Maarit Hallikainen

Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with impaired glucose and lipoprotein metabolism. However, the metabolism of cholesterol in NAFLD remains unexplored. We investigated how fatty liver influences cholesterol metabolism in 242 non-diabetic subjects. METHODS Liver fat content was measured with proton magnetic resonance spectroscopy. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of cholesterol synthesis and absorption. The analyses were performed with gas-liquid chromatography. RESULTS A total of 114 subjects had NAFLD and 128 subjects had normal liver fat content. Non-cholesterol sterols reflecting cholesterol synthesis (cholestenol, desmosterol, and lathosterol) were higher, and those reflecting cholesterol absorption (cholestanol and plant sterols) were lower in subjects with NAFLD than in controls, independent of body mass index. Liver fat content was positively associated with markers of cholesterol synthesis (r = from 0.262 to 0.344, p < 0.001 for all) and inversely associated with markers of cholesterol absorption (r = from -0.299 to -0.336, p < 0.001 for all). In the entire study group, synthesis and absorption markers were interrelated, indicating that the homeostasis of cholesterol metabolism was maintained. LDL cholesterol was similar in the two groups. CONCLUSIONS We demonstrated that although LDL cholesterol concentrations are unchanged, cholesterol metabolism in NAFLD is characterized by increased synthesis and diminished absorption of cholesterol. These changes are associated with liver fat content independent of body weight.

Effect of ezetimibe and/or simvastatin on coenzyme Q10 levels in plasma: a randomised trial.

AbstractBackground: HMG-CoA reductase inhibitors (‘statins’) have been associated with a decrease in ubidecarenone (ubiquinone) levels, a lipophilic enzyme also known as coenzyme Q10 (CoQ10), due to inhibition of mevalonate synthesis. There is speculation that a decrease in CoQ10 levels may be associated with statin-induced myopathy. The cholesterol absorption inhibitor ezetimibe increases endogenous cholesterol synthesis. The purpose of this study was to examine (i) the effects of ezetimibe and simvastatin on plasma CoQ10 levels and (ii) whether ezetimibe coadministered with simvastatin abrogates the suggested statin-induced decrease in the CoQ10 plasma levels. Methods: Seventy-two healthy male subjects were enrolled in a single-centre, randomised, parallel-group study with three arms. Subjects received ezetimibe 10 mg/day, simvastatin 40 mg/day or the combination of ezetimibe 10 mg/day plus simvastatin 40 mg/day for 14 days. Results: Baseline CoQ10 (0.99 ± 0.30 mg/L) levels for the combined groups remained unchanged in the ezetimibe group (0.95 ± 0.24 mg/L), and significantly decreased in the simvastatin and combination groups (0.82 ± 0.18 mg/L, p = 0.0002 and 0.7 ± 0.22 mg/L, p < 0.0001, respectively). There was a correlation between the percentage change in the levels of low-density lipoprotein-cholesterol (LDL-C) and the percentage change in CoQ10 levels in all treatment groups (correlation coefficient [R] = 0.67, p < 0.0001). The ratios of CoQ10 levels to LDL-C levels were significantly increased in all treatment groups (p < 0.0001). CoQ10 level was independent of cholesterol synthesis or absorption markers. Conclusions: Simvastatin and the combination of simvastatin and ezetimibe significantly decrease plasma CoQ10 levels whereas ezetimibe monotherapy does not. There is a significant correlation between the CoQ10 level decrease and the decrease in total and LDL-C levels in all three treatment groups, suggesting that the CoQ10 decrease may reflect the decrease in the levels of its lipoprotein carriers and might not be statin-specific. The statin-associated CoQ10 reduction is not abrogated through ezetimibe coadministration. Changes of CoQ10 levels are independent of cholesterol synthesis and absorption.

The effect of a very high daily plant stanol ester intake on serum lipids, carotenoids, and fat-soluble vitamins

BACKGROUND & AIMS Intake of 2-3 g/d of plant stanols as esters lowers LDL cholesterol level, but there is no information about the efficacy and safety of a respective very high daily intake. We studied the effects of 8.8 g/d of plant stanols as esters on serum lipids and safety variables in subjects with mild to moderate hypercholesterolemia. METHODS In a randomized, double-blind, placebo-controlled study the intervention (n=25) and control (n=24) groups consumed spread and drink enriched or not with plant stanol esters for 10 weeks. RESULTS Plant stanols reduced serum total and LDL cholesterol concentrations by 12.8 and 17.3% from baseline and by 12.0 and 17.1% from controls (P<0.01 for all). Liver enzymes, markers of hemolysis, and blood cells were unchanged. Serum vitamins A, D, and gamma-tocopherol concentrations, and the ratios of alpha-tocopherol to cholesterol were unchanged. Serum beta-carotene concentrations decreased significantly from baseline and were different from controls even when adjusted for cholesterol. Serum alpha-carotene concentration and alpha-carotene/cholesterol ratio were not different from controls. CONCLUSIONS High intake of plant stanols reduced LDL cholesterol values without any other side effects than reduction of serum beta-carotene concentration. However, the end product, serum vitamin A levels, were unchanged. The results suggest that plant stanol ester intake can be increased to induce a greater cholesterol lowering effect.

Insulin sensitivity regulates cholesterol metabolism to a greater extent than obesity: lessons from the METSIM Study

Cholesterol synthesis is upregulated and absorption downregulated in insulin resistance and in type 2 dia-betes. We investigated whether alterations in cholesterol metabolism are observed across the glucose tolerance status, from normoglycemia through impaired glucose tolerance to type 2 diabetes, in 781 randomly selected men 45 to 70 years of age from a population-based Metabolic Syndrome in Men Study. Cholesterol metabolism was assayed using surrogate serum markers, squalene, and noncholesterol sterols. The study population was classified into subgroups according to glucose tolerance as follows: normoglycemia, impaired fasting glucose, impaired glucose tolerance, and type 2 diabetes. LDL cholesterol did not differ between the groups. Cholesterol synthesis markers were lowest and absorption markers highest in normoglycemia. Sitosterol was lower in subjects with impaired fasting glucose compared with normoglycemic subjects (113 ± 7 vs. 136 ± 3 102 μmol/mmol of cholesterol, P < 0.05). LDL cholesterol was not associated with lathosterol/sitosterol ratio, a marker of cholesterol metabolism. Peripheral insulin sensitivity evaluated by the Matsuda index was associated with the lathosterol/sitosterol ratio in the entire population (r = −0.457, P < 0.001) and with that of lathosterol/cholestanol independently of obesity. In conclusion, cholesterol metabolism was altered already from subjects with impaired fasting glucose. Upregulated cholesterol synthesis was associated with peripheral insulin resistance independent of obesity.

Long-term consumption of plant stanol and sterol esters, vascular function and genetic regulation.

Polymorphisms of the ABCG5 and ABCG8 genes interfere with cholesterol absorption and synthesis. We determined whether common polymorphisms of these genes regulate the responses of serum cholesterol and vascular function during long-term inhibition of cholesterol absorption. Mildly to moderately hypercholesterolaemic subjects (n 282) completed a 1-year study consuming plant stanol or sterol ester (2 g stanol or sterol) or control spread. Serum cholesterol and non-cholesterol sterols, markers of cholesterol absorption and synthesis, and variables of vascular function and structure were analysed in relation to common polymorphisms of ABCG5 and ABCG8. At baseline, subjects with the 54K allele of ABCG8 had higher brachial endothelial-dependent flow-mediated dilatation than those without it (5.79 (se 0.31) v. 4.46 (se 0.44) %; P = 0.049), and subjects with the 632V allele of ABCG8 had larger brachial artery diameter than those without it. Polymorphisms of ABCG5 and ABCG8 were neither associated with serum cholesterol reduction nor changes in cholesterol metabolism or in vascular function. However, in subjects with the 400K allele of ABCG8, intima media thickness (IMT) was increased in all groups more than in those without it (P < 0.05). In conclusion, serum cholesterol lowering with absorption inhibition was not associated with polymorphic sites of ABCG5 and ABCG8. However, regulation of baseline cholesterol metabolism and vascular function and structure, and IMT progression during 1 year seemed to share some of the common polymorphic sites of these genes, suggesting a gene-regulated interaction between cholesterol metabolism and vascular function and structure.

The metabolism of plant sterols is disturbed in postmenopausal women with coronary artery disease.

In postmenopausal coronary artery disease (CAD) women, serum plant sterols are elevated. Thus, we investigated further whether serum plant sterols reflect absolute cholesterol metabolism in CAD as in other populations and whether the ABCG5 and ABCG8 genes, associated with plant sterol metabolism, were related to the risk of CAD. In free-living postmenopausal women with (n = 47) and without (n = 62) CAD, serum noncholesterol sterols including plant sterols were analyzed with gas-liquid chromatography, cholesterol absorption with peroral isotopes, absolute cholesterol synthesis with sterol balance technique, and bile acid synthesis with quantitating fecal bile acids. In CAD women, serum plant sterol ratios to cholesterol were 21% to 26% (P < .05) higher than in controls despite similar cholesterol absorption efficiency. Absolute cholesterol and bile acid synthesis were reduced. Only in controls were serum plant sterols related to cholesterol absorption (eg, sitosterol; in controls: r = 0.533, P < .001; in CAD: r = 0.296, P = not significant). However, even in CAD women, serum lathosterol (relative synthesis marker) and lathosterol-cholestanol (relative synthesis-absorption marker) were related to absolute synthesis and absorption percentage (P range from .05 to <.001) similarly to controls. Frequencies of the common polymorphisms of ABCG5 and ABCG8 genes did not differ between coronary and control women. In conclusion, plant sterol metabolism is disturbed in CAD women; so serum plant sterols only tended to reflect absolute cholesterol absorption. Other relative markers of cholesterol metabolism were related to the absolute ones in both groups. ABCG5 and ABCG8 genes were not associated with the risk of CAD.

Markers of absorption and synthesis of cholesterol in men with type 1 diabetes

Serum cholestanol and plant sterol ratios to cholesterol, surrogate markers of cholesterol absorption, are assumed to be high in type 1 diabetes (T1D), and the ratios of cholesterol precursor sterols (markers of synthesis) are assumed to be low reflecting downregulated cholesterol synthesis. To this end, we measured serum sterols with gas‐liquid‐chromatography in 56 men with T1D and in 18 controls to evaluate cholesterol metabolism. Subjects were categorised into tertiles by the cholestanol to cholesterol ratio of controls indicating low to high absorption of cholesterol.

Adolescent cholesterol metabolism predicts coronary risk factors at middle age: the Cardiovascular Risk in Young Finns Study

Atherosclerosis develops at an early age. We studied whether cholesterol metabolism in adolescence is related to coronary risk factors later during the adult years. A random population sample of 12-year-old (n=162), 15-year-old (n=158), and 18-year-old (n=148) boys who participated in the Cardiovascular Risk in Young Finns Study was studied for major coronary risk factors in 1980 and 2001. These values were related to noncholesterol sterols and their quartiles in 1980 (ie, markers of cholesterol absorption and synthesis). In 1980, serum triglycerides, body mass index (BMI), and systolic blood pressure were lower and high-density lipoprotein (HDL) cholesterol was higher in high absorbers versus low absorbers. This difference, except HDL cholesterol, was maintained after follow-up (eg, in 2001, systolic blood pressure was 123+/-1 mm Hg in low absorbers vs 119+/-1 mm Hg in high absorbers, P<0.01). Cholesterol synthesis (r = up to 0.470, P<0.001) and absorption (r = down to -0.347, P<0.001) were related to BMI at baseline and after follow-up. Significant associations were also found between cholesterol metabolism and serum triglycerides, blood pressure, and HDL cholesterol after follow-up. Cholesterol absorption was related to LDL cholesterol only in low absorbers (r=0.251, P<0.01). In conclusion, synthesis and absorption of cholesterol measured with serum noncholesterol sterols in adolescence were related to coronary risk factors later in adult life. High synthesis and low absorption of cholesterol are related to risk factors that determine the characteristics of the metabolic syndrome.

Relation of non-cholesterol sterols to coronary risk factors and carotid intima-media thickness: The Cardiovascular Risk in Young Finns Study

OBJECTIVES The aim of the present study was to evaluate the role of cholesterol metabolism in the development of atheromatous artery disease. METHODS Serum synthesis (cholesterol precursors) and absorption markers (cholestanol, campesterol, sitosterol, and avenasterol) were related to coronary risk factors and vascular structure in a population-based sample of 468 randomly selected 33-39-year-old men on their regular habitual diet. Carotid artery intima-media thickness (IMT) and serum lipids (including cholesterol) and sterols were measured in 2001, and the subjects were ranked to decreasing cholesterol synthesis depicted by serum cholestanol quartiles defined 21 years earlier in adolescence. RESULTS Serum cholesterol was correlated with absorption (e.g. serum campesterol, p<0.05), but not with synthesis, or with cholestanol quartiles. Cholesterol metabolism (synthesis/absorption markers) decreased linearly (about 50%) with the increasing cholestanol quartiles. IMT differed between the age groups, but not between cholestanol quartiles. Serum triglycerides, apoprotein B, and body mass index decreased, and non-HDL cholesterol/apoprotein B values increased between the cholestanol quartiles, whereas LDL cholesterol was unchanged. Cholesterol synthesis markers were related to blood pressure and serum triglycerides, and negatively to HDL cholesterol level in total population and in most of the cholestanol quartiles (p from 0.05 to 0.001). CONCLUSIONS Variables of metabolic syndrome accumulated in quartiles of high synthesis of cholesterol. Non-cholesterol sterols were related to many classic coronary risk factors, but virtually not to serum cholesterol or vascular structure.

Twenty-one year tracking of serum non-cholesterol sterols. The Cardiovascular Risk in Young Finns study

BACKGROUND AND AIM To show tracking of cholesterol metabolism, the ratios to cholesterol of e.g. serum cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis, and cholestanol, campesterol, avenasterol and sitosterol, reflecting cholesterol absorption, were measured 21 years apart. METHODS AND RESULTS In random population samples initially comprising 12- (n=162), 15- (n=158), and 18-year-old (n=148) males participating in the Cardiovascular Risk in Young Finns Study, serum sterols and squalene were measured with gas-liquid chromatography in 1980 and 2001. Quartiles of cholestanol, indicating low to high cholesterol absorption, were defined from the cholestanol values in 1980. Serum cholesterol increased in the oldest age group only, but synthesis markers (except desmosterol) increased in all age groups after the follow-up (e.g. lathosterol, total population +47.3+/-2.6% (SE), P<0.001). Campesterol (+69.0+/-3.0%, P<0.001) and sitosterol increased, avenasterol was unchanged, and cholestanol decreased (-6.2+/-0.7%, P<0.001), respectively. The 1980 synthesis and absorption markers were interrelated with respective values 21 years later in all age groups and quartiles (e.g. lathosterol, total population 1980 vs. 2001 r=0.460, cholestanol 1980 vs. 2001 r=0.593, P<0.001 for both). Synthesis markers were highest in the first and lowest in the fourth quartile both in 1980 and 2001 (e.g. 2001, desmosterol, quartile 1, 99+/-9, quartile 4, 83+/-2 microg/mg of cholesterol, P<0.05). CONCLUSIONS Cholesterol metabolism is significantly tracked in adolescent males over the follow-up of 21 years. Thus, high cholesterol synthesis and low absorption characterize subjects with the lowest cholestanol quartile, while those with the highest quartile have low synthesis and high absorption in both adolescence and later in young adult life.