Seiko Otokozawa

Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans

Studies in animals have documented that, compared with glucose, dietary fructose induces dyslipidemia and insulin resistance. To assess the relative effects of these dietary sugars during sustained consumption in humans, overweight and obese subjects consumed glucose- or fructose-sweetened beverages providing 25% of energy requirements for 10 weeks. Although both groups exhibited similar weight gain during the intervention, visceral adipose volume was significantly increased only in subjects consuming fructose. Fasting plasma triglyceride concentrations increased by approximately 10% during 10 weeks of glucose consumption but not after fructose consumption. In contrast, hepatic de novo lipogenesis (DNL) and the 23-hour postprandial triglyceride AUC were increased specifically during fructose consumption. Similarly, markers of altered lipid metabolism and lipoprotein remodeling, including fasting apoB, LDL, small dense LDL, oxidized LDL, and postprandial concentrations of remnant-like particle-triglyceride and -cholesterol significantly increased during fructose but not glucose consumption. In addition, fasting plasma glucose and insulin levels increased and insulin sensitivity decreased in subjects consuming fructose but not in those consuming glucose. These data suggest that dietary fructose specifically increases DNL, promotes dyslipidemia, decreases insulin sensitivity, and increases visceral adiposity in overweight/obese adults.

Extended-Release Niacin Alters the Metabolism of Plasma Apolipoprotein (Apo) A-I and ApoB-Containing Lipoproteins

Objectives—Extended-release niacin effectively lowers plasma TG levels and raises plasma high-density lipoprotein (HDL) cholesterol levels, but the mechanisms responsible for these effects are unclear. Methods and Results—We examined the effects of extended-release niacin (2 g/d) and extended-release niacin (2 g/d) plus lovastatin (40 mg/d), relative to placebo, on the kinetics of apolipoprotein (apo) A-I and apoA-II in HDL, apoB-100 in TG-rich lipoproteins (TRL), intermediate-density lipoproteins (IDL) and low-density lipoproteins (LDL), and apoB-48 in TRL in 5 men with combined hyperlipidemia. Niacin significantly increased HDL cholesterol and apoA-I concentrations, associated with a significant increase in apoA-I production rate (PR) and no change in fractional catabolic rate (FCR). Plasma TRL apoB-100 levels were significantly lowered by niacin, accompanied by a trend toward an increase in FCR and no change in PR. Niacin treatment significantly increased TRL apoB-48 FCR but had no effect on apoB-48 PR. No effects of niacin on concentrations or kinetic parameters of IDL and LDL apoB-100 and HDL apoA-II were noted. The addition of lovastatin to niacin promoted a lowering in LDL apoB-100 attributable to increased LDL apoB-100 FCR. Conclusion—Niacin treatment was associated with significant increases in HDL apoA-I concentrations and production, as well as enhanced clearance of TRL apoB-100 and apoB-48.

Small Dense LDL Cholesterol and Coronary Heart Disease: Results from the Framingham Offspring Study

OBJECTIVE We sought to establish reference values for a new direct assay for small dense LDL cholesterol (sdLDL-C) and to measure sdLDL-C concentrations in patients with established coronary heart disease (CHD) vs controls. METHODS Direct LDL-C and sdLDL-C were measured in samples from 3188 male and female participants of the Framingham Offspring Study, including 173 men and 74 women with CHD. RESULTS Postmenopausal status and male sex were associated with higher sdLDL-C concentrations (P < 0.0001). Cholesterol-lowering medication use was more frequent (P < 0.0001) in CHD patients than in controls (46.8% vs 11.4% in men; 35.1% vs 8.8% in women). In men, mean LDL-C was lower in CHD than in controls (3.22 vs 3.51 mmol/L, P < 0.0001), whereas mean sdLDL-C concentrations were similar (0.83 vs 0.84 mmol/L, P = 0.609). In women, mean LDL-C was similar in CHD and controls (3.53 vs 3.46 mmol/L, P = 0.543), but mean sdLDL-C was higher (0.83 vs 0.68 mmol/L, P = 0.0015). The mean percentage of LDL-C as sdLDL-C was higher in both men and women with CHD than controls (P < 0.01). Increased LDL-C and sdLDL-C were found in 10.4% and 22.0% of men and in 24.3% and 27.8% of women with CHD, respectively. CONCLUSIONS Despite 4-fold greater cholesterol-lowering therapy use, CHD patients had mean LDL-C concentrations above the LDL-C goal of <2.6 mmol/L (<100 mg/dL). Although women with CHD had higher sdLDL-C concentrations than controls, this difference was not seen in men. These findings may explain some of the high residual risk of future CHD events in CHD patients.

Adiponectin: An independent risk factor for coronary heart disease in men in the Framingham offspring Study

OBJECTIVE Our aim was to determine whether plasma adiponectin levels were an independent predictor of coronary heart disease (CHD) risk. METHODS AND RESULTS Plasma adiponectin levels were measured in 3188 male and female participants from cycle 6 of the Framingham offspring Study (mean age: 57 years in both men and women; BMI: 28.5 kg/m(2) in men and 27.3 kg/m(2) in women), using a novel fully automated assay. Plasma adiponectin levels (median [25th percentile, 75th percentile]) were significantly higher in female than in male CHD-free subjects (14.8 [10.7,20.5] μg/ml versus 9.0 [7.0,12.2] μg/ml, p<0.001). Participants were followed for a mean of 7.5 years. After adjustment for age, BMI, smoking status, systolic blood pressure, treatment for hypertension, diabetes, use of cholesterol-lowering medication, total cholesterol level, high-density lipoprotein cholesterol level, and C-reactive protein levels, a higher plasma adiponectin level was a significant predictor of lower risk of future CHD events (n=117) in men (HR 0.49, p<0.0022). A similar trend was observed in women, but was no longer significant after multivariate adjustments. CONCLUSIONS Our data indicate that plasma adiponectin levels are an independent predictor of CHD in Caucasian men initially free of CHD.

Effects of Maximal Atorvastatin and Rosuvastatin Treatment on Markers of Glucose Homeostasis and Inflammation

Studies have reported an increased risk of developing diabetes in subjects receiving statins versus placebo. Our purpose was to compare the effects of maximum doses of rosuvastatin and atorvastatin on the plasma levels of the insulin, glycated albumin, adiponectin, and C-reactive protein compared to baseline in hyperlipidemic patients. We studied 252 hyperlipidemic men and women who had been randomized to receive atorvastatin 80 mg/day or rosuvastatin 40 mg/day during a 6-week period. Atorvastatin and rosuvastatin were both highly effective in lowering the low-density lipoprotein cholesterol and triglyceride levels, with rosuvastatin more effective than atorvastatin in increasing high-density lipoprotein cholesterol. Atorvastatin and rosuvastatin at the maximum dosage both significantly (p <0.05) increased the median insulin levels by 5.2% and 8.7%, respectively, from baseline. However, only atorvastatin increased the glycated albumin levels from baseline (+0.8% for atorvastatin vs -0.7% for rosuvastatin, p = 0.002). Both atorvastatin and rosuvastatin caused significant (p <0.001) and similar median reductions in the C-reactive protein level of -40% and -26% compared to the baseline values. However, no statistically significant difference was found between the 2 groups in the adiponectin changes from baseline (-1.5% vs -4.9%, p = 0.15). In conclusion, our data have indicated that the maximum dosage of atorvastatin or rosuvastatin therapy significantly lower C-reactive protein levels but also moderately increase insulin levels.

Effects of Maximal Doses of Atorvastatin Versus Rosuvastatin on Small Dense Low-Density Lipoprotein Cholesterol Levels

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipoprotein (HDL) and its subclasses. Our purpose in this post hoc subanalysis of an open-label study was to compare the effects of daily oral doses of rosuvastatin 40 mg with atorvastatin 80 mg over a 6-week period on direct LDL cholesterol and small dense LDL (sdLDL) cholesterol in 271 hyperlipidemic men and women versus baseline values. Rosuvastatin was significantly (p<0.01) more effective than atorvastatin in decreasing sdLDL cholesterol (-53% vs -46%), direct LDL cholesterol (-52% vs -50%), total cholesterol/HDL cholesterol ratio (-46% vs -39%), and non-HDL cholesterol (-51% vs -48%), The magnitude of these differences was modest, and the 2 statins caused similar decreases in triglyceride levels (-24% and -26%). In conclusion, our data indicate that the 2 statins, given at their maximal doses, significantly and beneficially alter the entire spectrum of lipoprotein particles, but that rosuvastatin is significantly more effective than atorvastatin in lowering direct LDL cholesterol and sdLDL cholesterol.

Plasma glycated albumin level and atherosclerosis: Results from the Kyushu and Okinawa Population Study (KOPS)

BACKGROUND Glycated albumin (GA) is a measure of the mean plasma glucose concentration over approximately 2-3 weeks. This study was done to test the hypothesis that GA can serve as a marker for atherosclerosis, similar to glycosylated hemoglobin A1c (HbA1c). METHODS HbA1c, plasma GA and serum high-sensitivity C-reactive protein (hs-CRP) levels were measured for 1575 residents (age range 26-78 years) of a suburban town in Japan. Carotid artery intima-media thickness (IMT) was measured by ultrasound for each participant. RESULTS GA levels had significantly positive correlation coefficients with HbA1c level, hs-CRP level, and max-IMT (all P<0.001). Receiver operating characteristic curve analysis indicated a GA level of ≥ 15.5% to be optimal for predicting diabetes. A GA level of 15.5% corresponded to an HbA1c level of 5.8%. The hs-CRP and max-IMT values of participants with GA ≥ 15.5% were significantly higher than the values of those with GA <15.5% (median hs-CRP: 2.4 vs. 2.3mg/L, P=0.048; mean max-IMT 0.852 vs. 0.759 mm, P=0.003, respectively). Among obese participants, the hs-CRP and max-IMT values of those with GA ≥ 15.5% (7.5mg/L and 1.014 mm) were significantly higher than the values of those with GA <15.5% (4.7 mg/dL and 0.823 mm) (P=0.024 and P=0.001, respectively). CONCLUSIONS Increased IMT and hs-CRP levels were associated with a high GA level, especially for obese participants, suggesting that GA would be as a useful biomarker for assessing the risk of atherosclerosis.

Fasting and postprandial apolipoprotein B-48 levels in healthy, obese, and hyperlipidemic subjects

Apolipoprotein (apo) B-48 is the only specific marker of intestinal lipoproteins. We evaluated a novel enzyme-linked immunosorbent assay (ELISA) standardized with recombinant apo B-48 to measure apo B-48 in plasma and triglyceride-rich lipoproteins (TRLs, density <1.006 g/mL). Coefficients of variation were less than 2.5%. Assay values correlated well (r = 0.82, P < .001) with values obtained by gel scanning of TRLs (n = 75 samples); however, the gel scanning method yielded values that were about 50% lower than ELISA values. About 60% to 70% of apo B-48 was found in TRLs. In 12 healthy subjects, median fasting plasma apo B-48 levels were 0.51 mg/dL and were increased by 121% to 147% in the fed state. In 63 obese subjects, median fasting apo B-48 values were 0.82 mg/dL; and feeding resulted in almost no change in total cholesterol, non-high-density lipoprotein cholesterol, or total apo B values, whereas triglyceride, remnant lipoprotein cholesterol, and apo B-48 levels were significantly higher (P < .05; by +73%, +58%, and +106%), and direct low-density lipoprotein cholesterol and direct high-density lipoprotein cholesterol were significantly lower (P < .001, by -13% and -20%) than fasting values. Relative to controls, 270 hyperlipidemic subjects had significantly higher (P < .001, +115%) fasting total apo B and higher apo B-48 values (P = .06, +37%). Our data indicate that the apo B-48 ELISA tested provides highly reproducible results and is excellent for research studies. Median apo B-48 values in healthy subjects are about 0.5 mg/dL and increase more than 100% in the fed state. Elevated levels are observed in obese and hyperlipidemic subjects.

Familial Combined Hyperlipidemia Is Associated With Alterations in the Cholesterol Synthesis Pathway

OBJECTIVE Familial combined hyperlipidemia (FCH) is a common familial lipid disorder characterized by increases in plasma total cholesterol, triglyceride, and apolipoprotein B-100 levels. In light of prior metabolic and genetic research, our purpose was to ascertain whether FCH cases had significant abnormalities of plasma markers of cholesterol synthesis and absorption as compared to unaffected kindred members. METHODS AND RESULTS Plasma levels of squalene, desmosterol, and lathosterol (cholesterol synthesis markers) and campesterol, sitosterol, and cholestanol (cholesterol absorption markers) were measured by gas-liquid chromatography in 103 FCH patients and 240 normolipidemic relatives (NLR). Squalene, desmosterol, and lathosterol levels were 6% (0.078), 31%, (P<0.001) and 51% (P<0.001) higher in FCH as compared to NLR, and these differences were especially pronounced in women. An interaction with obesity was also noted for a subset of these markers. We did not observe any apparent differences for the cholesterol absorption markers among FCH patients and NLR. CONCLUSIONS Our data indicate that both men and women with FCH have alterations in the cholesterol synthesis pathway, resulting in 51% higher levels of lathosterol (and additionally desmosterol in women). Plasma levels of the cholesterol precursor sterol squalene were only slightly increased (6%), suggesting enhanced conversion of squalene to lathosterol in this disorder.

Association of angiopoietin-like protein 3 with hepatic triglyceride lipase and lipoprotein lipase activities in human plasma

Background The relationship between plasma angiopoietin-like protein 3 (ANGPTL3), and lipoprotein lipase (LPL) activity and hepatic triglyceride lipase (HTGL) activity has not been investigated in the metabolism of remnant lipoproteins (RLPs) and high-density lipoprotein (HDL) in human plasma. Methods ANGPTL3, LPL activity, HTGL activity, RLP-C and RLP-TG and small, dense LDL-cholesterol (sd LDL-C) were measured in 20 overweight and obese subjects in the fasting and postprandial states. Results Plasma TG, RLP-C, RLP-TG and sd LDL-C were inversely correlated with LPL activity both in the fasting and postprandial states, but not correlated with HTGL activity and ANGPTL3. However, plasma HDL-C was positively correlated with LPL activity both in the fasting and postprandial states, while inversely correlated with HTGL activity. ANGPTL3 was inversely correlated with HTGL activity both in the fasting and postprandial states, but not correlated with LPL activity. Conclusion HTGL plays a major role in HDL metabolism, but not RLP metabolism. These findings suggest that ANGPTL3 is strongly associated with the inhibition of HTGL activity and regulates HDL metabolism, but not associated with the inhibition of LPL activity for the metabolism of RLPs in human plasma.