HDL Particle Number Research Articles

Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD

The importance of the number of circulating low-density lipoprotein (LDL) cholesterol particles, in addition to total LDL level, has been increasingly recognized. The effects of extended-release niacin (ERN) on LDL particle numbers have not been studied. To evaluate ERN's effects on LDL particle numbers. Fifty-four patients with stable coronary artery disease (CAD) and well-controlled LDL levels were randomly assigned to 3 months of ERN (1 g/day) or placebo in addition to their baseline medications. Lipoprotein particle number was analyzed by proton nuclear magnetic resonance spectroscopy at baseline and after 3 months. Compared to baseline, the addition of ERN had no significant effect on total LDL cholesterol levels; however, ERN decreased the number of medium and small LDL particles (P < .005). After 3 months, ERN decreased the number of medium and small LDL particles compared to placebo-treated patients (P < .05). ERN raised HDL cholesterol levels by 2.7%, significantly increased the number of large HDL particles (P < .001), and decreased the number of small HDL particles (P = .027) compared to placebo. There were no significant changes in lipid values or particle numbers in the placebo-treated patients. In patients with stable coronary artery disease and well-controlled LDL cholesterol levels, ERN reduced the number of circulating particles of the more atherogenic subtypes of LDL, despite having no effect on total LDL cholesterol levels. ERN also favorably altered the number of HDL particles. ERN-induced alterations in lipoprotein particle numbers may contribute to its anti-atherosclerotic effects, and these effects may not be evident from the standard lipid profile.

Statins but not fibrates improve the atherogenic to anti-atherogenic lipoprotein particle ratio: a randomized crossover study

BackgroundPrior studies suggested low density lipoprotein particle (LDLP) size is a predictor of atherosclerosis. Knowledge of effects of lipid lowering drugs on lipoprotein subclasses is useful. We treated subjects with hyperlipidemia sequentially with statins and fibrates, the 2 main classes of lipid lowering therapy and studied changes in NMR lipoprotein subclasses.Methods35 subjects (21 males; 60 ± 12 y) were enrolled in a crossover study. Subjects had baseline lipid profile & apoB. Lipoprotein subclasses, particle numbers and diameters were assessed with NMR spectroscopy. Subjects were randomized to simvastatin 20 mg or fenofibrate 200 mg. Repeat testing was done at 12 weeks. After 6 week washout, subjects were started on alternate drug for 12 weeks with pre/post tests.ResultsBoth therapies resulted in expected changes in lipids and apoB. Decreases in total cholesterol, LDL and apoB were greater with simvastatin. Fenofibrate led to small increase in HDL. Both therapies decreased LDLP. Reduction in LDLP was greater with simvastatin (32%, p < .001) compared to fenofibrate (17%; p = .036 vs pre; p = .027 vs simvastatin end). Fenofibrate resulted in 17% rise in large LDLP (p = .06 vs pre) and 32% drop in small LDLP (p = .007 vs pre). Simvastatin led to decrease in both LDLP fractions (19% large LDLP; p = .001 vs fenofibrate end; 34% small LDLP, p = .019 vs pre). With fenofibrate, LDLP size increased from 20.4 nm to 20.8 nm (p = .037). There was no change in LDLP size with simvastatin. There was 18% increase in HDL particle number (HDLP) with fenofibrate (p = .05). There were no changes in HDLP with simvastatin. There were no changes in HDLP size with either drug. Pre- and post-therapy LDLP/HDLP ratio was similar with fenofibrate but was reduced by simvastatin (p = .045).ConclusionSimvastatin reduced LDLP across all subclasses with no effect on size. Simvastatin had no effect on HDLP. Fenofibrate had weak effect on LDLP number but increased LDLP size by raising large LDLP and reducing small LDLP. Fenofibrate had weak effect on HDLP number with no change in size. Importantly, net atherogenic to antiatherogenic lipoprotein ratio (LDLP/HDLP) was reduced by simvastatin but not by fenofibrate.

Cholesterol provided by eggs and carbohydrate restriction distinctly modulate lipoprotein metabolism in adult men

Twenty eight men (BMI 26‐37 kg/m2) between 40‐70 y were recruited to evaluate the effects of carbohydrate restriction (CR, ~10% energy from carbohydrates) and dietary cholesterol (CHOL) on lipoprotein metabolism. Subjects were randomly allocated to the EGG group (640 additional mg CHOL/d) or the SUB group (0 mg additional CHOL/d) for 12 wk. Lipoprotein size and subclasses determined by use of NMR, apolipoproteins (apo) A‐I, A‐II, B, C‐II, C‐III, and E measured by antibody‐immobilized beads and Luminex MAP technology and lecithin cholesterol acyltransferase (LCAT) and cholesterol ester transfer protein activities were measured both at baseline and post‐intervention. We observed a 45% decrease in plasma triglycerides for all subjects, which was associated with decreases in the large and medium VLDL subclasses (P &lt; 0.001). In agreement with these observations, a decrease in apo B (P &lt; 0.01) was also observed. In addition, CR resulted in a 133% increase in apo C‐II [lipoprotein lipase (LPL) activator] and a 65% decrease in apo C‐III, (LPL inhibitor) (P &lt; 0.0001). The smaller HDL subclasses and apo A‐II levels were also decreased at 12 wk (P &lt; 0.001). CHOL effects were mainly on LDL and HDL metabolism. Although an increase of the larger LDL subclass was observed for all subjects, the EGG group had a greater increase (P &lt; 0.05). The EGG group also presented increases in HDL‐C, higher number of large HDL particles (P &lt; 0.01) and an increased LCAT activity (P &lt; 0.05) compared to the SUB group. These results indicate that CR favorably alters VLDL metabolism while CHOL provided by eggs favors the formation of less atherogenic lipoproteins, larger LDL and HDL.

Effects of apoA-V on HDL and VLDL metabolism in APOC3 transgenic mice

Apolipoprotein A-V (apoA-V) and apoC-III are exchangeable constituents of VLDL and HDL. ApoA-V counteracts the effect of apoC-III on triglyceride (TG) metabolism with poorly defined mechanisms. To better understand the effects of apoA-V on TG and cholesterol metabolism, we delivered apoA-V cDNA into livers of hypertriglyceridemic APOC3 transgenic mice by adenovirus-mediated gene transfer. In response to hepatic apoA-V production, plasma TG levels were reduced significantly as a result of enhanced VLDL catabolism without alternations in VLDL production. This effect was associated with reduced apoC-III content in VLDL. Increased apoA-V production also resulted in decreased apoC-III and increased apoA-I content in HDL. Furthermore, apoA-V-enriched HDL was associated with enhanced LCAT activity and increased cholesterol efflux. This effect, along with apoE enrichment in HDL, contributed to HDL core expansion and alpha-HDL formation, accounting for significant increases in both the number and size of HDL particles. As a result, apoA-V-treated APOC3 transgenic mice exhibited decreased VLDL-cholesterol and increased HDL-cholesterol levels. ApoA-V-mediated reduction of apoC-III content in VLDL represents an important mechanism by which apoA-V acts to ameliorate hypertriglyceridemia in adult APOC3 transgenic mice. In addition, increased apoA-V levels accounted for cholesterol redistribution from VLDL to larger HDL particles. These data suggest that in addition to its TG-lowering effect, apoA-V plays a significant role in modulating HDL maturation and cholesterol metabolism.

Change in Plasma Lutein after Egg Consumption Is Positively Associated with Plasma Cholesterol and Lipoprotein Size but Negatively Correlated with Body Size in Postmenopausal Women

We investigated associations between plasma concentrations of cholesterol and lutein after consumption of eggs. Using a crossover design, 22 postmenopausal women (50–77 y) consumed an egg treatment (640 mg/d additional cholesterol and 600 μg/d additional lutein + zeaxanthin) or a baseline treatment (no additional cholesterol or lutein + zeaxanthin) for 30 d, followed by a 3-wk washout period and the alternate diet. The increases in plasma total cholesterol and lutein due to egg consumption were related (r = 0.48, P < 0.05). There was a positive correlation between LDL size (r = 0.45, P < 0.05), HDL size (r = 0.64, P < 0.01), and plasma lutein, but no relation with the number of LDL or HDL particles. The activities of cholesterol ester transfer protein and lecithin cholesterol acyltransferase, although important in the exchange of cholesterol among lipoproteins, were not associated with changes in plasma lutein. Plasma lutein concentrations observed during the baseline period were a strong predictor of the increase in plasma lutein after egg treatment (r = 0.50 P < 0.05). There was a negative association between the change in lutein due to egg consumption and BMI (r = −0.40, P < 0.06) and waist circumference (r = −0.49, P < 0.05). This was particularly evident in individuals with BMI >29. We conclude that the increase in plasma lutein after egg consumption is associated with the change in plasma total cholesterol, but that the effect is diminished by obesity. Lipoprotein size, but not number, also affects plasma response to dietary lutein.

Strategy for “raising HDL”; HDL-cholesterol or HDL particle numbers insight from cholesteryl ester transfer protein deficiency

Strategy for “raising HDL”; HDL-cholesterol or HDL particle numbers insight from cholesteryl ester transfer protein deficiency

Paraoxonase 1 response to a high-fat diet: gender differences in the factors involved.

Diets consumed in industrialized countries are rich in fat and increase the incidence of atherosclerosis, a process reported to be influenced by gender. Considering the anti-atherogenic role attributed to serum Paraoxonase 1 (PON1) activity, and given the pro-atherogenic effects described for saturated fatty acids (SFA), as opposed to the beneficial ones conferred to monounsaturated fatty acids (MUFA), the aim of this study was to investigate the response of male and female rat serum PON1 activity and its related factors to a high-fat (HF), hypercaloric diet (fat representing 55.2% of the energy) containing similar amounts of SFA and MUFA. The HF diet feeding did not alter total body weight, but increased adiposity. Nevertheless, and in spite of the increased adiposity, the HF diet did not entail a more pro-inflammatory serum adipokine or lipid profile or increased lipid peroxidation. Paraoxonase activity was reduced in both male and female HF fed rats, due to a reduction of PON1 mRNA levels in males and to a reduced stability and/or number of HDL particles responsible for PON1 transport in females. Both the maintenance of body weight and the MUFA content in the diet would be among the factors responsible for the attenuation of the negative effects usually related to excessive fat intake and for the reduction in PON activity, whose antioxidant activity would be less necessary in this situation.

Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD

The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1.5-3.0 and approximately 3.0-5.0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.

Lipoprotein particles, insulin, adiponectin, C-reactive protein and risk of coronary heart disease among men with metabolic syndrome

We tested the hypotheses whether nuclear magnetic resonance (NMR) determined lipoprotein particles, insulin and adiponectin, and C-reactive protein (CRP) and white blood cell (WBC) count as markers of inflammation predicted risk of coronary heart disease (CHD) death among 428 men age 35–57 years with metabolic syndrome (MetSyn) in a matched case control study within the multiple risk factor intervention trial. Blood samples collected at entry into the study and stored at −60 °C were obtained from central storage for blood analyte analysis. Two hundred and fourteen men with MetSyn who died of CHD were matched with 214 men with MetSyn who did not die of CHD during 18 years of follow-up. Cases were matched to controls on age, study group, number of factors present in the MetSyn, and presence or absence of a nonfatal CVD event during the trial. Mortality follow-up was determined using the National Death Index. Higher levels of high density lipoprotein particles (HDL-P), especially medium-sized HDL-P [hazard ratio (95% confidence interval) 0.45 (0.25–0.83, P < 0.01), quartile 1 as compared to quartile 4], were associated with lower risk of CHD death. Low density lipoprotein (LDL) particles were not associated with increased risk of CHD. Elevated LDL cholesterol (LDL-C), smoking and WBC count were, but levels of adiponectin, insulin and CRP were not significantly related to CHD death. In multivariate models adjusting for smoking and LDL-C, medium HDL-P and WBC count remained independent predictors of CHD death. Number of HDL particles, especially medium-sized HDL particles and WBC count were independent predictors of CHD death among men with MetSyn.

A Combination Therapy Including Psyllium and Plant Sterols Lowers LDL Cholesterol by Modifying Lipoprotein Metabolism in Hypercholesterolemic Individuals

We conducted a randomized, double blind, crossover, placebo-controlled study to determine the effects of a combination therapy including plant sterols (PS) and psyllium (PSY), provided via cookies, on plasma lipids and on the size and subfraction distribution of VLDL, LDL, and HDL. Thirty-three healthy free-living individuals (11 males and 22 females), aged 35–65 y, with a BMI between 25 and 35 kg/m2 and initial plasma LDL cholesterol (LDL-C) concentrations between 2.6 and 4.1 mmol/L (100 and 160 mg/dL), were randomly assigned to receive treatment cookies (7.68 g/d PSY and 2.6 g/d PS) or placebo cookies (0 g PSY+PS) for 4 wk. After a 3-wk washout period, subjects received the other cookies for an additional 4 wk. Plasma total cholesterol concentrations were significantly reduced for all subjects, from 5.65 ± 0.72 mmol/L after the placebo period to 5.28 ± 0.76 mmol/L after the PSY+PS cookie period (P < 0.01). These reductions were primarily in LDL-C, which decreased from 3.48 ± 0.70 to 3.14 ± 0.78 mmol/L after PSY+PS cookie consumption (P < 0.01). Intake of the PSY+PS cookie decreased the number of intermediate density lipoprotein (IDL), LDL, and HDL particles (P < 0.05) and plasma apo B concentrations (P < 0.01). The decreases in LDL and HDL particles were in the small subfractions. Because smaller LDL particles are associated with an increased risk of heart disease and because smaller HDL particles are indicative of diminished reverse cholesterol transport, we conclude that the combination therapy resulted in a less atherogenic lipoprotein profile. In addition, the evaluation of lipoprotein subfractions resulting from the action of the fiber and plant sterols in the intestinal lumen provides an insight on the secondary mechanisms of plasma LDL-C lowering.

Carbohydrate restriction (CR) and dietary cholesterol influence the number of lipoprotein particles and distribution of lipoprotein subfractions in guinea pigs

Guinea pigs (n=10) were randomly assigned to 3 different groups: 42% energy from carbohydrate (CHO) and 0.04% cholesterol (control), 42% CHO and 0.25% cholesterol (HCHO) or 11% energy from CHO and 0.25% cholesterol (CR) for 12 wk. Plasma lipids were evaluated and lipoprotein subclasses and size were analyzed by nuclear magnetic resonance. There were no differences in VLDL, LDL or HDL cholesterol or triglyceride concentrations between the CR and the HCHO groups; however all these plasma lipids were higher compared to the control group (P < 0.0001). High CHOL (HCHO and CR groups) resulted in larger VLDL particles (71.1 ± 6.9, 78.9 ± 3.33 nm, respectively) compared to control (44.3 ± 10.8 nm). In addition, there were higher concentrations of the large VLDL (>60nm) and the medium VLDL (> 27 nm) in the high CHOL groups compared to the control (P < 0.001). Similarly the number of HDL particles and the concentration of the medium (>8.2 nm) and small HDL (>7.2 nm) were higher with the high CHOL (P < 0.001). In contrast, CHO restriction significantly affected the size and concentration of LDL particles. Total LDL particles were lower in the CR (291.3 ± 85.0 nmol/L) compared to HCHO group (467.6 ± 113.1 nmol/L). The concentrations of medium LDL (> 19.8 nm) and small LDL (>18 nm) were lower in the CR group (98.4 ± 90.8 and 29.3 ± 24.9 nmol/L, respectively) than in the HCHO group (261.8 ± 105.8 and 64.9 ± 27.9 nmol/L, respectively) (P < 0.0001). These results indicate that CHOL increased the atherogenicity of both VLDL and HDL while CR decreased the number of LDL particles, specifically the more atherogenic smaller LDL.

A carbohydrate restricted diet (CRD) favorably affects lipoprotein metabolism in overweight men

To determine the effects of a CRD with and without soluble fiber on lipoprotein metabolism, 29 men were matched by age and BMI then randomly assigned to consume 3 g/d of a soluble fiber supplement (n=14) or placebo (n=15) with a macronutrient distribution of ~10%, carbohydrate, 65% fat, and 25% protein for 12 wks. Lipoprotein particle size and quantity were measured by nuclear magnetic resonance. No between groups differences were observed in any parameter, thus data were pooled and compared from baseline to 12 wks. After 12 wks, subjects lost a mean 7.5 kg (P<0.001). Plasma LDL-C decreased by 8.9% and mean LDL particle size increased by 2.5% (P<0.001). Consistent with the hypothesized metabolic origins of LDL heterogeneity, greatest reductions were seen in large VLDL particles (−47−7%) leading to significant reductions in small LDL particles (−29.9%) and increases in large LDL particles (35.4%). The 38.6% reduction in plasma triglycerides (TG) was associated with significant reductions in apolipoprotein C-I (−13.8%), C-III (− 21.2%), and E (−12.5%). HDL-C increased by 12% (P<0.05), with increased mean HDL particle diameter and large HDL particle number (P<0.001). Changes in plasma TG positively correlated with reductions in large VLDL (P<0.01) and negatively correlated with large HDL (P<0.01). We conclude that a CRD alters the secretion and processing of plasma lipoproteins rendering VLDL, LDL and HDL particles associated with decreased risk for atherosclerosis and coronary heart disease.

Antiatherogenic small, dense HDL—guardian angel of the arterial wall?

Our understanding of the relationship between the atheroprotective activities of HDL and heterogeneity of HDL particles has advanced greatly. HDL particles are highly heterogeneous in structure, intravascular metabolism and antiatherogenic activity. In this review, we discuss new findings on the antiatherogenic properties of HDL particles. Small, dense HDL possesses potent antioxidative activity but this is compromised under conditions of atherogenic dyslipidemia. HDL functional deficiency frequently coincides with reductions in HDL-cholesterol concentration and alterations in HDL metabolism and structure. Formation of small, dense HDL particles with attenuated antiatherogenic activity can be mechanistically related to HDL enrichment in triglycerides and in serum amyloid A, depletion of cholesteryl esters, covalent modification of HDL apolipoproteins and attenuated antiatherogenic function of apolipoprotein AI. Low circulating levels of HDL cholesterol might, therefore, be associated with the defective functionality of small HDL particles of abnormal structure and composition. In common metabolic diseases, such as type 2 diabetes and metabolic syndrome, deficiency of HDL particle number and function favor accelerated atherosclerosis. Therapeutic normalization of the quantity, quality and biological activities of HDL particles thus represents a novel approach to attenuating atherosclerosis in dyslipidemic individuals with metabolic disease. Cholesteryl ester transfer protein inhibitors, nicotinic acid, reconstituted HDL and other HDL-raising agents are being investigated. Induction of selective increase in the circulating concentrations of small, dense HDL3 particles with increased antiatherogenic activity seems especially promising, particularly for therapy of atherogenic dyslipidemia.

Plasma LDL and HDL characteristics and carotenoid content are positively influenced by egg consumption in an elderly population1

BackgroundApproximately 1/3 of individuals have a high plasma response to dietary cholesterol (hyper-responders). Although increases in both LDL and HDL cholesterol have been observed, limited data exist regarding effects of egg consumption on lipoprotein subclasses and circulating carotenoids.Methods29 postmenopausal women (50–68 y) and 13 men (60–80 y) were assigned to either 3 eggs (EGG, 640 mg cholesterol/d) or an equal volume of cholesterol-free egg substitute (SUB, 0 mg cholesterol/d) for 30 d. Following a 3 wk wash out, subjects crossed over to the alternate diet. Individuals with a response to dietary cholesterol > 2.2 mg/dL for each additional 100 mg of dietary cholesterol were classified as hyper-responders while hypo-responders were those with a response ≤ to 2.2 mg/dL. Nuclear Magnetic Resonance (NMR) spectroscopy determined LDL and HDL size & particle concentrations. Dietary records were used to evaluate carotenoid consumption.ResultsHyper-responders had higher concentrations of both LDL (LDL-C) and HDL (HDL-C) cholesterol after EGG. In contrast, the concentrations of plasma LDL-C and HDL-C did not differ between the EGG and SUB for the hypo-responders. After EGG, hyper-responders had larger (≥ 21.2 nm) less atherogenic LDL particle (P < 0.001) and larger HDL particle (> 8.8 nm) (P < 0.01), with no significant difference in the total number of LDL or HDL particles. Regardless of response classification, all individuals had an increase in plasma lutein (from 32.4 ± 15.2 to 46.4 ± 23.3 ng/L) and zeaxanthin (from 8.8 ± 4.8 to 10.7 ± 5.8 ng/L) during EGG, yet hyper-responders displayed higher concentrations of carotenoids when compared to hypo-respondersConclusionThese findings suggest that the increases in LDL-C and HDL-C due to increased egg consumption in hyper-responders are not related to an increased number of LDL or HDL particles but, to an increase in the less atherogenic lipoprotein subfractions. Also, increases in plasma carotenoids after EGG may provide a valuable dietary source for this population.

Fish protein improves blood pressure but alters HDL2 and HDL3 composition and tissue lipoprotein lipase activities in spontaneously hypertensive rats.

The two-month effects of dietary fish protein and casein on VLDL, HDL(2) and HDL(3) compositions and hepatic lipase (HTGL) and tissue lipoprotein lipase (LPL) activities were examined in spontaneously hypertensive rats (SHR) at 4 wk of age. After 2 mo of experiment, the fish protein diet induced lower blood pressure (-14 %) as compared to casein. Liver triacylglycerol and total cholesterol concentrations were 1.37- and 1.71-fold lower in the fish protein group than in the casein group, respectively. Total cholesterol concentration in plasma was also diminished by fish protein (-21 %) and was reflected in HDL(2) fraction (-44 %). SHR fed the fish protein diet as compared with those fed casein, showed a significantly low HDL(3) particle number, as measured by diminished HDL(3) mass and apo A-I. The consumption of fish protein did not affect VLDL particle number, but significantly decreased VLDL-triacylglycerol (-32 %) and adipose tissue total lipid concentrations as compared to casein. This was accompanied by diminished HTGL and adipose tissue LPL activities (-10%, -91%, respectively). These data demonstrate that fish protein plays an antihypertensive role and reduces plasma and tissue lipid concentrations. Thus, a fish protein intake might be beneficial for patients with hypertension.

An elevation of triglycerides reflecting decreased triglyceride clearance may not be pathogenic – relevance to high-carbohydrate diets

The fact that carbohydrate-rich diets often increase plasma triglycerides has led some to question the wisdom of such diets. This increase is primarily attributable to a decrease in the efficiency of triglyceride clearance – whereas the elevation of triglycerides observed in insulin-resistant subjects stems mainly from increased hepatic production of VLDL particles. There is growing reason to suspect that the increased coronary risk associated with elevated triglycerides in Western epidemiology reflects the fact that high triglycerides are a marker for insulin resistance syndrome, rather than any inherent pathogenic role of triglycerides per se. Thus, endothelial dysfunction is seen only in those hypertriglyceridemic subjects who are insulin resistant, and is absent in patients whose markedly elevated triglycerides reflect genetically defective lipoprotein lipase activity. Triglyceride levels are relatively high in certain Third World societies which are virtually immune to coronary disease so long as they persist in their traditional very-low-fat diets; in Ornish's celebrated study, a moderate rise in triglycerides coincided with a marked reduction in coronary events. Although the particle size of both LDL and HDL tends to decrease when triglyceride levels are high, it is questionable whether this effect has a major pathogenic impact. The one clear drawback of high-carbohydrate diets is a decrease in HDL particle number, resulting from decreased hepatic production of apoA-I; this effect is seen whether or not triglycerides increase. The very favorable effects of very-low-fat, whole food, quasi-vegan diets on LDL cholesterol, insulin sensitivity, and body weight appear to more than compensate for this decrease in HDL; it is notable that HDL levels tend to be quite low in Third World cultures at minimal risk for coronary disease. On the other hand, this decrease in HDL may be of more significance in the context of omnivore diets only moderately low in fat, as suggested by the fact that diets higher in unsaturated fats emerge as more protective in Western prospective epidemiology. The tendency of high-carbohydrate diets to boost triglycerides can be minimized by exercise training, supplemental fish oil, an emphasis on fiber-rich, low-glycemic-index whole foods, and the “spontaneous” weight loss often seen with ad libitum consumption of such diets – measures which are highly recommendable whether or not triglycerides are a concern.

Endothelial lipase is a major determinant of HDL level.

A new member of the lipase gene family, initially termed endothelial lipase (gene nomenclature, LIPG; protein, EL), is expressed in a variety of different tissues, suggesting a general role in lipid metabolism. To assess the hypothesis that EL plays a physiological role in lipoprotein metabolism in vivo, we have used gene targeting of the native murine locus and transgenic introduction of the human LIPG locus in mice to modulate the level of EL expression. Evaluation of these alleles in a C57Bl/6 background revealed an inverse relationship between HDL cholesterol level and EL expression. Fasting plasma HDL cholesterol was increased by 57% in LIPG(-/-) mice and 25% in LIPG(+/-) mice and was decreased by 19% in LIPG transgenic mice as compared with syngeneic controls. Detailed analysis of lipoprotein particle composition indicated that this increase was due primarily to an increased number of HDL particles. Phospholipase assays indicated that EL is a primary contributor to phospholipase activity in mouse. These data indicate that expression levels of this novel lipase have a significant effect on lipoprotein metabolism.

Apolipoprotein A-II/A-I ratio is a key determinant in vivo of HDL concentration and formation of pre-beta HDL containing apolipoprotein A-II.

Overexpression of human apolipoprotein A-II (apo A-II) in mice induced postprandial hypertriglyceridemia and marked reduction in plasma HDL concentration and particle size [Boisfer et al. (1999) J. Biol. Chem. 274, 11564-11572]. We presently compared lipoprotein metabolism in three transgenic lines displaying plasma concentrations of human apo A-II ranging from normal to 4 times higher, under ad libitum feeding and after an overnight fast. Fasting dramatically decreased VLDL and lowered circulating human apo A-II in transgenic mice; conversely, plasma HDL levels increased in all genotypes. The apo A-I content of HDL was inversely related to the expression of human apo A-II, probably reflecting displacement of apo A-I by an excess of apo A-II. Thus, the molar ratios of apo A-II/A-I in HDL were significantly higher in fed as compared with fasted animals of the same transgenic line, while endogenous LCAT activity concomitantly decreased. The number and size of HDL particles decreased in direct proportion to the level of human apo A-II expression. Apo A-II was abundantly present in all HDL particles, in contrast to apo A-I mainly present in large ones. Two novel findings were the presence of pre-beta migrating HDL transporting only human apo A-II in the higher-expressing mice and the increase of plasma HDL concentrations by fasting in control and transgenic mice. These findings highlight the reciprocal modifications of VLDL and HDL induced by the feeding-fasting transition and the key role of the molar ratio of apo A-II/A-I as a determinant of HDL particle metabolism and pre-beta HDL formation.

Transgenic animals with altered high-density lipoprotein composition and functions.

Our understanding of HDL metabolism in vivo has greatly advanced from studies with transgenic animals. Interactions between HDL apolipoproteins, transfer proteins, lipolytic enzymes and receptors modulate HDL size, particle number and fractional catabolic rate. The protective effect of HDL on atherosclerosis depends on the combined actions of HDL proteins and the metabolism of apo B-lipoproteins.

Lipid metabolism in experimental animals

Publications are scarce in the way in chich metabolic processes are affected by the ingestion of heated fats used to prepare food. Similarly studies measuring metabolic effects of the consumption on fried food are poorly known. The purpose of this presentation is to summarize information on frying fats and frying foods upon lipid metabolism in experimental animals. Food consumption is equivalent or even higher when oils or the fat content of frying foods are poorly alterated decreasing their acceptability when their alteration degree increase. After 4hr. experiment the digestibility and absorption coefficients of a single dosis of thermooxidized oils were significantly decreased in rats, however the digestive utilization of frying thermooxidized oils included in diets showed very little change in comparison with unused oils by feeding trials on rats. Feeding rats different frying fats induced a slight hypercholesterolemic effect being the magnitude of this effect related to the linoleic decrease in diet produced by frying. However HDL, the main rat-cholesterol carrier, also increased, thus the serum cholesterol/HDL-cholesterol ratio did not change. Results suggest that rats fed frying fats adapt their lipoprotein metabolism increasing the number of HDL particles. Deep fat frying deeply changed the fatty acid composition of foods, being possible to increase their n-9 or n-6 fatty acid and to decrease the saturated fatty acid contents by frying. When olive oil-and sunflower oil-fried sardines were used as the only protein and fat sources of rats-diets in order to prevent the dietary hypercholesterolemia it was provided that both fried-sardine diets showed a powerful check effect on the cholesterol raising effect induced by dietary cholesterol. The negative effect of feeding rats cholesterol plus bovine bile to induce hypercholesterolemia on some cell-damage markers such as lactate dehydrogenase, transaminases, alkaline phosphatase, was significantly check when olive oil- or sunflower oil-fired sardines were used in rats. However, gamma-glutamyltransferase increased when diets containing fried sardines from oils used several times for frying were consumed. In conclusion frying appears to be an useful tool to modify the fatty acid composition of food and the lipoprotein metabolism of consumers, however this culinary procedure has to be gently done to avoid high level of potential toxic compounds.