The Insulin Resistance—Dyslipidemic Syndrome of Visceral Obesity: Effect on Patients' Risk

Coronary heart disease (CHD) and type 2 diabetes mellitus represent two highly prevalent conditions in affluent societies. Although a dyslipidemic state is frequently found in type 2 patients with obesity, studies have shown that the high triglyceride, low high-density lipoprotein (HDL) cholesterol dyslipidemia is also found in nondiabetic patients with insulin resistance. Studies that have used imaging techniques to assess the regional distribution of body fat have shown that an excess of visceral adipose tissue, that is, a high accumulation of fat in the abdominal cavity, was associated with a cluster of metabolic disturbances such as insulin resistance, hyperinsulinemia, glucose intolerance, hypertriglyceridemia, elevated apolipoprotein B (apoB) concentrations, small, dense low-density lipoprotein (LDL) particles, as well as low HDL cholesterol levels. Prospective studies such as the Quebec Cardiovascular Study have shown that this cluster of metabolic abnormalities commonly found in patients with excess visceral adipose tissue substantially increases the risk of CHD. The high prevalence of visceral obesity in sedentary adult men and postmenopausal women is such that it may represent the most prevalent cause of atherogenic dyslipidemic states associated with CHD in our population.     

Relationships between exercise-induced reductions in thigh intermuscular adipose tissue, changes in lipoprotein particle size, and visceral adiposity

Small LDL and HDL particle size are characteristic of a proatherogenic lipoprotein profile. Aerobic exercise increases these particle sizes. Although visceral adipose tissue (VAT) has been strongly linked with dyslipidemia, the importance of intermuscular adipose tissue (IMAT) to dyslipidemia and exercise responses is less well understood. We measured exercise-associated changes in thigh IMAT and VAT and examined their relationships with changes in LDL and HDL particle size. Sedentary, dyslipidemic, overweight subjects (n = 73) completed 8-9 mo of aerobic training. Linear regression models were used to compare the power of IMAT change and VAT change to predict lipoprotein size changes. In men alone (n = 40), IMAT change correlated inversely with both HDL size change (r = -0.42, P = 0.007) and LDL size change (r = -0.52, P < 0.001). That is, reduction of IMAT was associated with a shift toward larger, less atherogenic lipoprotein particles. No significant correlations were observed in women. After adding VAT change to the model, IMAT change was the only significant predictor of either HDL size change (P = 0.034 for IMAT vs. 0.162 for VAT) or LDL size change (P = 0.004 for IMAT vs. 0.189 for VAT) in men. In conclusion, in overweight dyslipidemic men, exercise-associated change in thigh IMAT was inversely correlated with both HDL and LDL size change and was more predictive of these lipoprotein changes than was change in VAT. Reducing IMAT through aerobic exercise may be functionally related to some improvements in atherogenic dyslipidemia in men.     

Effect of apoC-III gene polymorphisms on the lipoprotein-lipid profile of viscerally obese men

Abdominal visceral adipose tissue (AT) accumulation is associated with an atherogenic metabolic profile that includes increased plasma triglyceride (TG), low HDL cholesterol levels, and an insulin-resistant hyperinsulinemic state. Whereas the apolipoprotein (apo) C-III C3238G gene variant, often referred to as the SstI polymorphism, has been related to variations in plasma TG concentrations, another variation within the insulin responsive element (C-482T) of the apoC-III gene has been associated with greater glucose and insulin responses to an oral glucose tolerance test (OGTT); however, these results were obtained in nonobese individuals. We therefore investigated the effects of three apoC-III gene polymorphisms, namely SstI, C-482T, and T-455C, on fasting plasma lipoprotein-lipid levels and response to a 75 g OGTT in a sample of 122 viscerally obese men (abdominal visceral AT area >or=130 cm(2)). Among the three gene variants that were examined, the SstI variation was the only one found to be associated with hypertriglyceridemia. Indeed, S1/S2 heterozygotes (n = 24) were characterized by increased fasting plasma TG concentrations compared with S1/S1 homozygotes (n = 98) (mean +/- SD: 3.03 +/- 1.58 vs. 2.34 +/- 0.95 mmol/l respectively, P < 0.05). The higher TG concentrations in S1/S2 were associated with the presence of smaller, denser LDL particles compared with S1/S1 subjects (LDL peak particle diameter: 24.8 +/- 0.5 nm vs. 25.1 +/- 0.5 nm respectively, P < 0.05). Furthermore, there was no association between the response to the OGTT and any of the apoC-III gene variants (SstI, T-455C, or C-482T) examined. Results of the present study support the notion of a hypertriglyceridemic effect associated with the apoC-III SstI polymorphism that could modulate the magnitude of the dyslipidemic state in abdominally obese patients.     

Hepatic lipase and dyslipidemia: interactions among genetic variants,obesity, gender,and diet

Hepatic lipase (HL) plays a central role in LDL and HDL remodeling. High HL activity is associated with small, dense LDL particles and with reduced HDL2 cholesterol levels. HL activity is determined by an HL gene promoter polymorphism, by gender (lower in premenopausal women), and by visceral obesity with insulin resistance. The activity is affected by dietary fat intake and selected medications. There is evidence for an interaction of the HL promoter polymorphism with visceral obesity, dietary fat intake, and with lipid-lowering medications in determining the level of HL activity.The dyslipidemia with high HL activity is a potentially proatherogenic lipoprotein profile in the metabolic syndrome, in Type 2 diabetes, and in familial combined hyperlipidemia.     

Hypertriglyceridemia secondary to obesity and diabetes

Hypertriglyceridemia is a common lipid abnormality in persons with visceral obesity, metabolic syndrome and type 2 diabetes. Hypertriglyceridemia typically occurs in conjunction with low HDL levels and atherogenic small dense LDL particles and is associated with increased cardiovascular risk. Insulin resistance is often an underlying feature and results in increased free fatty acid (FFA) delivery to the liver due to increased peripheral lipolysis. Increased hepatic VLDL production occurs due to increased substrate availability via FFAs, decreased apolipoprotein B100 degradation and increased lipogenesis. Postprandial hypertriglyceridemia also is a common feature of insulin resistance. Small dense LDL that coexist with decreased HDL particles in hypertriglyceridemic states are highly pro-atherogenic due to their enhanced endothelial permeability, proteoglycan binding abilities and susceptibility to oxidation. Hypertriglyceridemia also occurs in undertreated individuals with type 1 diabetes but intensive glucose control normalizes lipid abnormalities. However, development of visceral obesity in these patients unravels a similar metabolic profile as in patients with insulin resistance. Modest hypertriglyceridemia increases cardiovascular risk, while marked hypertriglyceridemia should be considered a risk for pancreatitis. Lifestyle modification is an important therapeutic strategy. Drug therapy is primarily focused on lowering LDL levels with statins, since efforts at triglyceride lowering and HDL raising with fibrates and/or niacin have not yet been shown to be beneficial in improving cardiovascular risk. Fibrates, however, are first-line agents when marked hypertriglyceridemia is present. This article is part of a Special Issue entitled Triglyceride Metabolism and Disease.     

Endothelial lipase and the metabolic syndrome

PURPOSE OF REVIEW: Several in-vitro and in-vivo animal studies indicate that endothelial lipase plays a key role in the intravascular remodeling of lipoproteins, particularly HDL. This review integrates this body of knowledge with more recent data in humans linking endothelial lipase to HDL metabolism and other features of the metabolic syndrome. RECENT FINDINGS: Human studies generally support the involvement of endothelial lipase in modulating plasma HDL. The association between endothelial lipase and metabolism of apolipoprotein B-containing lipoproteins in humans, however, has not been entirely consistent with previous findings in vitro and in animals. Finally, elevated plasma endothelial lipase has been associated with abdominal obesity and hypertension, and there is now compelling evidence that inflammation and in-vivo regulation of endothelial lipase may be intrinsically related. SUMMARY: Accumulating evidence indicates that endothelial lipase plays a role in the etiology of the atherogenic plasma lipoprotein profile characteristic of the metabolic syndrome. Increased endothelial lipase activity is linked to the underlying proinflammatory state in this condition. Further studies are required, however, to define the extent to which endothelial lipase contributes to the dyslipidemia of the metabolic syndrome relative to other important regulating factors, such as lipoprotein lipase, hepatic lipase, and cholesterol ester transfer protein.     

Recent studies of lipoprotein kinetics in the metabolic syndrome and related disorders

PURPOSE OF REVIEW: Dyslipoproteinemia is a cardinal feature of the metabolic syndrome that accelerates atherosclerosis. Recent in-vivo kinetic studies of dyslipidemia in the metabolic syndrome are reviewed here. RECENT FINDINGS: The dysregulation of lipoprotein metabolism may be caused by a combination of overproduction of VLDL apolipoprotein B-100, decreased catabolism of apolipoprotein B-containing particles, and increased catabolism of HDL apolipoprotein A-I particles. Nutritional modifications and increased physical exercise may favourably alter lipoprotein transport by collectively decreasing the hepatic secretion of VLDL apolipoprotein B and the catabolism of HDL apolipoprotein A-I, as well as by increasing the clearance of LDL apolipoprotein B. Conventional and new pharmacological treatments, such as statins, fibrates and cholesteryl ester transfer protein inhibitors, can also correct dyslipidemia by several mechanisms, including decreased secretion and increased catabolism of apolipoprotein B, as well as increased secretion and decreased catabolism of apolipoprotein A-I. SUMMARY: Kinetic studies provide a mechanistic insight into the dysregulation and therapy of lipid and lipoprotein disorders. Future research mandates the development of new tracer methodologies with practicable in-vivo protocols for investigating fatty acid turnover, macrophage reverse cholesterol transport, cholesterol transport in plasma, corporeal cholesterol balance, and the turnover of several subpopulations of HDL particles.     

The Visceral Adiposity Syndrome in Japanese-American Men

Japanese-Americans have an increased prevalence of non-insulin-dependent diabetes mellitus and coronary heart disease when compared to native Japanese. This increase has been associated with fasting hyperinsulinemia, hypertriglyceridemia, and low plasma levels of high-density lipoprotein (HDL) cholesterol. The purpose of this study was to examine the relationship of both visceral adiposity and insulin resistance to this metabolic syndrome and to the presence of a predominance of small, dense low-density lipoprotein (LDL) particles (LDL subclass phenotype B) that has been associated with increased atherogenic risk. Six Japanese-American men with non-insulin-dependent diabetes, each receiving an oral sulfonylurea, were selected. One or 2 nondiabetic Japanese-American men, matched by age and body mass index, were selected for each diabetic subject, giving a total of 9 nondiabetic men. Diabetic subjects had significantly higher fasting plasma glucose (p=0.0007) and lower insulin sensitivity (S_I, p=0.018) using the minimal model technique than nondiabetic subjects matched for body mass index. Six men (2 with diabetes) had LDL phenotype A and 8 (4 with diabetes) had phenotype B. One nondiabetic subject had an intermediate low-density lipoprotein pattern. Significantly greater amounts of intra-abdominal fat (p=0.045) measured by computed tomography were found in the men with phenotype B while fasting insulin (p=0.070) and triglycerides (p=0.051) tended to be higher. Intra-abdominal fat was significantly correlated with S_I (r=-0.559), plasma triglycerides (r=0.541), plasma free fatty acids (r=0.677), LDL density (relative flotation rate, r=-0.803), and plasma HDL-cholesterol (r=-0.717). S_I was significantly correlated only with plasma free fatty acids (r=-0.546) and tended to be correlated with hepatic lipase activity (r=-0.512, p=0.061). In conclusion, these observations indicate that in non-obese Japanese-American men, the metabolic features of the so-called insulin resistance syndrome, including LDL phenotype B, are more strongly correlated with visceral adiposity than with S_I. It may therefore be more appropriate to call this the visceral adiposity syndrome. Although questions concerning mechanisms still remain, we postulate that visceral adiposity plays a central role in the development of many of the metabolic abnormalities, including LDL subclass phenotype B, that occur in this metabolic syndrome.     

Relations between particle size of HDL and LDL lipoproteins and cholesterol esterification rate

Particle size of low density (LDL) and high density (HDL) lipoproteins and cholesterol esterification rate in HDL plasma (FER(HDL)) are important independent predictors of coronary artery diseases (CAD). In this study we assessed the interrelations between these indicators and routinely examined plasma lipid parameters and plasma glucose concentrations. In 141 men, healthy volunteers, we examined plasma total cholesterol (TC), triglycerides (TG), HDL and LDL cholesterol (HDL-C, LDL-C) and HDL unesterified cholesterol (HDL-UC). Particle size distribution in HDL and LDL was assessed by gradient gel electrophoresis and FER(HDL) was estimated by radioassay. An effect of particle size and FER(HDL) on atherogenic indexes as the Log(TG/HDL-C) and TC/HDL-C was evaluated. Subjects in the study had plasma concentrations (mean +/- S.D.) of TC 5.2+/-0.9 mmol/l, HDL-C 1.2+/-0.3 mmol/l, TG 2.1+/-1.7 mmol/l, glucose 5+/-0.8 mmol/l. Relative concentration of HDL(2b) was 17.6+/-11.5 % and 14.6+/-11.8 % of HDL(3b,c). The mean diameter of LDL particles was 25.8+/-1.5 nm. The increase in FER(HDL) significantly correlated with the decrease in HDL(2b) and LDL particle size (r = -0.537 and -0.583, respectively, P<0.01) and the increase in HDL(3b,c) (0.473, P<0.01). Strong interrelations among TG and HDL-C or HDL-UC and FER(HDL) and particle size were found, but TC or LDL-C did not have such an effect. Atherogenic indexes Log(TG/HDL-C) and TC/HDL-C correlated with FER(HDL) (0.827 and 0.750, respectively, P<0.0001) and with HDL and LDL particle size.     

Cholesterol esterification and atherogenic index of plasma correlate with lipoprotein size and findings on coronary angiography

We examined the association between rate of cholesterol esterification in plasma depleted of apolipoprotein B-containing lipoproteins (FER(HDL)), atherogenic index of plasma (AIP) [(log (TG/HDL-C)], concentrations, and size of lipoproteins and changes in coronary artery stenosis in participants in the HDL-Atherosclerosis Treatment Study. A total of 160 patients was treated with simvastatin (S), niacin (N), antioxidants (A) and placebo (P) in four regimens. FER(HDL) was measured using a radioassay; the size and concentration of lipoprotein subclasses were determined by nuclear magnetic resonance spectroscopy. The S+N and S+N+A therapy decreased AIP and FER(HDL), reduced total VLDL (mostly the large and medium size particles), decreased total LDL particles (mostly the small size), and increased total HDL particles (mostly the large size). FER(HDL) and AIP correlated negatively with particle sizes of HDL and LDL, positively with VLDL particle size, and closely with each other (r = 0.729). Changes in the proportions of small and large lipoprotein particles, which were reflected by FER(HDL) and AIP, corresponded with findings on coronary angiography. Logistic regression analysis of the changes in the coronary stenosis showed that probability of progression was best explained by FER(HDL) (P = 0.005). FER(HDL) and AIP reflect the actual composition of the lipoprotein spectrum and thus predict both the cardiovascular risk and effectiveness of therapy. AIP is already available for use in clinical practice as it can be readily calculated from the routine lipid profile.     

Atherogenic lipoprotein profile in families with and without history of early myocardial infarction

In this study we compared several parameters characterizing differences in the lipoprotein profile between members of families with a positive or negative family history of coronary artery disease (CAD). In addition to regular parameters such as the body mass index (BMI), total plasma cholesterol (TC), low density (LDL-C) and high density (HDL-C) cholesterol and triglycerides (TG) we estimated the fractional esterification rate of cholesterol in apoB lipoprotein-depleted plasma (FER(HDL)) which reflects HDL and LDL particle size distribution. A prevalence of smaller particles for the atherogenic profile of plasma lipoproteins is typical. Log (TG/HDL-C) as a newly established atherogenic index of plasma (AIP) was calculated and correlated with other parameters. The cohort in the study consisted of 29 young (< 54 years old) male survivors of myocardial infarction (MI), their spouses and at least one offspring (MI group; n=116). The control group consisted of 29 apparently healthy men with no family history of premature CAD in three generations, their spouses and at least one offspring (control group; n=124). MI families had significantly higher BMI than the controls, with the exception of spouses. Plasma TC did not significantly differ between MI and the controls. MI spouses had significantly higher TG. Higher LDL-C had MI survivors only, while lower HDL-C had both MI survivors and their spouses compared to the controls. FER(HDL) was significantly higher in all the MI subgroups (probands 25.85+/-1.22, spouses 21.55+/-2.05, their daughters 16.93+/-1.18 and sons 19.05+/-1.33 %/h) compared to their respective controls (men 20.80+/-1.52, spouses 14.70+/-0.98, daughters 13.23+/-0.74, sons 15.7+/-0.76 %/h, p<0.01 to p<0.05). Log(TG/HDL-C) ranged from negative values in control subjects to positive values in MI probands. High correlation between FER(HDL) and Log (TG/HDL-C) (r=0.80, p<0.0001) confirmed close interactions among TG, HDL-C and cholesterol esterification rate. The finding of significantly higher values of FER(HDL) and Log (TG/HDL-C) indicate higher incidence of atherogenic lipoprotein phenotype in members of MI families. The possibility that, in addition to genetic factors, a shared environment likely contributes to the familial aggregation of CAD risk factors is supported by a significant correlation of the FER(HDL) values within spousal pairs (control pairs: r=0.51 p<0.01, MI pairs: r=0.41 p<0.05).     

Plasma fatty acid binding protein 4 is associated with atherogenic dyslipidemia in diabetes

The aim of this study was to evaluate the impact of adipocyte fatty acid binding protein 4 (FABP4) on the lipid profile in type 2 diabetic subjects. Plasma levels of FABP4 and adiponectin and an extensive lipid profile were analyzed in 169 type 2 diabetic subjects and 105 controls. Type 2 diabetic subjects were categorized according the presence of atherogenic dyslipidemia. Univariate statistical analyses, partial correlation tests, and binary logistic regression models were applied. In type 2 diabetic subjects, FABP4 was positively correlated with plasma triglycerides (P = 0.007), apolipoprotein C-III (apoC-III) (P = 0.009), and all the components of triglyceride-rich lipoproteins, including VLDL triglycerides (P = 0.002), VLDL-cholesterol (P = 0.001), and VLDL apoB (P = 0.001). FABP4 was inversely correlated with apoA-I (P = 0.038), HDL-cholesterol (P = 0.002), and HDL apoA-I (P = 0.010) in type 2 diabetic subjects. These correlations are not significantly affected by age, gender, body mass index, adiponectin, insulin, or any pharmacological treatment. The associations are even stronger when the FABP4/adiponectin ratio is considered. None of these associations were observed in controls. High FABP4 and low adiponectin levels are independent predictors of atherogenic dyslipidemia. In conclusion, FABP4 plasma concentrations hold strong potential for development as a clinical biomarker for atherogenic dyslipidemia, independent of obesity and insulin resistance, in type 2 diabetic subjects.     

Obesity-related changes in high-density lipoprotein metabolism

Obesity is associated with a 3-or-more-fold increase in the risk of fatal and nonfatal myocardial infarction (1,2,3,4,5,6). The American Heart Association has reclassified obesity as a major, modifiable risk factor for coronary heart disease (7). The increased prevalence of premature coronary heart disease in obesity is attributed to multiple factors (8,9,10). A principal contributor to this serious morbidity is the alterations in plasma lipid and lipoprotein levels. The dyslipidemia of obesity is commonly manifested as high plasma triglyceride levels, low high-density lipoprotein cholesterol (HDLc), and normal low-density lipoprotein cholesterol (LDLc) with preponderance of small dense LDL particles (7,8,9,10). However, there is a considerable heterogeneity of plasma lipid profile in overweight and obese people. The precise cause of this heterogeneity is not entirely clear but has been partly attributed to the degree of visceral adiposity and insulin resistance. The emergence of glucose intolerance or a genetic predisposition to familial combined hyperlipidemia will further modify the plasma lipid phenotype in obese people (11,12,13,14,15).     

Species-related variations in lipoprotein metabolism: the impact of FER(HDL) on susceptibility to atherogenesis

Several animal models have been used to investigate the mechanisms of atherogenesis. Each animal species has advantages and disadvantages with regard to similarity with human lipoprotein metabolism. In humans, fractional esterification rate in apolipoprotein B-depleted plasma (FER(HDL)) has been shown to correlate with the quality of high density lipoprotein particles. Increased values of FER(HDL) indicate an atherogenic lipoprotein profile. Such an association has not been defined in animal models. Thus, we have characterized plasma lipoprotein profile and FER(HDL) values in four animal species namely, cats, pigs, guinea pigs and rabbits. These animal species have been used in experimental dyslipidemia and atherosclerosis. Our data indicate a wide rage of variations among various animal species. High-density lipoprotein (HDL) particles contain approximately 40% of total plasma cholesterol concentrations in rabbits, pigs and cats <10% in guinea pigs. A negative association between FER(HDL) values and plasma HDL-cholesterol levels was observed in pigs, rabbits and guinea pigs. On the other hand, FER(HDL) values showed a positive association with plasma triglyceride levels in all animal species tested. These findings are in agreement with data reported in humans. More research is needed to identify the better animal models which closely resemble human lipoprotein metabolism.     

Conversion of apolipoprotein-specific high-density lipoprotein populations during incubation of human plasma

Incubation studies were performed on plasma obtained from subjects selected for relatively low levels of high-density lipoprotein cholesterol (HDL-C) (no greater than 30 mg/dl) and particle size distributions enriched in the HDL3 subclass. Incubation (12 h, 37 degrees C) of plasma in the presence or absence of lecithin: cholesterol acyltransferase activity produces marked alteration in size profiles of both major apolipoprotein-specific HDL3 populations (HDL3(AI w AII), HDL3 species containing both apolipoprotein A-I and apolipoprotein A-II, and HDL3(AI w/o AII), HDL3 species containing apolipoprotein A-I) as isolated by immunoaffinity chromatography. In the presence or absence of lecithin: cholesterol acyltransferase activity, plasma incubation results in a shift of HDL3(AI w AII) species (initial mean sizes of major components, approx. 8.8 and 8.0 nm) predominantly to larger particles (mean size, 9.8 nm). A less prominent shift to smaller particles (mean size, 7.8 nm) accompanies the conversion to larger particles only when the enzyme is active. Combined shifts to larger (mean size, 9.8 nm) and smaller (mean size, 7.4 nm) particles are observed for HDL3(AI w/o AII) particles (mean size, 8.3 nm) also only in the presence of enzyme activity. However, in the absence of enzyme activity, HDL3(AI w/o AII) species, unlike the HDL3(AI w AII) species, are converted to smaller (mean size 7.4 nm) rather than to larger particles. Like native HDL2b(AI w/o AII) particles, the larger HDL3(AI w/o AII) conversion products exhibit a protein moiety with molecular weight equivalent to four apolipoprotein A-I molecules per particle; small HDL3(AI w/o AII) products are comprised predominantly of particles with two apolipoprotein A-I per particle. Incubation-induced conversion of HDL3 particles in the presence of lecithin: cholesterol acyltransferase activity is associated with increased binding of both apolipoprotein-specific HDL populations to low-density lipoproteins (LDL). The present studies indicate that, in the absence of lecithin: cholesterol acyltransferase activity, the two HDL3 populations follow different conversion pathways, possibly due to apolipoprotein-specific activities of lipid transfer protein or conversion protein in plasma. Our studies also suggest that lecithin: cholesterol acyltransferase activity may play a role in the origins of large HDL2b(AI w/o AII) species in human plasma by participating in the conversion of HDL3(AI w/o AII) particles, initially with three apolipoprotein A-I, to larger particles with four apolipoprotein A-I per particle.     

Sex steroid hormones, sex hormone-binding globulin, and obesity in men and women.

Sex steroid hormones in both males and females have been closely related to the regulation of adiposity, either through direct or indirect physiological mechanisms. Evidence also suggests a direct relationship between sex hormones and risk factors for cardiovascular disease. In the present review article, we will discuss recent studies that have examined the complex interrelationships between sex hormones, SHBG, obesity and risk factors for cardiovascular disease. Male obesity and excess abdominal adipose tissue accumulation is associated with reductions in gonadal androgen and low adrenal C19 steroid concentrations. Reduced C19 steroids are also related to an altered metabolic risk factor profile including glucose intolerance and an atherogenic dyslipidemic state. However, the concomitant visceral obese state appears as a major correlate in these associations. In women, menopause-induced estrogen deficiency and increased androgenicity are associated with increased abdominal obesity and with the concomitant alterations in the metabolic risk profile. The accelerated accretion of adipose tissue in the intra-abdominal region coincident with the onset of menopause may explain part of the increased risk of cardiovascular disease in postmenopausal women. In both men and women, plasma levels of sex hormone-binding globulin are strong correlates of obesity and risk factors for cardiovascular disease, and more importantly, the relationships between low SHBG and altered plasma lipid levels appear to be independent from the concomitant increased levels of visceral adipose tissue. SHBG concentration may, therefore, represent the most important and reliable marker of the sex hormone profile in the examination of the complex interrelation of sex steroid hormones, obesity, and cardiovascular disease risk.     

Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis

Insulin resistance plays a central role in the development of the metabolic syndrome, but how it relates to cardiovascular disease remains controversial. Liver insulin receptor knockout (LIRKO) mice have pure hepatic insulin resistance. On a standard chow diet, LIRKO mice have a proatherogenic lipoprotein profile with reduced high-density lipoprotein (HDL) cholesterol and very low-density lipoprotein (VLDL) particles that are markedly enriched in cholesterol. This is due to increased secretion and decreased clearance of apolipoprotein B-containing lipoproteins, coupled with decreased triglyceride secretion secondary to increased expression of Pgc-1 beta (Ppargc-1b), which promotes VLDL secretion, but decreased expression of Srebp-1c (Srebf1), Srebp-2 (Srebf2), and their targets, the lipogenic enzymes and the LDL receptor. Within 12 weeks on an atherogenic diet, LIRKO mice show marked hypercholesterolemia, and 100% of LIRKO mice, but 0% of controls, develop severe atherosclerosis. Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome.     

Eicosapentaenoic acid in serum phospholipids relates to a less atherogenic lipoprotein profile in subjects with familial hypercholesterolemia

Familial hypercholesterolemia (FH) carries an increased vascular risk due to lifelong elevation of the number of circulating low-density lipoprotein (LDL) particles, but also to alterations in triglyceride and high-density lipoprotein (HDL) metabolism. Supplementation with eicosapentaenoic (EPA) or docosahexaenoic (DHA) acids reduced LDL particle number and/or increased LDL size in different populations, but studies in FH are scarce. We investigated cross-sectionally whether intake of EPA and DHA in the usual diet is associated with a less atherogenic lipoprotein profile in subjects with FH (n=215). Lipoprotein particle number and size distributions were assessed with nuclear magnetic resonance spectroscopy. EPA and DHA proportions in serum phosphatidylcholine, a biomarker of fish intake, were determined by gas chromatography. After adjusting for cardiovascular risk factors, including fasting triglycerides, serum phosphatidylcholine EPA (but not DHA) related inversely to medium VLDL, total LDL particle number and very small LDL, resulting in a net direct association with LDL size. Additionally, EPA was directly associated with concentrations of large HDL. We conclude that increased serum phosphatidylcholine EPA derived from seafood intake with the usual diet is associated with a less atherogenic lipoprotein profile in subjects with FH. Increased fish intake and/or EPA supplements might contribute to reduce the residual risk of statin-treated FH subjects.     

Cholesterol Forms and Traditional Lipid Profile for Projection of Atherogenic Dyslipidemia: Lipoprotein Subfractions and Erythrocyte Membrane Cholesterol

Atherogenic dyslipidemia characterized by abnormal changes in plasma lipid profile such as low high-density lipoprotein (HDL) and increased triglyceride (TG) levels is strongly associated with atherosclerotic diseases. We aimed to evaluate the levels of pro- and antiatherogenic lipids and erythrocyte membrane cholesterol (EMC) content in normo- and dyslipidemic subjects to investigate whether EMC content could be a useful marker for clinical presentation of atherogenic dyslipidemia. Low-density lipoprotein (LDL), HDL and their subfraction levels and erythrocyte lipid content were determined in 64 normolipidemic (NLs), 42 hypercholesterolemic (HCs) and 42 mixed-type dyslipidemic subjects (MTDs). Plasma atherogenic lipid indices [small–dense LDL (sdLDL)/less-dense HDL (LHDL), TC/HDL-C, TG/HDL-C and Apo B/AI] were higher in MTDs compared to NLs (p < 0.001). The highest sdLDL level was observed in HCs (p < 0.01). Despite a slight increase in EMC level in dyslipidemic subgroups, the difference was not statistically significant. A significant negative correlation, however, was observed between EMC and sdLDL/LHDL in HCs (p < 0.035, r = ?0.386). Receiver operating characteristic curves to predict sdLDL level showed that TG and EMC levels had higher area under curve values compared to other parameters in HCs. We showed that diameters of larger LDL and HDL particles tend to shift toward smaller values in MTDs. Our results suggest that EMC content and TG levels may be a useful predictor for sdLDL level in hypercholesterolemic patients.     

N‐6 From Different Sources Protect From Metabolic Alterations to Obese Patients: A Factor Analysis

First, to analyze the interactions among fatty acids (FAs) from diet, plasma and subcutaneous and visceral adipose tissue (AT), and second, the relationship among FAs from these different sources and obesity‐related alterations in extreme obesity. We studied 20 extreme obese subjects. A food‐frequency questionnaire was used to determine the FA intakes. Serum and AT (subcutaneous and visceral) FA concentrations were determined by gas chromatography. Cardiometabolic risk parameters were assessed. Principal factor analysis was performed to define specific FA factors in the metabolic alterations. We found important associations among diet, plasma, and AT FA and cardiometabolic parameters. In this regard, it is interesting to highlight the negative associations between plasma cholesterol and dietary n‐3 FA. In the subcutaneous depot, as occurred in plasma, n‐6 and polyunsaturated FAs (PUFA) were negatively associated with triacylglycerols (TGs). Factor analysis revealed TGs as the unique cardiovascular risk parameter appearing in the first factor (F1), together with n‐6 (load factor = 0.94) and PUFA (0.91). Besides, n‐3 from diet and plasma appeared in the third factor inversely related to cholesterol, low‐density lipoprotein cholesterol (LDL‐c), and insulin. In an opposite way, dietary and AT trans FAs and saturated FA (SFA) were associated to an increase of the metabolic risk. We have shown, for the first time, the importance of n‐6 and PUFAs composition as protective factors against metabolic alterations in extreme obese subjects. These findings support current dietary recommendations to increase PUFA intakes and restrict saturated and trans FA intakes even in extreme obesity.