T. W. A. De Bruin

Impaired fatty acid metabolism in familial combined hyperlipidemia. A mechanism associating hepatic apolipoprotein B overproduction and insulin resistance.

To establish whether insulin resistance and/or postprandial fatty acid metabolism might contribute to familial combined hyperlipidemia (FCH) we have examined parameters of insulin resistance and lipid metabolism in six FCH kindreds. Probands and relatives (n = 56) were divided into three tertiles on the basis of fasting plasma triglycerides (TG). Individuals in the highest tertile (TG > 2.5 mM; n = 14) were older and had increased body mass index, systolic blood pressure, and fasting plasma insulin concentrations compared with individuals in the lowest tertile (n = 24). The former also presented with decreased HDL cholesterol and increased total plasma cholesterol, HDL-TG, and apoprotein B, E, and CIII concentrations. Insulin concentrations were positively correlated with plasma apo B, apo CIII, apo E, and TG, and inversely with HDL cholesterol. Fasting nonesterified fatty acids (NEFA) were elevated in FCH subjects compared to six unrelated controls and five subjects with familial hypertriglyceridemia. Prolonged and exaggerated postprandial plasma NEFA concentrations were found in five hypertriglyceridemic FCH probands. In FCH the X2 minor allele of the AI-CIII-AIV gene cluster was associated with increased fasting plasma TG, apo CIII, apo AI, and NEFA concentrations and decreased postheparin lipolytic activities. The clustering of risk factors associated with insulin resistance in FCH indicates a common metabolic basis for the FCH phenotype and the syndrome of insulin resistance probably mediated by an impaired fatty acid metabolism.

Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia

Abstract. The role of the lipoprotein lipase (LPL) gene in familial combined hyperlipidaemia (FCH) is unclear at present. We screened a group of 28 probands with familial combined hyperlipidaemia and a group of 91 population controls for two LPL gene mutations. D9N and N291S. LPL‐D9N was found in two probands and one normolipidaemic population control. LPL‐N291S was found in four probands and four population controls. Subsequently, two pedigrees from probands with the D9N mutation and two pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridaemia [2.69± 1.43 (SD) mmol L‐1] and reduced plasma high‐density lipoprotein cholesterol (HDL‐C) concentrations (0.92± 0.21 mmol L‐1) compared with 11 non‐carriers (triglyceride 1.75± 0.64 mmol L‐1; HDL‐C 1.23± 0.30 mmol L‐1, P= 0.03 and P= 0.025 respectively). LPL‐D9N carriers had higher diastolic blood pressures than non‐carriers. LPL‐N291S carriers (n= 6) showed significantly higher (26%) apo B plasma concentrations (174± 26 mg dL‐1) than non‐carriers (138± 26 mg dL‐1; P= 0.023), with normal post‐heparin plasma LPL activities. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridaemia, hypercholesterolaemia or increased apo B concentrations). It is concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidaemia in the four pedigrees studied, but that the LPL‐D9N and LPL‐N291S mutations had significant additional effects on lipid and apolipoprotein phenotype.

Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia

BACKGROUND Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. METHODS We evaluated in a parallel, double-blind randomized fashion the effect of gemfibrozil (1200 mg/day) (n = 40) or simvastatin (20 mg/day) (n = 41) on lipids, apolipoprotein-B (apo-B)-containing lipoproteins, apo-CIII and lipoprotein(a) [Lp(a)], in 81 well-defined FCH patients. RESULTS While both drugs lowered plasma cholesterol and triglyceride levels, gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL, whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol. High-density lipoprotein (HDL) increased to an equal extent on both therapies. Total serum apo-B levels were reduced with both drugs; however, gemfibrozil decreased apo-B only in VLDL + IDL, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL. In keeping with a more effective reduction of VLDL particles, a more pronounced reduction of apo-CIII also was observed after gemfibrozil, which correlated with the reduction in plasma triglycerides. Baseline concentrations of Lp(a) showed a wide range in both treatment groups. Median Lp(a) levels increased after simvastatin, but were not affected by gemfibrozil. CONCLUSION Both therapies exhibited their specific effects, although none of the drugs alone completely normalized the lipid profiles of these patients with FCH. Therefore, the choice of treatment should be based on the most elevated lipoprotein fraction, and in some cases a combination of the two drugs may be indicated.

Reverse cholesterol transport : relationship between free cholesterol uptake and HDL3 in normolipidaemic and hyperlipidaemic subjects

Abstract. High density lipoproteins (HDL) are responsible for the Reverse Cholesterol Transport (RCT). The role of the composition of the HDL particle in RCT, involving free cholesterol (chol) uptake from cell membranes, is not completely understood. We have therefore studied the uptake capacity from subjects with a wide variety of plasma HDL cholesterol concentrations in an HDL‐receptor free model consisting of bovine heart mitochondrial membranes labeled with [14C]cholesterol. HDL were isolated by molecular sieve chromatography from fresh plasma samples of eight subjects with low plasma HDL chol concentrations (≤ 1.0 mmol L‐1) and 15 subjects with normal HDL chol concentrations. The latter were subdivided into an intermediate (HDL chol: 1.0–1.4 mmol L‐1; n= 9) and a high HDL chol group (>1.4 mmol L‐1; n= 6). In the HDL fractions isolated by chromatography (cHDL), total chol and apolipopro‐tein (apo) A1 were measured. Free chol uptake was significantly decreased by 32% in the tertile with the lowest plasma HDL chol (49 1 ± 15.8 arbitrary units; mean ± SD), compared to the tertile with high HDL chol (72.1 ± 16.6 au). Linear regression analysis showed a positive correlation between the free choi uptake and plasma HDL3 concentrations (r= 0.61; P<0.01), HDL chol (r= 0.56; P<0.01), HDL associated apo A1 (r = 0.46; P<0.05), cHDL apo AT (r = 0.56; P<0.05) and cHDL chol (r = 0.46; P<0.05) in all subjects combined. Stepwise multiple‐regression analysis confirmed the association of [14C]cholesterol uptake with plasma HDL3 concentrations (β, 061; P= 0.004). No correlations were found between free chol uptake and total plasma apoAI (r = 0.26; ns) or HDL2 (r = 0.27; ns). After an oral fat load in four FCH patients, free chol uptake parallelled the changes in plasma HDL3 chol concentrations. We conclude that HDL3 is involved in the early steps of RCT and low HDL3 levels may result in less efficient RCT in hypertriglyceridemia.

Melatonin and jet lag

Jet lag is an ill-defined phenomenon resulting from rapid transmeridional flight and is considered to be due to desynchronization of circadian rhythms. The role of the pineal gland hormone, melatonin, in the synchronization of biological rhythms has raised interest in its use to alleviate jet lag. Indeed, recent studies support the use of this well-tolerated drug as a remedy for jet lag on long-haul flights.

Danaparoid: an antithrombotic agent without major impact on triglyceride hydrolysis capacity in humans.

van Barlingen HHJJ, van Beek A, Erkelens DW, de Bruin TWA (Department of Internal Medicine, Laboratory of Lipid Metabolism, University Hospital, Utrecht University, PO Box 85 500, 3508 GA Utrecht, The Netherlands). Danaparoid: an antithrombotic agent without major impact on triglyceride hydrolysis capacity in humans. J Intern Med 1997; 242: 125–29.