (group effect: all P < 0.01, ANCOVA for age). The patients at high CMR have increased concentrations of CD in LDL, the sign of subclinical oxidative stress,²⁹ and higher levels of uric acid (group effect: both P < 0.001, ANCOVA for age). We did not prove the effect of gender and group on the only available marker for inflammation, high-sensitivity C-reactive protein (hsCRP).

The abovementioned differences between the CON and CMR group are not influenced by gender except for concentrations of uric acid, where the women have lower levels than men (gender effect: P < 0.001, ANCOVA for age); in HDL-C and anthropometric parameters, women exhibit higher levels than men (gender effect: all P < 0.001, ANCOVA for age). This difference is also seen in total cholesterol concentrations (gender effect: P = 0.015, ANCOVA for age).

The higher concentrations of lathosterol related to TC are influenced by gender (gender effect: P = 0.048, ANCOVA for age), whereas the ratios of campesterol (β-sitosterol, respectively) to TC are lower in CMR group (group effect: P < 0.001 and P = 0.002, ANCOVA for age).

Tables 2 and 3 present the results of multivariate regression analysis for CMR group. In women, the surrogate parameters of cholesterol biosynthesis (lathosterol to TC ratio) and biosynthesis/absorption balance (lathosterol to campesterol or β-sitosterol ratios) were highly dependent on age (all P < 0.001) and waist (P = 0.02 and P = 0.03, respectively). Ratio of campesterol to total cholesterol was only weakly dependent on uric acid (P = 0.08). The lathosterol/campesterol ratio was influenced by age (P < 0.001), waist circumference (P = 0.01), and only moderately by uric acid (P = 0.08).

Table 2.

The Results of Multivariate Linear Regression in Group with High Cardiometabolic Risk—Women

Parameter	Intercept	TAG	Waist	HDL-C	HTN	Glucose	Uric acid	apoB	Age	HOMA-IR	VAI	adj R ²
Lathosterol/TC	−0.3887	0.8006	0.0124^*	0.0195	−0.0040	0.0356	0.0003	0.1089	−0.0170^***	0.0090	−0.7336	0.1700^**
Campesterol/TC	1.829^*	−0.3245	−0.0095	−0.1651	0.0295	−0.0313	−0.0017⁺	−0.0821	0.0072	0.0174	0.2625	0.0138
β-sitosterol/TC	1.268	0.2833	−0.0077	−0.2100	−0.0472	−0.0429	−0.0012	0.0304	0.0094	0.0091	−0.1745	0.0245
Lathosterol/campesterol	−2.019	0.8962	0.0199^*	0.1930	−0.0227	0.0591	0.0020⁺	0.2281	−0.0253^***	−0.0101	−0.8206	0.2117^**
Lathosterol/β-sitosterol	−1.567	0.3065	0.0188^*	0.2579	0.0602	0.0639	0.0016	0.1003	−0.0273^***	−0.0027	−0.3985	0.1921^**

Regression coefficients are presented; significance: ⁺ P < 0.08, ^* P < 0.05, ^** P < 0.01, ^*** P < 0.001.

adj R ², adjusted R-squared; HTN, presence of hypertension; VAI, visceral adiposity index.

Table 3.

The Results of Multivariate Linear Regression in Group with High Cardiometabolic Risk—Men

Parameter	Intercept	TAG	Waist	HDL-C	HTN	Glucose	Uric acid	apoB	Age	HOMA-IR	VAI	adjR ²
Lathosterol/TC	−0.2006	−0.1047	−0.0031	−0.3321	0.2999^*	0.0291	0.0019^*	0.4156^*	−0.0069	−0.0037	0.0904	0.1027^*
Campesterol/TC	1.557	−0.0683	−0.0047	−0.0242	0.0506	0.0222	−0.0012	−0.3764^*	0.0065	0.0092	0.0049	0.0961^*
β-sitosterol/TC	1.725^*	−0.2749	−0.0132^*	−0.0725	0.0553	0.0193	−0.0012	−0.0342	0.0069	0.0351	0.2553	0.1035^*
Lathosterol/campesterol	−1.276	−0.2221	−0.0002	−0.2331	0.2296	0.0063	0.0026^**	0.5802^**	−0.0108	−0.0021	0.2285	0.2069^**
Lathosterol/β-sitosterol	−1.816^*	0.0367	0.0099	−0.2458	0.1982	0.0414	0.0026^**	0.2838	−0.0101	−0.0246	0.0417	0.1769^**

Regression coefficients are presented; significance: ^* P < 0.05, ^** P < 0.01.

In men, the effect of age was not significant; the ratio of lathosterol to total cholesterol was positively influenced by uric acid (P = 0.03), apoB (P = 0.02), and presence of hypertension (P = 0.03). The lathosterol concentrations related to campesterol or β-sitosterol concentrations were highly dependent on uric acid levels (P = 0.007 and P = 0.005, respectively), the former being dependent also on apoB (P = 0.002).

Discussion

In this observational study, we found that serum concentration of uric acid is positively associated with surrogate markers of cholesterol biosynthesis (lathosterol/TC) and ratio of biosynthesis to intestinal absorption of cholesterol ratio (represented by lathosterol/campesterol index) in the CMR group (individuals with one or two present components of MetS). These associations were stronger in men. To our knowledge, this is the first study focusing on the link between uric acid and indices of cholesterol homeostasis.

Moreover, we found in men positive dependence of surrogate markers of cholesterol biosynthesis on apoB and presence of arterial hypertension. It is known that obese subjects with MetS secrete higher amounts of very low density lipoproteins-apoB (VLDL)-apoB particles that are catabolized more slowly.³⁰ The same subjects exhibited higher concentrations of lathosterol.³¹ Unexpectedly, the parameters of cholesterol biosynthesis in our study did not depend on the defining components of MetS (TC, TAG, HDL-C, glucose, HOMA-IR, waist circumference, and visceral adiposity index), which also entered the multivariate analyses. The surrogate marker for cholesterol absorption (campesterol/TC) only moderately depended (negatively) on uric acid in women.

Both epidemiologic and clinical studies link hyperuricemia with higher incidence of MetS components, such as hypertension, dyslipidemia, impaired glucose tolerance, and type 2 diabetes mellitus.^32

–37 The association of uric acid with MetS were reported differently for men and women.^11,38 Uric acid seems to be an independent RF for the development of MetS in women.³⁹ In the PREDIMED study (Prevención noc Dieta Mediterranéa), the populations with normal concentrations of TAG and HDL-C, but levels of uric acid belonging to the upper quintile exhibited higher risk for the development of MetS.⁴⁰ The retrospective cohort study in Japanese women proved that SUA/creatinine ratio was associated with incident MetS.⁴¹

Hyperuricemia is considered to be a RF for CVDs.⁴² The meta-analysis of prospective cohort studies showed that hyperuricemia slightly increases the risk for CVD and total mortality rate, more in women.⁴³ In patients with coronary artery disease, the level of SUA was a prognostic factor.⁴⁴

According to this study, the association of uric acid with CVD could be partially caused by the modulation of cholesterol homeostasis (e.g., supporting higher endogenous cholesterol biosynthesis). In the literature, the link of uric acid to the plasma lipid levels is described as positive correlation with TAG, LDL-C,^37,45 whereas uric acid correlates negatively with HDL-C.⁴⁶ Of interest, our results correspond with results of the recently published retrospective study, which at the first time showed that increased uric acid level over 5 years was independent risk for developing high LDL cholesterol and hypertriglyceridemia, but not for low HDL.⁴⁷ Moreover, in a sample of healthy, untreated persons, uric acid was significantly associated to oxidatively modified LDL and diene levels.⁴⁸

The precise explanation of positive link of uric acid and higher de novo cholesterol biosynthesis is not known. One possible mechanism could arise from associations between hyperuricemia, IR, and activity of HMG-CoA reductase, the enzyme catalyzing the rate-limiting step in cholesterol biosynthesis. Hyperuricemia is associated with IR^49,50 even in nondiabetic individuals.⁵¹ Moreover, hyperuricemia led to increased both early- and late-phase secretion of insulin in healthy nonobese individuals with normal glucose tolerance.⁵²

Strengths of this study: To our knowledge, this the first study focusing on the link between the serum concentrations of uric acid and indexes for endogenous synthesis/intestinal absorption of cholesterol in individuals at high CMR (with present one or two components of MetS). Furthermore, the results of this study support the importance of intervention for hyperuricemia in individuals with high CV risk. Limits of the study include relatively low number of probands of the Czech population, hsCRP as the only marker of inflammation, and the absence of dietary data. Data about physical activity were not available, as well. Moreover, group of women included both pre- and postmenopausal individuals. It is also not known which mechanisms provide background for the described associations.

Conclusions

The results of this study show that the concentration of uric acid in individuals at high CMR (with one or two present components of MetS) is associated with the indices of de novo cholesterol biosynthesis. This association is probably influenced by interaction of arterial hypertension and apoB levels with cholesterol homeostasis.

Footnotes

Acknowledgment

Conducting of statistical analyses by Barbora Pejchalova is greatly acknowledged.

Author Disclosure Statement

No conflicting financial interests exist.

Funding Information

This study was supported by the projects PROGRES Q25/LF1 UK (MŠMT ČR) and RVO VFN64165/2012 (MZ ČR).

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