Metabolic Syndrome: Focus on Dyslipidemia (2006)

In 2001, the National Cholesterol Education Program Adult Treatment Panel III guidelines defined a cluster of metabolic factors that increase the risk for atherosclerotic cardiovascular disease (ASCVD)1 (1). They called this cluster the “metabolic syndrome” and defined afflicted individuals by the presence of three of the following five characteristics: central obesity, hypertriglyceridemia, low high-density lipoprotein (HDL)-cholesterol levels, hypertension, and either impaired fasting glucose or type 2 diabetes (Table 1). An analysis of data from 8814 men and women in the Third National Health and Nutrition Examination Survey (1988 to 1994) that used the Adult Treatment Panel III definition of the metabolic syndrome indicates that the age-adjusted prevalence of the syndrome was 23.7% in the U.S. population ≥20 years of age (2). A recent update of National Health and Nutrition Examination Survey data (3) indicates increases in the prevalence of the metabolic syndrome in all age and both sex groups. Although Reaven (4) popularized the concept of the clustering of insulin resistance, a dyslipidemia characterized by hypertriglyceridemia, low HDL-cholesterol, and hypertension, in his Banting Lecture of 1988, the initial observations of associations between components of the metabolic syndrome were published much earlier by Vague (5), Albrink and Meigs (6), and Reaven et al. (7). Furthermore, the World Health Organization defined a slightly different version of the metabolic syndrome in 1998 (8). However, the formal presentation of the metabolic syndrome by the Adult Treatment Panel III panel has made the metabolic syndrome into a major topic for medical discussion. The contribution of the metabolic syndrome to atherosclerotic disease can be illustrated, at least in part, by the more extensively examined relationship of diabetes to atherosclerotic disease. Atherosclerosis accounts for ∼80% of all diabetic mortality (9), with 75% attributed to coronary atherosclerosis and 25% to cerebral or peripheral vascular disease. Atherosclerosis also accounts for >75% of all hospitalizations for diabetic complications. It has been estimated that >50% of patients with newly diagnosed type 2 diabetes have coronary heart disease (CHD). Among 350, 977 non-diabetic and 5245 diabetic subjects screened for enrollment in the Multiple Risk Factor Intervention Trial (10), the risk of ASCVD mortality in both groups increased with an increasing number of classical risk factors, but ASCVD mortality was significantly increased in the diabetics at all levels of risk. In a study by Haffner et al. (11), the 7-year incidence rates of myocardial infarction (MI) among 1373 patients without diabetes were 3.5% in those without prior MI and 18.8% in those with prior MI. Among the 1059 diabetic patients, the MI rate in those without prior MI was 20.2% (comparable with that in non-diabetic patients with prior MI), whereas the rate was 45% in patients with prior MI. Data such as these led the Adult Treatment Panel III to designate diabetes as a CHD equivalent. Although ∼80% to 90% of individuals with type 2 diabetes meet the criteria of the metabolic syndrome, it is important to look carefully at the risk for ASCVD in the group with metabolic syndrome but without diabetes. Epidemiological data indicate that impaired glucose tolerance increases risk for ASCVD mortality. In the 10-year Paris Prospective Study follow-up of >7000 men (12), CHD mortality rates were significantly increased by ∼2-fold in subjects with impaired glucose tolerance or with diabetes newly diagnosed on the basis of glucose tolerance testing. In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe study group analysis (13) of data from 10 European studies involving more than 22, 000 participants (15, 388 men and 7126 women) followed for a median of 8.8 years, impaired glucose tolerance was associated with multivariate-adjusted hazard ratios of 1.28 (95% CI, 1.02 to 1.59) for CHD death, 1.34 (95% CI, 1.14 to 1.57) for cardiovascular death, and 1.40 (95% CI, 1.27 to 1.54) for all-cause mortality. In an analysis of 3174 subjects in the U.S. Second National Health and Nutrition Examination Survey Mortality Study who underwent oral glucose tolerance testing and were followed from 1976–1980 through 1992 (14), impaired glucose tolerance was associated with multivariate-adjusted relative risks of 1.42 (95% CI, 1.08 to 1.87) for all-cause mortality and 1.15 (95% CI, 0.81 to 1.62) for cardiovascular mortality. All of these studies, however, predated the Adult Treatment Panel III publication defining the metabolic syndrome. A number of recent studies have used the definition of the metabolic syndrome by either Adult Treatment Panel III or the World Health Organization to determine the impact of this syndrome on ASCVD or CHD. Isomaa et al. (15) assessed cardiovascular morbidity and mortality associated with the World Health Organization metabolic syndrome (defined as having type 2 diabetes or impaired fasting glucose/impaired glucose tolerance or insulin resistance and at least two other phenotypic characteristics, including obesity, hypertension, dyslipidemia, and microalbuminuria). During 6.9 years of follow-up, the investigators assessed cardiovascular mortality in 3606 men and women in the Botnia study who had insulin resistance with normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or type 2 diabetes. The metabolic syndrome was seen in 10% of women and 15% of men with normal glucose tolerance; in 42% and 64% of women and men, respectively, with impaired fasting glucose/impaired glucose tolerance; and in 78% of women and 84% of men with type 2 diabetes. In patients with the metabolic syndrome, relative risk of CHD was 2.96 (95% CI, 2.36 to 3.72), and cardiovascular mortality was significantly increased to 12% compared with 2.2% in subjects without the metabolic syndrome. However, these investigators did not adjust for the components of the metabolic syndrome, although most of them were also predictors of increased morbidity and mortality. Several studies followed that, in some cases, supported the study by Isomaa et al. (16, 17, 18), but in others did not show that the definition of the metabolic syndrome added significantly to the usual predictors of cardiovascular events (18, 19, 20). Furthermore, even the studies showing an “independent” predictive power for the term metabolic syndrome showed only modest relative risks after adjustment for traditional risk factors. Importantly, none of these studies analyzed the risk associated with the metabolic syndrome after adjusting for the components; that would not really be a legitimate analysis, but the inability to separate the “syndrome” from its components analytically shows the difficulties inherent in conducting these studies. One conclusion that can be drawn from the studies described above is that the increase in risk of ASCVD and CHD observed in patients with the metabolic syndrome may not be greater than that associated with the components of the syndrome. On the other hand, insulin resistance may be a risk factor itself or may impart additional risk through its effects on the components. In the latter instance, each of the traditional risk factors could be more atherogenic because they are driven by insulin resistance and have, therefore, a more atherogenic pathophysiology. In the former case, insulin resistance has proatherogenic effects beyond the risk factors included in the definition of the metabolic syndrome: inflammation and hypercoagulability are important atherogenic factors that are increased in the insulin-resistant patient but are not included in the definition of the metabolic syndrome. Thus, individuals with the metabolic syndrome who also have significant insulin resistance may have greater risk than simply the sum of the components of the syndrome would indicate. In the remainder of this review, we will focus on the well-characterized interaction between insulin resistance and one of the components of the metabolic syndrome, dyslipidemia, with special reference to the increased atherogenicity produced by that interaction. We will also discuss new findings concerning the role of inflammation in the metabolic syndrome. The dyslipidemia of the metabolic syndrome is characterized by elevated levels of triglycerides (TGs), low HDL-cholesterol, and small, dense low-density lipoprotein (LDL) particles with normal or slightly elevated LDL-cholesterol levels. Data from the Framingham Offspring Study (21) showed the high prevalence of elevated TGs and low HDL-cholesterol in individuals with diabetes. Among men, HDL-cholesterol <35 mg/dL was present in 20.3% of non-diabetic controls and 43.9% of diabetic patients, TGs >250 mg/dL were present in 9.3% vs. 22.6% of participants, respectively, and their combination was present in 4.9% of controls vs. 11.7% of patients with diabetes. The prevalence of low HDL-cholesterol, high TGs, and elevations of both HDL-cholesterol and TG levels were 37.7%, 29.3%, and 23.4%, respectively, for women with diabetes and 9.3%, 3%, and 1% for controls. In addition, diabetic women were more likely to have elevated LDL-cholesterol and total cholesterol levels. The triad of lipid abnormalities present in patients with type 2 diabetes is also present in non-diabetics who are insulin resistant. Indeed, the evidence is clear that insulin resistance is the major underlying abnormality that drives the dyslipidemia; there may be some exacerbation of each abnormality, and in particular, hypertriglyceridemia, when significant hyperglycemia is present, but in general, individuals with type 2 diabetes that is reasonably well controlled have the same dyslipidemia that is found in non-diabetics with only insulin resistance. Furthermore, although each of the components of the dyslipidemia may be affected by insulin resistance, there are convincing data that the effect of insulin resistance on the assembly and secretion of very-low-density lipoprotein (VLDL) apolipoprotein B (apo B) and TGs is central abnormality. Specifically, insulin resistance leads to increased assembly and secretion of VLDL, and the resulting hypertriglyceridemia leads, in turn, to lower HDL-cholesterol levels and smaller, cholesteryl ester depleted LDL. The basis for the interaction between insulin resistance and VLDL secretion is the complex post-translational regulation of apo B. Regulation of the assembly and secretion of VLDLs by the liver has been under intense study for the past 25 years, and much as been learned (22, 23, 24). Of particular relevance to this review, there is significant post-transcriptional and post-translational regulation of the hepatic assembly of apo B100 (and in rodents apo B48) with lipids to form VLDLs. Thus, studies in cultured liver cells indicate that a significant proportion of newly synthesized apo B100 may be degraded before secretion and that this degradation is inhibited when hepatic lipids are abundant. Studies in rodents support the tissue culture data. There is also abundant evidence that microsomal triglyceride transfer protein is essential for the assembly and secretion of VLDLs (25). Once in the plasma, VLDL TG is hydrolyzed by lipoprotein lipase (LPL); this step can be modified by the ratio of apo CII to apo CIII. Apo CII is the necessary activator of LPL, whereas apo CIII can inhibit LPL activity. Lipolysis generates smaller and denser VLDLs, and, subsequently intermediate density lipoprotein (IDL). These small VLDLs, together with IDLs, are similar to chylomicron remnants in that the small VLDLs and IDLs can be removed by the liver. However, unlike chylomicron remnants, small VLDLs and IDLs can also undergo further catabolism to become LDLs. It also seems that apo E, hepatic lipase, and LDL receptors play important roles in this metabolic cascade that ends with the generation of LDLs. Thus, the levels of VLDL TGs in the blood will be determined by the rates of secretion of VLDL TGs and apo B100, rates of lipolysis of VLDL TGs by LPL, and the rates of both removal of small VLDLs from the circulation and conversion to IDLs. Each of these processes can be affected by insulin resistance. This review will focus on VLDL TGs and apo B100 secretion, but the other metabolic steps will be discussed as well. Overproduction of VLDLs, with increased secretion of both TGs and apo B100, seems to be the central and most important etiology of increased plasma VLDL levels in patients with insulin resistance or type 2 diabetes (26). As noted above, the series of steps whereby apo B100 assembles with lipids and VLDL is secreted is regulated post-transcriptionally. Recent studies in cell culture, rodents, and humans have provided significant insights regarding the mechanisms whereby insulin resistance can drive increased VLDL secretion. First, the targeting of apo B100 for secretion as VLDLs is regulated significantly by the availability of its lipid ligands, particularly TGs. If hepatic lipids are unavailable for assembly into VLDLs, apo B can be degraded by the proteasome, after cotranslational ubiquitination (24). Limited lipid availability can also target apo B100 for post-translational degradation: some of that is in the endoplasmic reticulum and some distal to the endoplasmic reticulum. Insulin resistance is associated with increases in the three main sources of TGs for VLDLs assembly: fatty acid (FA) flux from adipose tissue to the liver, hepatic uptake of VLDLs, IDLs, and chylomicron remnants, and de novo lipogenesis (Figure 1). There are three major sources of TGs, the main substrate regulating apoB secretion as VLDL. They are FAs from peripheral tissues, particularly adipose tissue; chylomicron and VLDL remnants; and de novo hepatic lipogenesis. In insulin resistance, FA flux through the plasma to the liver is increased, and peripheral removal (by lipolysis) of chylomicron and VLDL TGs is reduced, leaving TG-enriched remnants for hepatic uptake; de novo lipogenesis can be increased. All of these sources of TGs may contribute to the increased VLDL secretion present in insulin-resistant people. Increased FA levels in blood and increased fatty acid flux to the liver have been known to occur in humans with insulin resistance with and without type 2 diabetes for >30 years. It is also known that plasma albumin-bound FAs are a source of VLDL TGs (27, 28). More recently, Lewis (29) showed that acutely raising plasma FA levels could increase VLDL secretion in normal individuals. We confirmed the role of FAs in chronically catheterized normal mice; intravenous of acid to hepatic secretion of apo B100 (and apo is synthesized in both the liver and in We have also in a of insulin resistance and increased secretion of VLDLs, that FA flux to the liver was increased similar findings were observed in a of insulin resistance and increased VLDL secretion In that lipase, one of the to FAs from cell TGs, have low levels of FAs in the blood and VLDL TGs The increased FA flux to the liver from insulin resistance in It is not clear this insulin resistance in only some adipose such as adipose or is present in all in insulin-resistant individuals. et al. showed that of fatty was increased in diabetics from all tissue including and uptake and of FAs and TGs on glucose because the latter is the necessary of the of TGs. of glucose uptake by insulin resistance in of FA in In addition, insulin lipase, the the is insulin lipase may be increased, resulting in greater lipolysis of TGs and increased of FAs from The of insulin resistance in the the underlying of insulin resistance syndrome but factors, similar to other complex atherosclerosis and Although and factors have been in their in insulin resistance has been to The roles of such as and in the and of VLDLs to be of the basis for insulin resistance, FAs are not in their levels in the circulation will and this is associated with resistance to both glucose uptake and in and an increase in glucose and by the liver. in because insulin secretion will be increased to for the increased plasma glucose levels. In the liver, increased uptake of FAs from the the of TGs and the assembly and secretion of VLDL The additional roles of in VLDL assembly and secretion will be discussed uptake of an important role in regulating both and fasting levels of TGs in the is in insulin-resistant and this is associated with hepatic uptake of remnants that more TGs than remnants in normal people. This will VLDL assembly and secretion, as the liver to regarding its FA and TG of TG FAs will to increased VLDL secretion. This has been in cultured liver cells and humans the chronically catheterized normal described above, we showed that of an of TGs and could both apo B and TG secretion Of we found that TG FAs through uptake were not as a for VLDL secretion as were FAs by We are with studies to these in the effects of different sources of fatty on VLDL assembly and secretion. The source of TGs for assembly and secretion with apo B100 is de novo fatty acid in the liver. In rodents, lipogenesis is an important source of VLDL data in humans are but recent have that lipogenesis contribute significantly to VLDL TGs and is increased in individuals with and insulin resistance et al. defined in the regulation of hepatic lipogenesis by the protein that hepatic was regulated by through the in was increased Of in their studies with it that, although insulin resistance in the regulating this resistance did not to to lipogenesis In recent studies we found that lipogenesis is increased in the apo a of obesity, insulin resistance, and increased VLDL secretion but that or was not On the other hand, the and of the was increased in the of apo and that together with published data an important role of in hepatic lipogenesis in other of and insulin resistance has led to this and Studies a number of years in cultured liver cells have that insulin not only lipogenesis but also a role in apo B is for secretion or degradation through a can target apo B for This degradation is post-translational and reticulum. In recent studies, et al. that of apo B degradation in cultured liver cells may be to high levels of in in cultured cells have been to in studies in rodents and In the both Lewis et al. and et al. showed VLDL secretion, both TGs and apo in normal subjects with of insulin and glucose Importantly, the effects of insulin on apo B degradation to significantly insulin resistance was this is in cultured cells and humans In studies in we are at the of hepatic insulin resistance in that insulin receptors only in the liver indicate that, in the presence of and and TG secretion, the rates of secretion of apo B100 and apo from the liver are either normal or increased. This of TG and apo B secretion a role of in the of insulin apo B is degraded and more is even when hepatic lipid availability and secretion are A important and of the described above to the increasing prevalence of fatty in with the metabolic syndrome Although such individuals to be to increase VLDL secretion as they to hepatic lipid in the of increased sources of TGs, they and hepatic TG It is that the relative of both insulin resistance and determine fatty liver will Thus, there is insulin resistance, increased uptake of albumin-bound and remnants and of the of there may be apo B of to the TGs through VLDL there is insulin resistance and, in particular, there is through the apo B degradation VLDLs may be and and a fatty liver may (Figure This further Insulin de novo hepatic through its to increase the of the major Insulin also can target apoB for degradation In an insulin-resistant liver, the relative effects of insulin to increase FA and TG and to availability of apoB to TGs from the liver will be a major of both hepatic TG and plasma TG levels. The hypertriglyceridemia of the metabolic syndrome is however, driven by of VLDLs. in LPL levels have been in some type 2 and this may contribute significantly to elevated TG levels, particularly in VLDLs and can for the same for TG removal from the because is more in patients with the metabolic syndrome, the with both and VLDLs are from the circulation will be hepatic uptake of VLDL remnants is a complex involving and Insulin resistance to LDL lipase is increased in individuals with diabetic dyslipidemia, and although high hepatic lipase may be important for the low levels and the of small dense of this lipid the that it is elevated that hepatic TG of VLDL remnants is as a of elevated levels of either or VLDLs. In with insulin resistance and type 2 regulation of plasma levels of that of its VLDLs, is In the presence of hypertriglyceridemia, cholesteryl are Thus, individuals with type 2 diabetes and to hypertriglyceridemia may have the B of LDL described by and The increase in small dense in insulin resistance is in from the of cholesteryl ester transfer This is associated with in the can the of VLDL TGs for LDL cholesteryl a cholesteryl LDL The TGs in LDL can be by LPL or hepatic lipase, the small, dense LDLs. The that small dense are present in insulin-resistant and type 2 diabetic patients even when they have normal TG levels other factors are at One factor is hepatic lipase, as noted is increased in insulin resistance and therefore, more TGs in LDLs. levels of blood FAs have also been to of cholesterol and TGs between and VLDLs. HDL-cholesterol and apo levels are in insulin-resistant people. of this as in the of small dense from the of cholesteryl ester transfer transfer of cholesteryl from to and A is the relationship between plasma insulin are of insulin resistance, and HDL-cholesterol levels. catabolism of apo is increased in type 2 diabetics with low as it is in non-diabetics with similar lipoprotein Although apo levels are of hypertriglyceridemia not apo levels. Studies have that apo may from TG-enriched and be by the Increased hepatic lipase in insulin resistance, with increased of TGs and the generation of smaller may also play a role in this of cholesterol or increased of cholesteryl ester to is in the low levels present in insulin resistance is under However, the the low HDL-cholesterol and apo are present even when TG levels are normal ester transfer protein mechanisms are During the past 10 years, it has become clear that insulin-resistant are associated with increases in such as protein During that same studies have that adipose tissue is not simply a for but is an that a number of that have been Among these are activator and of these are that have been to in insulin In particular, has been to play an important role in of and insulin resistance has been to hypertriglyceridemia in rodents by increasing VLDL secretion In two recent investigators showed that adipose tissue of and humans is by and that these are the source of most of the and significant of the and that the circulation from the adipose driven by these is the basis of insulin resistance or a to other that insulin resistance, increased FA from to be However, these new data it clear that in adipose tissue will be associated with not only in but with secretion of that are to the insulin resistance or metabolic syndrome. The metabolic syndrome, is in most to insulin resistance, is a the and will impact on both the incidence of type 2 diabetes and the between insulin resistance and the components of the metabolic syndrome will and to the phenotypic dyslipidemia, in a more and In this review, we have the complex between insulin resistance and dyslipidemia, with a particular focus on the regulation of the assembly and secretion of VLDLs and the to lower plasma TG levels, plasma HDL-cholesterol levels, and LDL will have to be at least in part, on VLDL secretion. adipose tissue is the most to insulin and VLDL secretion. This study was supported by and