BACKGROUND:Smaller, denser LDL particles are associated with an increased risk for cardiovascular diseases (CVD). In youths, data on the distribution of LDL particle size and on its association with other CVD risk factors are limited.METHODS:We determined LDL peak particle size by nondenaturing 2%-16% gradient gel electrophoresis in a representative sample of 2249 youths 9, 13, and 16 years of age who participated in a school-based survey conducted in 1999 in the province of Quebec, Canada. Standardized clinical measurements and fasting plasma lipid, glucose, and insulin concentrations were available.RESULTS:The LDL peak particle size distribution was gaussian. The 5th, 50th (median), and 95th percentiles by age and sex were 255.5-258.6, 262.1-263.2, and 268.1-269.5 A, respectively. The prevalence of the small, dense LDL phenotype (LDL peak particle size <or=255 A) was 10% in participants with insulin resistance syndrome (IRS), in contrast to 1% in those without IRS. In a multiple regression analysis, the association of LDL size with other CVD risk factors [apolipoprotein B, HDL-cholesterol (HDL-C), triglyceride (TG), and insulin concentrations, and body mass index] was strongest with TG and HDL-C concentrations: a 1 SD increase in log(e)-transformed TG concentration was associated with a 1.2 A reduction in LDL size, and a 1 SD increase in HDL-C was associated with a 1.1 A increase in LDL size.CONCLUSIONS:Although the small, dense LDL phenotype is less prevalent in youths than adults, its prevalence is clearly increased in childhood IRS. Metabolic correlates of LDL size are similar in youths and adults.

Apolipoprotein (apo) A-IV, first identified 28 years ago as a plasma lipoprotein moiety, is now known to participate in the regulation of various metabolic pathways. It is synthesized primarily in the enterocytes of the small intestine during fat absorption. After entry into the bloodstream, the 46-kDa glycoprotein apo A-IV appears associated with chylomicrons, high-density lipoproteins, and in the lipoprotein-free fraction. It has a role in lipid absorption, transport and metabolism, and may act as a post-prandial satiety signal, an anti-oxidant and a major factor in the prevention of atherosclerosis. After summarizing and discussing these functions for reader's comprehension, the current review focuses on the regulation of apo A-IV by nutrients, biliary components, drugs, hormones and gastrointestinal peptides. The understanding of the involved mechanisms that underline apo A-IV regulation may in the long run allow us to switch on its gene, which may confer multiple beneficial effects, including the protection from atherosclerosis.

The liver plays a central role in lipoprotein metabolism and cholesterol homeostasis. As the physiopathology of lipid disorders in non-insulin-dependent diabetes mellitus (NIDDM) is multifactorial and still imperfectly known, we evaluated its onset on plasma lipid transport and hepatic cholesterol metabolism in Psammomys obesus. This sand rat lapses into hyperinsulinemia and hyperglycemia when transferred from its native food to laboratory rodent diets. Marked hypertriglyceridemia and hypercholesterolemia developed in hyperinsulinemic (Group B) and hyperglycemic/ hyperinsulinemic (Group C), compared with normal P. obesus (Group A). Group B showed significantly (P<0.05) higher plasma VLDL-cholesterol (41.9%) and LDL-cholesterol (47.3%) concentrations, whereas Group C was characterized by an even more marked increase in VLDL-cholesterol (176%, P<0.001) compared with Group A. Lipoprotein composition was also altered, displaying impaired lipid and apolipoprotein moiety distribution in IDL, LDL, HDL(2) and HDL(3) lipoprotein fractions of Groups B and C. The activity of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, was consistently lower in Group B (P<63.4%, P<0.001) and C (43.9%, P<0.005). In contrast, the direct measurement of microsomal acyl-CoA:cholesterol acyltransferase (ACAT), controlling the acylation of cholesterol, showed an increase averaging 53% in Group B (P<0.01) and 61% in Group C (P<0.005). Similarly, elevated activity (171.1%, P<0.05 and 291.4%, P<0.001, respectively) was related to cholesterol 7alpha-hydroxylase, the rate-limiting enzyme in bile acid biosynthesis. These alterations were accompanied with abundant deposition of triglycerides and cholesterol in the liver. Changes in circulating lipids and liver parameters were related to glucose and insulin levels, indicating the implication of insulin resistance and diabetes. Therefore, our findings demonstrate various disturbances in plasma lipid profile and lipoprotein composition, as well as in liver cholesterol metabolism during the sequential development of insulin resistance and diabetes in P. obesus rats. Furthermore, the current data point to an undoubtedly important role of the liver in the pathogenesis of metabolic disorders in the progression of nutritionally-induced insulin resistance and diabetes in P. obesus. Finally, current research shows that more marked plasma and hepatic lipid perturbations occur in insulin resistance than in diabetes, which may culminate in the development of atherosclerosis.

It has been established that leptin displays a number of effects on peripheral tissues. We have investigated the effect of the hormone on lipid synthesis, apolipoprotein biogenesis and lipoprotein secretion in Caco-2 cells. Immunocytochemistry revealed the presence of leptin receptors (Ob-Rb) on the basolateral membrane. Incubation of cells with 200 nM leptin resulted in a decreased export of triglycerides in the basolateral medium without affecting monoglyceride, diglyceride and cholesterol ester lipid classes. It also significantly reduced the output of de novo-synthesized apolipoprotein (Apo)B-100 and ApoB-48 as well as that of newly formed chylomicrons and of low-density lipoproteins. It also enhanced that of ApoA-I, ApoA-IV and ApoE. Our results support the hypothesis that leptin can affect energy balance at the gut level by reducing lipid release into the circulation.

Based on titration microcalorimetry and Caco-2 cell line transfection studies, it has been suggested that the A54T of the FABP2 gene plays a significant role in the assimilation of dietary fatty acids. However, reports were divergent with regard to the in vivo interaction between this polymorphism and postprandial lipemia. We therefore determined the influence of this intestinal fatty acid-binding protein polymorphism on intestinal fat transport using the human jejunal organ culture model, thus avoiding the interference of various circulating factors capable of metabolizing in vivo postprandial lipids. Analysis of DNA samples from 32 fetal intestines revealed 22 homozygotes for the wild-type Ala-54/Ala-54 genotype (0.83) and 10 heterozygotes for the polymorphic Thr-54/Ala-54 genotype (0.17). The Thr-encoding allele was associated with increased secretion of newly esterified triglycerides, augmented de novo apolipoprotein B synthesis, and elevated chylomicron output. On the other hand, no alterations were found in very low density lipoprotein and high density lipoprotein production, apolipoprotein A-I biogenesis, or microsomal triglyceride transfer protein mass and activity. Similarly, the alanine to threonine substitution at residue 54 did not result in changes in brush border hydrolytic activities (sucrase, glucoamylase, lactase, and alkaline phosphatase) or in glucose uptake or oxidation. Our data clearly document that the A54T polymorphism of FABP2 specifically influences small intestinal lipid absorption without modifying glucose uptake or metabolism. It is proposed that, in the absence of confounding factors such as environmental and genetic variables, the FABP2 polymorphism has an important effect on postprandial lipids in vivo, potentially influencing plasma levels of lipids and atherogenesis.

To examine the multiple stages of lipoprotein packaging during development, we studied localization, ontogeny, and regulation of microsomal transfer protein (MTP), a crucial protein for lipid transport. With the use of immunofluorescence, MTP was identified in villus and crypt epithelial cells in different regions of human fetal intestine, including colon. Staining was detected as early as the 13th wk of gestation in all gut segments and was almost entirely confined to the columnar epithelial cells of the jejunum and colon. Unlike immunofluorescence, which provides qualitative but not quantitative information on MTP signal, enzymatic assays revealed a decreasing gradient from proximal small intestine to distal, as confirmed by immunoblot. Activity of MTP in small intestinal explants cultured for different incubation periods (0, 4, 8, and 24 h) peaked at 4 h but remained insensitive to different concentrations of oleic acid. Also, a trend toward increasing MTP activity was observed at 20-22 wk of gestation. Finally, in strong contrast to jejunal efficiency, colonic explants displayed impaired lipid production, apolipoprotein biogenesis, and lipoprotein assembly, in association with poor expression of MTP. These findings provide the first evidence that human fetal gut is able to express MTP and emphasize the distinct regional distribution, regulation by oleic acid, and ontogeny of MTP.

It has been postulated that apolipoprotein (apo) A-IV plays various significant roles in lipid transport and lipoprotein metabolism. Although it is controlled by fat feeding, so far little else is known about its regulation by specific fatty acids. In this study, we focused on the modulation of apo A-IV mRNA levels, mass, and biogenesis by mono- and polyunsaturated fatty acids (FA) in the human intestinal Caco-2 cell line. In confluent cells incubated with 1 mM oleic (n-9), linoleic (n-6), alpha-linolenic (n-3), or docosahexaenoic (n-3) acids for a long-term period, both apo A-IV protein levels and de novo synthesis were increased. The induction resulted from the up-regulation of apo A-IV mRNA transcripts. In contrast, an inhibitory effect was evident with short-term incubation. FA chain length and degree of unsaturation had little effect altering apo A-IV transcript and biogenesis. These data offer evidence that isolated fatty acids regulate gene expression and the production of apo A-IV in the enterocyte.