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Genome-wide multipoint linkage analyses were performed to identify chromosomal regions harboring genes influencing LDL-cholesterol, total apolipoprotein B (apoB), and LDL-apoB levels using 654 markers. They were assessed in a sedentary state (baseline) and after a 20 week endurance training program. Strong evidence for two quantitative trait loci (QTLs) for baseline levels was found. There is linkage evidence in black families on chromosomes 1q41-q44 [at marker D1S2860, 238 centimorgan (cM), with a maximum log of the odds (LOD) score of 3.7 for LDL-apoB] and in white families on chromosome 8q24 (at marker D8S1774, 142 cM, with LOD scores of 3.6, 3.3, and 2.5 for baseline LDL-cholesterol, LDL-apoB, and apoB, respectively). There were no strong signals for the lipoprotein training responses (as computed as the difference in posttraining minus baseline levels). In conclusion, QTLs for baseline apoB and LDL-cholesterol levels on chromosomes 1q41-q44 (in blacks) and 8q24 (in whites) were found. As there are no known strong candidate genes in these regions for lipids, follow-up studies to determine the source of those signals are needed.

The aim of this study was first to examine the relationships between adiponectin gene (Apm1) polymorphisms and anthropometric indices as well as plasma adiponectin and lipoprotein/lipid levels, and then to investigate whether the presence of visceral obesity or insulin resistance may modulate the impact of these polymorphisms on metabolic risk variables. Molecular screening of the Apm1 gene was achieved, and a sample of 270 unrelated men recruited from the greater Quebec City area and selected to cover a wide range of body fatness values was genotyped. Sequencing of the Apm1 gene revealed two previously reported polymorphisms (c.45T>G and c.276G>T) as well as two newly identified genetic variations (−13752delT and −13702G>C). Carriers of the c.276T allele had higher LDL-cholesterol and lower HDL-triglyceride concentrations than did 276G/G homozygotes (P = 0.02 and P = 0.01, respectively). Carriers of the c.45G allele exhibited higher plasma adiponectin concentrations than did 45T/T homozygotes (P = 0.04). After dividing each genotype group into subgroups for visceral AT, homozygotes for the normal allele at position −13752delT, carriers of the c.45G allele, and carriers of the c.276T allele had similar total apolipoprotein B (apoB) concentrations, whether they were viscerally obese or not. These results suggest that some Apm1 gene polymorphisms influence plasma adiponectin concentrations and lipoprotein/lipid levels. In addition, the impact of these polymorphisms is modulated by the presence of visceral obesity.

The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2. Adding those findings to the database highlighted the fact that the former is reported as a lipid-related locus for the first time, whereas the latter has been observed before. However, concerns arise when displaying all data on the same map, because a large portion of the genome is now covered with loci supported by at least suggestive evidence of linkage.

A genome-wide linkage study was performed to identify chromosomal regions harboring genes influencing lipid and lipoprotein levels. Linkage analyses were conducted for four quantitative lipoprotein/lipid traits, i.e., total cholesterol, triglyceride, HDL-cholesterol (HDL-C), and LDL-C concentrations, in 930 subjects enrolled in the Quebec Family Study. A maximum of 534 pairs of siblings from 292 nuclear families were available. Linkage was tested using both allele-sharing and variance-component linkage methods. The strongest evidence of linkage was found on chromosome 12q14.1 at marker D12S334 for HDL-C, with a logarithm of the odds (LOD) score of 4.06. Chromosomal regions harboring quantitative trait loci (QTLs) for LDL-C included 1q43 (LOD = 2.50), 11q23.2 (LOD = 3.22), 15q26.1 (LOD = 3.11), and 19q13.32 (LOD = 3.59). In the case of triglycerides, three markers located on 2p14, 11p13, and 11q24.1 provided suggestive evidence of linkage (LOD > 1.75). Tests for total cholesterol levels yielded significant evidence of linkage at 15q26.1 and 18q22.3 with the allele-sharing linkage method, but the results were nonsignificant with the variance-component method. In conclusion, this genome scan provides evidence for several QTLs influencing lipid and lipoprotein levels. Promising candidate genes were located in the vicinity of the genomic regions showing evidence of linkage.

Postprandial plasma triglyceride (ppTG) and NEFA clearance were stratified by plasma acylation-stimulating protein (ASP) and gender to determine the contribution of fasting ASP in a normal population (70 men; 71 women). In the highest ASP tertile only, ASP decreased over 8 h (90 ± 9.7 nM to 70 ± 5.9 nM, P < 0.05 males; 61.9 ± 4.0 nM to 45.6 ± 6.2 nM, P < 0.01 females). Fasting ASP correlated positively with ppTG response. ppTG (P < 0.0001, 2-way ANOVA, both genders) and NEFA levels progressively increased from lowest to highest ASP tertile, with the greatest differences in males. By stepwise multiple regression, the best prediction of ppTG was: (fasting ASP + apolipoprotein B + insulin + TG; r = 0.806) for men and (fasting ASP + total cholesterol; r = 0.574) for women. Leptin, body mass index, and other fasting variables did not improve the prediction. Thus, in men and women, ASP significantly predicted ppTG and NEFA clearance and, based on lower ASP, women may be more ASP sensitive than men.Plasma ASP may be useful as a fasting variable that will provide additional information regarding ppTG and NEFA clearance.

The objective of the present study was to examine the impact of the T111I missense mutation in exon 3 of the endothelial lipase (EL) gene on HDL and its potential interaction effect with dietary fat. The study sample included 281 women and 216 men aged between 17 and 76 years from the Quebec Family Study. Plasma HDL3-C levels of I111I homozygote women were higher compared with those of women carrying the wild-type allele (P = 0.03). These differences were not attenuated when adjusted for levels of obesity and were not observed among men. Dietary PUFA interacted with the T111I mutation to modulate apolipoprotein A-I (apoA-I) and HDL3-C levels among women. Specifically, a diet rich in PUFA was associated with increased apoA-I levels among women carriers of the I111 allele and with decreased apoA-I among women homozygotes for the wild-type allele (P = 0.002). A similar interaction was observed with plasma HDL3-C levels (P = 0.003). These interactions were not observed among men. In conclusion, the EL T111I mutation appears to have a modest effect on plasma HDL levels. The gene-diet interaction among women, however, suggests that the T111I missense mutation may confer protection against the lowering effect of a high dietary PUFA intake on plasma apoA-I and HDL3-C levels.

This study examined the postprandial lipemia of two groups of men displaying similar age, body weight, and regional fat distribution, but characterized by either low (n = 11) or high (n = 15) α2-adrenergic sensitivity of subcutaneous abdominal adipocytes. In addition to fat cell lipolysis, adipose tissue lipoprotein lipase (AT-LPL) as well as postheparin plasma LPL activities were measured in the fasting state. Fasting AT-LPL and PH-LPL activities were similar in both groups. Maximal adipose cell lipolysis induced by isoproterenol (β-adrenergic agonist) as well as the β-adrenergic sensitivity did not differ between both groups of men. The selective α2-adrenergic agonist UK-14304 promoted a similar antilipolytic response in subcutaneous abdominal adipocytes from both groups. However, the α2-adrenergic sensitivity, defined as the dose of UK-14304 that produced half-maximal inhibition of lipolysis (IC50), was significantly different between groups (P < 0.0001). Men with low versus high subcutaneous abdominal fat cell α2-adrenergic sensitivity showed higher fasting TG levels. In the whole group, a positive relationship was observed between log-transformed IC50 UK-14304 values of subcutaneous adipocytes and fasting TG levels (r = 0.39, P < 0.05), suggesting that a low abdominal adipose cell α2-adrenergic sensitivity is associated with high TG levels. After the consumption of a high-fat meal, subjects with low subcutaneous abdominal adipose cell α2-adrenergic sensitivity showed higher TG levels in total, medium, and small triglyceride-rich lipoprotein (TRL) fractions at 0- to 6-h time points than men with high adipocyte α2-adrenergic sensitivity (P values ranging from 0.01 to 0.05). Stepwise regression analysis showed that the fasting TG concentration was the only variable retained as a significant predictor of the area under the curve of TG levels in total TRL fractions (73% of variance) among independent variables such as body weight, percent body fat, visceral and subcutaneous abdominal adipose tissue accumulation measured by CT, as well as subcutaneous abdominal fat cell α2-adrenoceptor sensitivity. Taken together, these results indicate that a reduced antilipolytic sensitivity of subcutaneous abdominal adipocytes to catecholamines may increase fasting TG levels, which in turn play a role in the etiology of an impaired postprandial TRL clearance in men. —Imbeault, P., C. Couillard, A. Tremblay, J-P. Després, and P. Mauriège. Reduced α2-adrenergic sensitivity of subcutaneous abdominal adipocytes as a modulator of fasting and postprandial triglyceride levels in men. J. Lipid Res. 2000. 41: 1367–1375.

Catecholamine-induced lipolysis was investigated in 32 obese subjects (14 men and 18 premenopausal women), aged 36–50 years, whose body mass index ranged from 30 to 42 kg/m2. Isolated subcutaneous (subc) abdominal and femoral adipocytes were studied before and after a 15-week weight reducing program, during which mean body weight loss averaged 9 vs. 10 kg in women and men, respectively (P < 0.0001). Participants were re-examined when they were weight-stable. Fat cell weight decreased by about 15–20% in both depots (P values ranging from 0.01 to 0.05). Epinephrine (mixed α2-/β-adrenoceptor (AR) agonist) induced antilipolysis at low concentrations and a net lipolytic response at higher doses, irrespective of subjects' fatness and anatomic location of fat. Basal lipolysis, maximal lipolytic responses to isoprenaline (β-AR agonist), dobutamine and procaterol (β1- and β2-AR agonists, respectively) as well as maximal antilipolytic effects of epinephrine or UK-14304 (α2-AR agonist) were similar before and after weight reduction. However, both β- and β2-AR lipolytic sensitivities and the β-AR density were increased in both genders after weight reduction, this effect being more marked in subc abdominal than in femoral adipocytes (P values ranging from 0.001 to 0.05). The α2-AR antilipolytic sensitivity was reduced in adipose cells from both regions in women, but only in subc abdominal adipocytes in men (P < 0.05), although the α2-AR density remained unchanged after weight reduction. In conclusion, a moderate weight loss leads to a higher adipose cell lipolytic efficiency which is associated with changes at receptor levels (mainly an increased β2- and a decreased α2-AR sensitivities), in both genders.—Mauriège, P., P. Imbeault, D. Langin, M. Lacaille, N. Alméras, A. Tremblay, and J. P. Després. Regional and gender variations in adipose tissue lipolysis in response to weight loss. J. Lipid Res. 1999. 40: 1559–1571.

Lipolytic and lipoprotein lipase (LPL) activities were studied in isolated human adipocytes obtained from two intraabdominal depots (round ligament and omental) and from the subcutaneous abdominal region of nine severely obese premenopausal women (with body mass indices ranging from 37 to 51 kg/m2), aged 36 +/- 3 yr, undergoing gastrointestinal surgery. Both fat cell weight and LPL activity were significantly greater in round ligament adipose cells than in subcutaneous abdominal or in omental adipocytes (P < 0.05). The antilipolytic effect of insulin and the sensitivity to this hormone were also higher in round ligament adipose cells than in omental adipocytes (P < 0.05). Although epinephrine initiated a similar biphasic profile of response in all cell types, the catecholamine promoted a weaker inhibition of lipolysis in omental adipocytes than in subcutaneous abdominal adipose cells (P < 0.05). In addition, a lack of regional variation was found in the maximal antilipolysis initiated by UK 14304 and the alpha 2-adrenoceptors was higher in both subcutaneous abdominal and round ligament fat cells than in omental adipocytes. Moreover, the maximal lipolytic response to isoproterenol or to agents acting at post-receptor levels was not different among fat depots. Finally, a lower beta-adrenergic lipolytic sensitivity associated with a reduced beta-adrenoceptor density was observed in round ligament as compared to omental adipose cells. These data suggest that in massively obese premenopausal women, omental and round ligament adipose tissues show distinct metabolic properties that may contribute to limit the impact of intraabdominal obesity.

Biopsies of adipose tissue were obtained from two subcutaneous regions (abdominal and femoral) in a sample of 54 men (32 obese and 22 lean subjects). Clonidine-induced antilipolysis in femoral adipose cells was similar in both groups, whereas subcutaneous abdominal adipocytes of obese individuals showed a higher alpha 2-adrenergic response than did subcutaneous abdominal adipose cells from lean subjects. In addition, epinephrine had a biphasic effect in subcutaneous abdominal adipocytes from obese individuals, as it induced antilipolysis at low concentrations, and a net lipolytic response at higher doses. In contrast, the physiological amine promoted lipolysis in subcutaneous abdominal adipose cells of lean subjects. Epinephrine- and clonidine-induced antilipolysis of subcutaneous abdominal adipocytes was positively associated with the level of subcutaneous abdominal fat measured by computed tomography (CT). Finally, men with a high alpha 2-adrenergic response of subcutaneous abdominal fat cells were fatter than those with a low alpha 2-adrenergic component. These results suggest that, in men with a wide range of body fatness, variations in the lipolytic response of subcutaneous abdominal adipose cells to epinephrine appear to involve changes in the functional balance between alpha 2- and beta-adrenoceptors.

The aim of the present study was to investigate the associations between total adiposity, body fat distribution, and plasma lipoprotein levels within groups of women defined on the basis of apolipoprotein E phenotypes, in order to verify whether apoE polymorphism could modify these associations. In women having only apolipoprotein E3 isoforms (n = 24), body fat mass, the waist: hip circumference ratio, and computed tomography-derived total and intra-abdominal fat areas were all positively correlated with very low density lipoprotein (VLDL) and low density lipoprotein (LDL) lipids and apolipoprotein B concentrations. These body fatness variables were also negatively correlated with plasma high density lipoprotein (HDL) cholesterol concentration. These associations were, however, altered in the groups of women carrying either apoE2 or E4 isoforms. Indeed, in women carrying the apoE2 isoform (n = 22), body fatness variables were predominantly associated with VLDL components concentration (0.05 greater than P less than 0.01) and with LDL triglyceride content. No association was found between adiposity and LDL cholesterol or apolipoprotein B levels in these women. In contrast, no relationship was found between total adiposity, regional fat accumulation, and VLDL fraction in women carrying the apolipoprotein E4 isoform (n = 17). In this latter group, computed tomography-measured total abdominal fat accumulation was positively correlated with LDL apolipoprotein B (r = 0.58, P less than 0.05) concentration, whereas intra-abdominal fat accumulation was positively correlated with both LDL cholesterol and apolipoprotein B concentrations (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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.