Atherogenic Lipoprotein Abnormalities Research Articles

Relationship of fibroblast growth factor 21 levels with inflammation, lipoproteins and non-alcoholic fatty liver disease

Background and aimsNon-alcoholic fatty liver disease (NAFLD) is associated with inflammation and atherogenic lipoprotein abnormalities. Previous studies suggest an association of fibroblast growth factor 21 (FGF21) with NAFLD. Therefore, we assessed the association of circulating FGF21 levels with inflammatory markers, lipoprotein profile and NAFLD in the Multi-Ethnic Study of Atherosclerosis (MESA). MethodsAmong 6814 participants free of apparent cardiovascular disease at baseline (2000–2002), 3634 participants had valid data on variables of interest. After excluding participants with excessive alcohol consumption, 3446 participants were included in the analysis. NAFLD was defined using non-contrast cardiac computed tomography with a liver-to-spleen ratio (LSR) < 1 or liver attenuation <40 Hounsfield units (HU). ResultsThe mean age of the participants was 63.5 years with 54% females, 36% Caucasian, 10% Chinese American, 31% African American and 23% Hispanic. 17% of the participants had NAFLD. After adjustment for demographic, socioeconomic and other confounders, a 1-SD increment in ln-transformed FGF21 level was associated with a 5.1% higher IL-6 level, a 0.31 nm larger very-low-density lipoprotein particle diameter, a 0.014 nm smaller high-density lipoprotein particle diameter, and a 5.25 nmol/L lower intermediate-density lipoprotein particle concentration (all p < 0.05). A 1-SD increment in ln-transformed FGF21 level was associated with LSR<1 and liver attenuation <40 HU (OR = 1.38 and 1.48; both p < 0.01), even after adjusting for the aforementioned inflammation and lipoprotein parameters. ConclusionsThis study suggests an association between FGF21 and NAFLD, independent of inflammation and atherogenic lipoprotein abnormalities. Further studies are needed to assess FGF21 as a biomarker for future NAFLD risk.

Relationship of pericardial fat with lipoprotein distribution: The Multi-Ethnic study of atherosclerosis.

Pericardial fat and lipoprotein abnormalities contribute to increased risk of cardiovascular disease (CVD). We investigated the relationship between pericardial fat volume and lipoprotein distribution, and whether the association of pericardial fat volume with subclinical atherosclerosis and incident CVD events differs according to lipoprotein distribution. We analyzed data from 5407 participants from the Multi-Ethnic Study of Atherosclerosis who had measurements of pericardial fat volume, lipoprotein distribution, carotid intima-media thickness (IMT), and coronary artery calcium (CAC). All participants were free of clinically apparent CVD at baseline. Incident CVD was defined as any adjudicated CVD event. After adjusting for demographic factors, traditional risk factors, and biomarkers of inflammation and hemostasis, a larger pericardial fat volume was associated with higher large VLDL particle (VLDL-P) concentration and small HDL particle (HDL-P) concentration, and smaller HDL-P size (regression coefficients=0.585nmol/L, 0.366μmol/L, and-0.025nm per SD increase in pericardial fat volume respectively, all P<0.05). The association of pericardial fat volume with large VLDL-P concentration and HDL-P size, but not small HDL-P concentration, remained significant after further adjusting for each other as well as LDL cholesterol, HDL cholesterol, and triglycerides. The relationship of pericardial fat volume with incident CVD events, carotid IMT, and prevalence and severity of CAC did not differ by quartiles of large VLDL-P concentration, small HDL-P concentration, or HDL-P size (P for interaction>0.05). Pericardial fat is associated with atherogenic lipoprotein abnormalities. However, its relationship with subclinical atherosclerosis and incident CVD events does not differ according to lipoprotein distribution.

Increased large VLDL and small LDL particles are related to lower bilirubin in Type 2 diabetes mellitus

ObjectivesBilirubin may protect against atherosclerotic cardiovascular disease by virtue of its anti-oxidative properties, but lower bilirubin may also be associated to atherogenic lipoprotein abnormalities. We determined associations of plasma (apo)lipoproteins and lipoprotein subfractions in subjects with and without type 2 diabetes mellitus (T2DM). Design and methodsPlasma (apo)lipoproteins, lipoprotein subfractions (nuclear magnetic resonance spectroscopy) and serum total bilirubin levels were determined in 53 T2DM patients and in 53 non-diabetic subjects. ResultsTriglycerides, large VLDL, small LDL and small HDL particles were increased (all p<0.05), whereas HDL cholesterol, apoA-I and large HDL particles were decreased (all p<0.05), coinciding lower bilirubin levels in T2DM (p<0.001). In age- and sex-adjusted analysis, total cholesterol, non-HDL cholesterol, triglycerides, apoB, apoE, large VLDL and small LDL were negatively correlated with bilirubin, but HDL cholesterol was positively correlated with bilirubin in T2DM (p<0.05 to p<0.001). Multivariable linear regression analyses demonstrated that in all subjects combined total cholesterol, non-HDL cholesterol, triglycerides and apoE were negatively associated with bilirubin after adjustment for age, sex, T2DM, body mass index and alanine aminotransferase (all p<0.05). Further multivariable linear regression analysis showed that large VLDL and small LDL particles were negatively associated with bilirubin, whereas large HDL particles were associated positively with bilirubin (p<0.05). ConclusionsIncreased triglycerides, as well as large VLDL and small LDL particles are associated negatively, whereas HDL cholesterol is associated positively with bilirubin in T2DM. The proposed pro-atherogenic effects of low bilirubin could in part be attributed to relationships with abnormalities in (apo)lipoproteins and lipoprotein subfraction characteristics.

HIV/hepatitis C virus coinfection ameliorates the atherogenic lipoprotein abnormalities of HIV infection

Higher levels of small low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) subclasses have been associated with increased risk of cardiovascular disease. The extent to which HIV infection and HIV/hepatitis C virus (HCV) coinfection are associated with abnormalities of lipoprotein subclasses is unknown. Lipoprotein subclasses were measured by nuclear magnetic resonance (NMR) spectroscopy in plasma samples from 569 HIV-infected and 5948 control participants in the Fat Redistribution and Metabolic Change in HIV Infection (FRAM), Coronary Artery Risk Development in Young Adults (CARDIA), and Multi-Ethnic Study of Atherosclerosis (MESA) studies. Multivariable regression was used to estimate the association of HIV and HIV/HCV coinfection with lipoprotein measures with adjustment for demographics, lifestyle factors, and waist-to-hip ratio. Relative to controls, small LDL levels were higher in HIV-monoinfected persons (+381 nmol/l, P <0.0001), with no increase seen in HIV/HCV coinfection (-16.6 nmol/l). Levels of large LDL levels were lower (-196 nmol/l, P <0.0001) and small HDL were higher (+8.2 μmol/l, P < 0.0001) in HIV monoinfection with intermediate values seen in HIV/HCV coinfection. Large HDL levels were higher in HIV/HCV-coinfected persons relative to controls (+1.70 μmol/l, P <0.0001), whereas little difference was seen in HIV-monoinfected persons (+0.33, P = 0.075). Within HIV-infected participants, HCV was associated independently with lower levels of small LDL (-329 nmol/l, P <0.0001) and small HDL (-4.6 μmol/l, P <0.0001), even after adjusting for demographic and traditional cardiovascular risk factors. HIV-monoinfected participants had worse levels of atherogenic LDL lipoprotein subclasses compared with controls. HIV/HCV coinfection attenuates these changes, perhaps by altering hepatic factors affecting lipoprotein production and/or metabolism. The effect of HIV/HCV coinfection on atherosclerosis and the clinical consequences of low small subclasses remain to be determined.

Nonalcoholic fatty liver disease and serum lipoproteins: The Multi-Ethnic Study of Atherosclerosis

ObjectiveWhile nonalcoholic fatty liver disease (NAFLD) is associated with the metabolic syndrome, it is not known if NAFLD plays an independent role in the atherogenic dyslipidemia phenotype. Methods and resultsThe Multi-Ethnic Study of Atherosclerosis (MESA) is a population-based prospective cohort study of adults free of clinical cardiovascular disease at enrollment. We tested for a relationship between NAFLD, defined as a liver/spleen (L/S) attenuation ratio of <1 on a non-contrast cardiac CT scan, and multiple measures of fasting serum lipoprotein size, cholesterol and particle concentrations.NAFLD was present in 569 (17%) of 3362 participants. After adjustment for multiple metabolic risk factors, adiposity and measures of insulin resistance (HOMA-IR), NAFLD was independently associated with higher fasting serum triglycerides and lower serum HDL-C. Despite a lack of association with LDL-C, NAFLD was associated with higher LDL particle concentration and lower LDL particle size. Modeling the L/S ratio as a continuous variable, a severity dependent association was observed between atherogenic lipoprotein abnormalities and NAFLD. ConclusionIn a large, multi-ethnic, gender balanced cohort, CT-diagnosed NAFLD was associated with the atherogenic dyslipidemia phenotype in a dose dependent fashion. These relationships persisted after adjustment for several metabolic risk factors and HOMA-IR, suggesting a possible independent pathophysiologic role between NAFLD and dyslipidemia.

Proprotein convertase subtilisin–kexin type 9 is elevated in proteinuric subjects: Relationship with lipoprotein response to antiproteinuric treatment

ObjectiveLDL-receptor deficiency may provide a mechanism which contributes to atherogenic lipoprotein abnormalities in experimental nephrosis and in humans with glomerular proteinuria. The proprotein convertase subtilisin–kexin type 9 (PCSK9) pathway plays a key role in lipoprotein metabolism by promoting LDL-receptor degradation. We tested whether plasma PCSK9 is elevated in proteinuric states, and determined relationships of PCSK9 with lipoprotein responses to proteinuria reduction. MethodsThirty-nine kidney patients (e-GFR 61 ± 29 mL/min/1.73 m2, proteinuria 1.9 [0.9–3.3] g/day; 19 on statin treatment) were studied during 2 randomized double-blind 6-week periods on either lisinopril (40 mg/day) and a regular sodium diet (194 ± 49 mmol Na+/day; baseline treatment) or lisinopril plus valsartan (320 mg/day) and a low sodium diet (102 ± 52 mmol Na+/day; maximal treatment), and compared to age- and sex-matched controls. Maximal treatment decreased proteinuria to 0.5 [0.3–1.1] g/day (P < 0.001). ResultsPlasma PCSK9 was increased at baseline in proteinuric subjects (213 [161–314] vs. 143 [113–190] ug/L in controls, P ≤ 0.001), irrespective of statin use, e-GFR and BMI. PCSK9 correlated with proteinuria at baseline (R = 0.399, P = 0.018) and at maximal antiproteinuric treatment (R = 0.525, P = 0.001), but did not decrease during proteinuria reduction (P = 0.84). Individual changes in total cholesterol (R = 0.365, P = 0.024), non-HDL cholesterol (R = 0.333, P = 0.041), and LDL cholesterol (R = 0.346, P = 0.033) were correlated positively with individual PCSK9 responses. PCSK9 at baseline independently predicted the total/HDL cholesterol ratio response to treatment (P = 0.04). ConclusionPlasma PCSK9 was elevated in proteinuria, predicted lipoprotein responses to proteinuria reduction but remained unchanged after proteinuria reduction. Inhibition of the PCSK9 pathway may provide a novel treatment strategy in proteinuric subjects.

Abstract 9515: NMR Spectroscopy Uncovers Important Atherogenic Lipoprotein Abnormalities in Nonalcoholic Fatty Liver Disease: The Insulin Resistance Atherosclerosis Study (IRAS).

Introduction: Nonalcoholic fatty liver disease may be the most frequent cause of chronically elevated transaminase levels in the general population. One of these inexpensive and routinely measured enzymes, alanine aminotransferase (ALT) is an independent predictor of future cardiovascular disease and diabetes. ALT has been associated with dyslipidemia, but the extent of this relationship is not well described. Hypothesis: Because to its advantage over conventional methods, we hypothesized that proton nuclear magnetic resonance (NMR) spectroscopy could be better for detecting atherogenic lipoprotein abnormalities in nonalcoholic fatty liver disease. Thus, we analyzed the relation of ALT to lipoproteins measured by NMR spectroscopy and conventional methods in non-diabetic participants in the IRAS. Methods: Cross-sectional analysis of lipoproteins and apolipoproteins in 912 non-diabetic participants in the IRAS. In fasting single fresh plasma samples, we measured plasma lipoproteins by conventional methods and NMR spectroscopy and apolipoprotein B (apo B) by immunoprecipitation. Insulin sensitivity was measured by the frequently sampled intravenous glucose tolerance test. Results: After adjusting for age, sex, race/ethnicity, and clinic, ALT was associated with triglycerides, LDL and HDL cholesterol, and apo B ( Table ). ALT had significant relationships with large VLDL, total LDL, IDL, small LDL, and large HDL particle concentrations plus VLDL, LDL, and HDL particle sizes. ALT remained associated with total LDL, IDL, and small LDL particle concentrations, LDL particle size, and apo B after the additional adjustment for waist circumference and insulin sensitivity. Conclusions: NMR spectroscopy uncovers a more extensive relationship between atherogenic lipoprotein abnormalities and ALT in non-diabetic individuals. These abnormalities could partially explain the relation of ALT to future cardiovascular disease.

NMR identifies atherogenic lipoprotein abnormalities in early diabetic nephropathy that are unrecognized by conventional analysis

Lipoprotein abnormalities are likely contributors to the high risk of cardiovascular disease in the chronic kidney disease (CKD) population, although information is limited. Specifically, little is known about lipoprotein abnormalities during the early stages of diabetic kidney disease. The aim of this study was to investigate the relationship between lipoproteins and early manifestations of CKD in the 517 Type 2 diabetes mellitus (T2DM) patients who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Lipoprotein abnormalities were measured by conventional lipid analysis, nuclear magnetic resonance (NMR) spectroscopy, gel gradient electrophoresis (GE), immunoprecipitation (IP), and ELISA. We grouped the cases into albumin to creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) quartiles. In the conventional lipid analysis, triglycerides (TG) correlated directly with ACR and inversely with eGFR quartiles (p = 0.01), while LDL, HDL cholesterol did not correlate with change in ACR or eGFR. ACR was directly associated with apoB, total VLDL, medium VLDL, IDL and small LDL particle concentrations (p < or = 0.03), and inversely with large LDL particles (p = 0.01) and LDL size (p = 0.008). Estimated GFR quartiles were inversely associated with total VLDL, small VLDL, IDL, and medium HDL particles (p < or = 0.01). In subjects with T2DM, mild albuminuria and reduction in eGFR were associated with numerous atherogenic lipoprotein abnormalities that were detected by the combination of NMR spectroscopy, gel gradient electrophoresis, immunoprecipitation and ELISA but not by the standard clinical lipid analysis.

168: NMR Identifies Atherogenic Lipoprotein Abnormalities in Early Diabetic Nephropathy That Are Unrecognized by Conventional Analysis

168: NMR Identifies Atherogenic Lipoprotein Abnormalities in Early Diabetic Nephropathy That Are Unrecognized by Conventional Analysis

Mild elevations of urine albumin excretion are associated with atherogenic lipoprotein abnormalities in the Multi-Ethnic Study of Atheroslcerosis (MESA)

Objective Elevated urine albumin excretion is an established risk factor for cardiovascular disease. Increased cardiovascular risk may be partly mediated by abnormalities in lipoprotein metabolism. We examined cross-sectional associations of urine albumin–creatinine ratio (ACR) with standard lipid measurements and with lipoprotein particle concentrations measured by nuclear magnetic resonance (NMR) in the Multi-Ethnic Study of Atheroslcerosis. Methods and results Among 5633 participants who were not using lipid-lowering medications, greater ACR was associated with greater triglyceride concentration and lesser high density lipoprotein cholesterol concentration (women only), but not with low density lipoprotein (LDL) cholesterol calculated using conventional methods. In contrast, unadjusted mean small LDL particle concentrations measured by NMR were 770, 827 and 935 nmol/L for women ( p < 0.001) and 996, 1030 and 1040 nmol/L for men ( p = 0.037) among participants with normal, high normal and elevated ACR. Adjusting for age, race/ethnicity, diabetes, impaired fasting glucose, hypertension, smoking, medications, body mass index and serum creatinine, each two-fold greater ACR was associated with an increase in small LDL particle concentration of 27 nmol/L for women ( p < 0.001) and 14 nmol/L for men ( p = 0.008). Greater ACR was also associated with greater intermediate density lipoprotein particle concentration and smaller mean LDL particle size. Conclusions Mild elevations of urine ACR are associated with atherogenic lipoprotein abnormalities that are not directly observed with a standard lipid panel.

Apolipoprotein E genotype is a determinant of low-density lipoprotein cholesterol and of its response to a low-cholesterol diet in Type 1 diabetic patients with elevated urinary albumin excretion.

The effect of the apolipoprotein (apo) E genotype on the lipoprotein response to a 1 year low cholesterol diet (200 mg cholesterol per day) was evaluated in 36 patients with Type 1 diabetes mellitus with albuminuria between 10 and 200 microg min(-1). Apo E genotype was characterized by polymerase chain reaction and restriction isotyping. In 11 IDDM patients with at least one epsilon4 allele (apo E4 group), baseline serum total and low density lipoprotein (LDL) cholesterol were higher (p < 0.05 for both) than in 25 patients without an epsilon4 allele and with at least one epsilon3 allele (apo E3 group). Dietary counselling resulted in a similar decrease in cholesterol intake in both groups, whereas linoleic acid did not change. In the apo E4 group, serum total and LDL cholesterol at follow-up fell (p < 0.01 for both) to levels that were not different from those in the apo E3 group, and the changes in these parameters were greater (p < 0.02) than those in the apo E3 group. We conclude that the apo E4 allele is associated with atherogenic lipoprotein abnormalities in Type 1 DM patients with minor elevations in albuminuria when they use their habitual diet. Apo E4 carrying patients respond better to a low cholesterol diet.

Apolipoprotein E genotype is a determinant of low‐density lipoprotein cholesterol and of its response to a low-cholesterol diet in Type 1 diabetic patients with elevated urinary albumin excretion

The effect of the apolipoprotein (apo) E genotype on the lipoprotein response to a 1 year low cholesterol diet (200 mg cholesterol per day) was evaluated in 36 patients with Type 1 diabetes mellitus with albuminuria between 10 and 200 μg min−1. Apo E genotype was characterized by polymerase chain reaction and restriction isotyping. In 11 Type 1 DM patients with at least one ϵ4 allele (apo E4 group), baseline serum total and low density lipoprotein (LDL) cholesterol were higher (p < 0.05 for both) than in 25 patients without an ϵ4 allele and with at least one ϵ3 allele (apo E3 group). Dietary counselling resulted in a similar decrease in cholesterol intake in both groups, whereas linoleic acid did not change. In the apo E4 group, serum total and LDL cholesterol at follow-up fell (p < 0.01 for both) to levels that were not different from those in the apo E3 group, and the changes in these parameters were greater (p < 0.02) than those in the apo E3 group. We conclude that the apo E4 allele is associated with atherogenic lipoprotein abnormalities in Type 1 DM patients with minor elevations in albuminuria when they use their habitual diet. Apo E4 carrying patients respond better to a low cholesterol diet. Copyright © 1998 John Wiley & Sons, Ltd.

Studies in Asymptomatic Primary Hyperlipidaemia

The occurrence of early signs of peripheral vascular disease (PVD) of the lower limbs has been studied with digital pulse plethysmography in 160 men and 123 women above the age of 35, who were all subjectively healthy but were found to have primary hyperlipoproteinaemia (HLP) at a health control centre. Quantitative analysis of serum lipoproteins with cholesterol and triglyceride (TG) determination of each of the very low (VLDL), low (LDL) and high (HDL) density lipoprotein clases together with lipoprotein paper electrophoresis was performed. Identical investigations were performed on control subjects with non-elevated serum lipids. Inclination time (IT) was substantially prolonged in 12% of HLP males and 7% of HLP females. The frequency of male subjects with prolonged IT was lower when only LDL was elevated (type IIA) than in the other types of HLP. The subjects with prolonged IT had three characteristic features. 1) Moderate elevations of both serum cholesterol and TG. These elevations occurred often in both VLDL and LDL lipoprotein classes. IT prolongations were not seen when VLDL or LDL lipoproteins were singly maredly elevated. 2) High frequency of smokers. 3) Most of the subjects were above the age of 50. The results suggest that the most atherogenic lipoprotein abnormalities to the arteries of the lower limb are on the one hand the relatively TG-rich part of the LDL (LDL1) fraction and on the other hand the relatively cholesterol-rich part of the VLDL fraction. Furthermore the results stress the deleterious influence of smoking even in the preclinical stage of PVD.