Relationship between lipoprotein lipase activity and plasma sex steroid level in obese women.

In obese women (n = 16) at their weight, fasting adipose tissue lipoprotein lipase (LPL) activity, obtained by elution with serum and heparin at 4 degrees and 37 degrees C, was inversely correlated to plasma estradiol levels (r = -0.724; P = 0.002) and (r = -0.641; P = 0.010), respectively. Furthermore, fasting postheparin plasma LPL activity during a heparin infusion, showed an even stronger inverse correlation to plasma estradiol when measured at 60 min (r = -0.815; P less than 0.001). None of the above parameters was correlated to the body mass index. Postprandial LPL activity in postheparin plasma, measured 10 min after a heparin injection, showed a strong positive correlation with plasma free testosterone (r = 0.780; P = 0.001). Neither of these parameters was correlated with the body mass index. The origin of this LPL activity is presently unknown but could conceivably represent a pool of LPL from skeletal muscle. Since it has been shown convincingly that estrogen decreases adipose tissue LPL activity in the rat, the present studies strongly suggest that estradiol is a major negative regulator of fasting adipose tissue LPL activity in women.

Increase of adipose tissue lipoprotein lipase activity with weight loss.

Obese subjects have elevated adipose tissue lipoprotein lipase activity per fat cell when compared with lean control subjects. This enzyme, which is rate limiting for the uptake and storage of lipoprotein triglyceride in adipose tissue, has been shown to be further elevated in a group of previously obese subjects who had been weight stable at a reduced weight for 4-28 mo. In the present prospective study of eight obese subjects, adipose tissue lipoprotein lipase activity was demonstrated to increase after weight stabilization at a reduced weight (0.33 mU/10(6) cells). In three subjects who lost weight and subsequently regained their lost weight, the enzyme activity increased after weight loss and then returned toward the original basal level with weight gain. One subject who maintained his weight loss for 10 mo. continued to have an elevated level of enzyme activity. Because adipose tissue lipoprotein lipase activity does not "normalize" after weight loss, we hypothesize that this enzyme may play a counterregulatory role in resisting deviation from a "set point" for fat mass or fat cell size and thereby predispose to reattainment of the original obese state.

Determinants of human adipose tissue lipoprotein lipase. Effect of diabetes and obesity on basal- and diet-induced activity.

The role of insulin in the regulation of human adipose tissue lipoprotein lipase was evaluated. Adipose tissue heparin-releasable lipoprotein lipase (thought to be related to peripheral clearance of plasma triglycerides) was low in insulin-deficient, untreated hyperglycemic diabetic subjects (P less than 0.001) and treatment of hyperglycemia returned the activity to normal. In chronic hyperinsulinism, represented by obesity, heparin-releasable activity among control subjects was correlated to percent of ideal body weight (r=0.53, P less than 0.05) and to fat cell size (r=0.61, P less than 0.02). Acetone-ether powder lipoprotein lipase activity (presumed to reflect total tissue enzyme) was also related to percent of ideal body weight (r=0.76, P less than 0.001 for controls; r=0.67, P less than 0.05 for diabetics) and to fat cell size (r=0.71, P less than 0.01 for controls; r=0.85, P less than 0.01 for diabetics. Postprandial-stimulated insulin secretion was related to diet-induced changes in lipoprotein lipase in control subjects; both were dependent upon the amount of dietary carbohydrate. In contrast, the diabetic patients with low insulin responses, failed to increase lipoprotein lipase activity with feeding. The changes in heparin-releasable (r=0.66, P less than 0.01) and acetone-ether powder (r=0.69, P less than 0.01) activity during feeding were related to the percent increase in plasma insulin. Thus, insulin appears to be important in the regulation of human adipose tissue lipoprotein lipase activity. Elevated insulin levels in obesity and increased insulin secretion after eating were associated with increased lipoprotein lipase activity. Defects in insulin secretion, both in postabsorptive and postprandial states, are associated with low adipose tissue lipoprotein lipase and may lead to hypertriglyceridemia in diabetic man.

Lipoprotein lipase secretion by human monocyte-derived macrophages.

Human monocyte-derived macrophages in culture produced lipoprotein lipase. Although freshly isolated blood monocytes did not secrete much lipase activity, 1 d in culture was sufficient to trigger measureable enzyme production. During 3 wk in culture, maximal activity was attained after 7 d. At all times, the culture medium contained more enzyme activity than did a serum-heparin eluate or a detergent extract of the cell layer. The lipase activity was stimulated by serum and was inhibited by preincubation with antiserum to bovine lipoprotein lipase or when assayed at a high salt concentration. Furthermore, the enzyme bound to a heparin-Sepharose affinity column at physiological ionic strength. Cells cultured from a subject with primary lipoprotein lipase deficiency secreted no detectable enzyme. Since macrophages are prominent components of atherosclerotic lesions in man, their ability to synthesize and secrete lipoprotein lipase may be important to atherogenesis.

Evidence for a common, saturable, triglyceride removal mechanism for chylomicrons and very low density lipoproteins in man.

Hypertriglyceridemic subjects were fed diets in which dietary fat calories were held constant, but carbohydrate calories were varied. Three subjects with fasting chylomicronemia (Type V) were given less carbohydrate and four subjects without fasting chylomicronemia (Type IV) were fed diets with more calories as carbohydrate. The restricted carbohydrate intake led to disappearance of chylomicronemia in those subjects who had chylomicronemia on a normal diet (Type V to IV). In those subjects without chylomicronemia, chylomicronemia appeared in response to increased carbohydrate intake (Type IV to V). Thus chylomicron concentrations in plasma were altered even though fat intake and presumably chylomicron input into plasma was kept constant. These findings provide evidence for saturation of chylomicron removal mechanisms by alteration of endogenous triglyceride-rich lipoprotein concentrations. They suggest that chylomicrons compete with very low density lipoproteins for similar removal mechanisms. The relationship between endogenous triglyceride concentration and the lipolytic activity in plasma following heparin was then evaluated with the use of long-term heparin infusions to release and maintain lipolytic activity in the circulation. 10 subjects were placed on fatfree diets to remove circulating dietary fat. The plasma lipolytic rate during the heparin infusion was measured consecutively on different days in individuals whose triglyceride concentrations were varied by either increasing or decreasing calories. The lipolytic rate was curvilinearly related to the plasma triglyceride concentrations. This curvilinear relationship followed Michaelis-Menton saturation kinetics over a wide range of triglyceride concentrations on fat-free, high-carbohydrate diets, in multiple studies in a group of individuals. These studies suggest that endogenous and exogenous triglyceride compete for a common, saturable, plasma triglyceride removal system related to lipoprotein lipase.

Effect of estrogen on post-heparin lipolytic activity. Selective decline in hepatic triglyceride lipase.

The rise in plasma triglyceride (TG) levels associated with estrogen administration has been thought to arise from impaired clearance because of the uniform suppression of post-heparin lipolytic activity (PHLA). Recently PHLA has been shown to consist of two activities: hepatic TG lipase and extrahepatic lipoprotein lipase (LPL). To determine whether estrogen might induce a selective decline in one of these activities, both hepatic TG lipase and extrahepatic LPL were measured in post-heparin plasma from 13 normal women before and after 2 wk of treatment with ethinyl estradiol (1 mug/kg per day). Hepatic TG lipase and extrahepatic LPL were determined by two techniques: (a) separation by heparin-Sepharose column chromatography, and (b) selective inhibition with specific antibodies to post-heparin hepatic TG lipase and milk LPL. Estrogen uniformly depressed hepatic TG lipase as measured by affinity column (-68 +/- 12%, mean +/- SD, P less than 0.001) or antibody inhibition (-63 +/- 11%, P less than 0.001). Extrahepatic LPL was not significantly changed by affinity column (-22 +/- 40%) or antibody inhibition (-3 +/- 42%). Direct measurement of adipose tissue LPL from buttock fat biopsies also showed no systematic change in the activated form of LPL measured as heparin-elutable LPL (+64 +/- 164%) or in the tissue form of LPL measured in extracts of acetone-ether powders (+21 +/- 77%). The change in hepatic TG lipase correlated with the change in PHLA (r = 0.969, P less than 0.01). However, neither the change in PHLA nor hepatic TG lipase correlated with the increase in TG during estrogen. The decrease in PHLA during estrogen thus results from a selective decline in hepatic TG lipase.

Gene-environment interaction in the conversion of a mild-to-severe phenotype in a patient homozygous for a Ser172-->Cys mutation in the lipoprotein lipase gene.

Normal pregnancy is associated with a two- to threefold increase in plasma triglyceride levels, particularly in the third trimester, due both to the overproduction of VLDLs and to the possible suppression of lipoprotein lipase (LPL) activity. Numerous mutations in the human LPL gene causing complete LPL deficiency have been described, but naturally occurring mutations that result in defective LPL with partial activity have not yet been reported. Here we describe a 30-yr-old woman who was first diagnosed with LPL deficiency during pregnancy after she developed pancreatitis. Her plasma triglyceride levels remained mildly elevated at approximately 300 mg/dl (3.4 mmol/liter) after the first pregnancy but rose significantly after she became pregnant again (1800 to 2000 mg/dl) (20.2 to 22.5 mmol/liter). DNA sequence analysis of the LPL gene showed that the patient is homozygous for a Ser172-->Cys missense mutation in exon 5. In vitro mutagenesis revealed that the Ser172-->Cys mutation caused a mutant LPL protein that had residual activity higher than that seen in all eight other missense mutations in patients with LPL deficiency identified in our laboratory. We propose that some mutations in the LPL gene produce a defective LPL with partial activity, which usually leads to mild hypertriglyceridemia.

Amino acid substitution (Ile194----Thr) in exon 5 of the lipoprotein lipase gene causes lipoprotein lipase deficiency in three unrelated probands. Support for a multicentric origin.

Studies on the molecular biology of lipoprotein lipase (LPL) deficiency have been facilitated by the availability of LPL gene probes and the recent characterization of gene mutations underlying human LPL deficiency. Typically, missense mutations have predominated and show a preferential localization to exons 4 and 5. This distribution supports earlier studies attributing functional significance to residues encoded by these exons. We now report a further missense mutation within exon 5 of the LPL gene in three unrelated patients. Amplification of individual exons by the polymerase chain reaction and direct sequencing revealed a T----C transition at codon 194 of the LPL cDNA which results in a substitution of threonine for isoleucine at this residue. The catalytic abnormality induced by this mutation was confirmed through in vitro mutagenesis studies in COS-1 cells. Transfection with a LPL cDNA containing the codon 194 transition resulted in the synthesis and secretion of a catalytically defective protein. The Thr194 substitution was associated with two different DNA haplotypes, consistent with a multicentric origin for this mutation.

Proteinuria and lipoprotein lipase activity in Miniature Schnauzer dogs with and without hypertriglyceridemia.

Spontaneous hyperlipidemia in rats causes glomerular disease. Idiopathic hypertriglyceridemia (HTG) is prevalent in Miniature Schnauzers, but its relationship with proteinuria is unknown. Decreased activity of major lipid metabolism enzymes, lipoprotein lipase (LPL) and hepatic lipase (HL), may play a role in the cyclic relationship between hyperlipidemia and proteinuria. These enzymes have also not been previously investigated in Miniature Schnauzers. The aims of this study were to determine the relationship between HTG and proteinuria in Miniature Schnauzers and to measure LPL and HL activities in a subset of dogs. Fifty-seven Miniature Schnauzers were recruited (34 with and 23 without HTG). Fasting serum triglyceride concentrations and urine protein-to-creatinine ratios (UPC) were measured in all dogs, and LPL and HL activities were determined in 17 dogs (8 with and 9 without HTG). There was a strong positive correlation between triglyceride concentration and UPC (r = 0.77-0.83, P < 0.001). Proteinuria (UPC ≥ 0.5) was present in 60% of dogs with HTG and absent from all dogs without HTG (P < 0.001). Proteinuric dogs were not azotemic or hypoalbuminemic. Dogs with HTG had a 65% reduction in LPL activity relative to dogs without HTG (P < 0.001); HL activity did not differ. Proteinuria occurs with HTG in Miniature Schnauzers and could be due to lipid-induced glomerular injury. Reduced LPL activity may contribute to the severity of HTG, but further assay validation is required.

Mapping of the epitope on lipoprotein lipase recognized by a monoclonal antibody (5D2) which inhibits lipase activity.

A monoclonal antibody, 5D2, which inhibits human lipoprotein lipase (hLPL) activity has been widely used for assessment of LPL immunoreactive mass in the clinical evaluation of patients [1] and for analysis of structure-function relationships of LPL [2,3]. We have mapped the epitope on LPL, recognized by the 5D2 antibody, within residues 396-405. Ala400 is the critical amino acid residue conferring epitope specificity. This knowledge confirms that the C-terminal domain of LPL plays a critical role in LPL activity and also provides important information for studies exploring the structure-function relationship of LPL using this antibody.

Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density.

BACKGROUND: Small, dense LDL particles are associated with coronary artery disease (CAD) and predict angiographic changes in response to lipid-lowering therapy. Intensive lipid-lowering therapy in the Familial Atherosclerosis Treatment Study (FATS) resulted in significant improvement in CAD. This study examines the relationship among LDL density, hepatic lipase (HL), and CAD progression, identifying a new biological mechanism for the favorable effects of lipid-altering therapy. METHODS AND RESULTS: Eighty-eight of the subjects in FATS with documented coronary disease, apolipoprotein B levels >/=125 mg/dL, and family history of CAD were selected for this study. They were randomly assigned to receive lovastatin (40 mg/d) and colestipol (30 g/d), niacin (4 g/d) and colestipol, or conventional therapy with placebo alone or with colestipol in those with elevated LDL cholesterol levels. Plasma hepatic lipase (HL), lipoprotein lipase, and LDL density were measured when subjects were and were not receiving lipid-lowering therapy. LDL buoyancy increased with lovastatin-colestipol therapy (7.7%; P<0.01) and niacin-colestipol therapy (10.3%; P<0.01), whereas HL decreased in both groups (-14% [P<0.01] and -17% [P<0.01] with lovastatin-colestipol and niacin-colestipol, respectively). Changes in LDL buoyancy and HL activity were associated with changes in disease severity (P<0.001). In a multivariate analysis, an increase in LDL buoyancy was most strongly associated with CAD regression, accounting for 37% of the variance of change in coronary stenosis (P<0.01), followed by reduction in apolipoprotein Bl (5% of variance; P<0.05). CONCLUSIONS: These studies support the hypothesis that therapy-associated changes in HL alter LDL density, which favorably influences CAD progression. This is a new and potentially clinically relevant mechanism linking lipid-altering therapy to CAD improvement.

Common hepatic lipase gene promoter variant determines clinical response to intensive lipid-lowering treatment.

BACKGROUND: The common -514 C-->T polymorphism in the promoter region of the hepatic lipase (HL) gene affects HL activity. The C allele is associated with higher HL activity, more dense and atherogenic LDL, and lower HDL(2) cholesterol. Intensive lipid-lowering therapy lowers HL activity, increases LDL and HDL buoyancy, and promotes coronary artery disease (CAD) regression. We tested the hypothesis that subjects with the CC genotype and a more atherogenic lipid profile experience the greatest CAD regression from these favorable effects. METHODS AND RESULTS: Forty-nine middle-aged men with dyslipidemia and established CAD who were undergoing intensive lipid-lowering therapy were studied. Change in coronary stenosis was assessed by quantitative angiography, HL polymorphism by polymerase chain reaction amplification, HL activity by (14)C-labeled substrate, and LDL buoyancy by density-gradient ultracentrifugation. The response to lipid-lowering therapy was significantly different among subjects with different HL promoter genotypes. Subjects with the C:C genotype had the greatest decrease in HL activity (P<0.005 versus TC and TT by ANOVA) and the greatest improvement in LDL density (P<0.005) and HDL(2)-C (P<0.05) with therapy. These subjects had the greatest angiographic improvement, with 96% of them experiencing CAD regression, compared with 60% of TC and none of the TT patients (P:<0.001). CONCLUSIONS: -In middle-aged men with established CAD and dyslipidemia, the HL gene -514 C-->T polymorphism significantly predicts changes in coronary stenosis with lipid-lowering treatment that appear to involve an HL-associated effect on LDL metabolism. This study identifies a gene polymorphism that strongly influences the lipid and clinical response to lipid-lowering drugs.

Cardiovascular disease mortality in familial forms of hypertriglyceridemia: A 20-year prospective study.

BACKGROUND: Familial combined hyperlipidemia (FCHL) and familial hypertriglyceridemia (FHTG) are 2 of the most common familial forms of hyperlipidemia. There is a paucity of prospective data concerning the risk of cardiovascular disease (CVD) in such families. The purposes of this study were to estimate 20-year total and CVD mortality risk among relatives in these families and to evaluate plasma triglyceride as a predictor of death. METHODS AND RESULTS: The study was based on lipid and medical history data from 101 families ascertained in 2 studies conducted in the early 1970s. Vital status and cause of death was determined during 1993 to 1997 for 685 family members, including first-degree relatives of the probands and spouse control subjects. Compared with spouse control subjects, 20-year CVD mortality risk was increased among siblings and offspring in FCHL (relative risk 1.7, P=0.02) after adjustment for baseline covariates. In FHTG families, the relative risk was also 1.7 but was not statistically significant (P=0.39). Baseline triglyceride was associated with increased CVD mortality risk independent of total cholesterol among relatives in FHTG families (relative risk 2.7, P=0.02) but not in FCHL families (relative risk 1.5, P=0.16) after adjustment for baseline covariates. CONCLUSIONS: This prospective study establishes that relatives in FCHL families are at increased risk for CVD mortality and illustrates the need for effective prevention strategies in this group. Baseline triglyceride level predicted subsequent CVD mortality among relatives in FHTG families, adding to the growing evidence for the importance of hypertriglyceridemia as a risk factor for CVD.

Reduced plasma peroxyl radical trapping capacity and increased susceptibility of LDL to oxidation in poorly controlled IDDM.

Oxidation of low-density lipoproteins (LDLs) has been postulated to play an important role in atherogenesis. Because oxidant stress may be increased and antioxidant defenses reduced in diabetes, the susceptibility of LDL to oxidative modification and total peroxyl radical trapping potential (TRAP) of plasma were evaluated in subjects with poorly controlled insulin-dependent diabetes mellitus (IDDM). The lag phase of conjugated diene formation after initiation of LDL oxidation by the addition of copper was shorter in diabetic subjects than in normal control subjects (126 +/- 11 vs. 165 +/- 15 min [means +/- SE], P < 0.05). This could not be attributed to the presence of oxidation-susceptible, small, dense LDL particles in the diabetic subjects, whose lipoprotein particle distribution did not differ from the control subjects. However, the total TRAP of plasma, a measure of antioxidant defense, was reduced (626 +/- 34 vs. 877 +/- 41 microM, P < 0.0001) in diabetes. Of the plasma antioxidants measured, only uric acid and vitamin A were decreased in diabetes (P < 0.01), and both levels correlated with TRAP (r = 0.75, P < 0.001; r = 0.54, P < 0.001, respectively). The correlation between uric acid levels and TRAP persisted when the diabetes and control groups were analyzed separately. The reduced TRAP of plasma and the increased susceptibility of LDL to oxidative modification observed is consistent with a role for lipoprotein oxidation in the pathogenesis of atherosclerosis in IDDM.

Gastric inhibitory polypeptide enhanced lipoprotein lipase activity in cultured preadipocytes.

Fat feeding stimulated the release of gastric inhibitory polypeptide (GIP) without concomitant insulin secretion. Since antilipolytic effects of GIP have been demonstrated and the uptake of triglyceride fatty acid by adipose tissue postprandially is a process reciprocally regulated with lipolysis, a stimulatory role of GIP on adipose tissue lipoprotein lipase activity may be present. After cultured preadipocytes were incubated for 2 h with GIP, the release of lipoprotein lipase activity into the culture medium and the total cellular activity present in acetone-ether powders of cells were measured. GIP stimulated significant increases in the lipoprotein lipase activity released into the culture medium and in cells. A dose response relationship was strongest for the effect of GIP on the enzyme activity in extracts of acetone-ether powders of the cells. The increased lipoprotein lipase activity produced by GIP could provide a mechanisms for clearance of chylomicron triglyceride after feeding in man.

The response of plasma triglyceride, cholesterol, and lipoprotein lipase to treatment in non-insulin-dependent diabetic subjects without familial hypertriglyceridemia.

The effects of treatment on plasma total triglyceride, total cholesterol, and plasma postheparin lipase activities have not been evaluated in non-insulin-dependent diabetic (NIDD) subjects without a coexisting familial lipid disorder. In 49 untreated NIDD subjects, there was a linear relationship between glycosylated hemoglobin (GHb) and triglyceride (r = 0.35, P less than 0.02). This correlation was improved after adjusting for the effects of obesity by a partial correlation analysis. After therapy, there was a significant relationship between the change in GHb and the change in triglyceride. To determine whether changes in lipid removal from plasma may contribute to the decrease in plasma lipid concentrations during treatment, the plasma postheparin lipoprotein lipase and hepatic lipase activities were evaluated in a subgroup (N = 8) of these NIDD subjects before and after 1 and 3 mo of therapy. Plasma postheparin hepatic lipase activity in the NIDD subjects was not different from that observed in six normal control subjects and did not change during therapy. In contrast, plasma postheparin lipoprotein lipase activity was lower in the untreated NIDD subjects than in the control subjects. Analysis of the two phases (early and late) of the postheparin lipoprotein lipase activity in plasma showed that the abnormal early phase in untreated NIDD corrected to normal values in less than a month, but the late phase was not corrected until the 3-mo measurement. These findings suggest that some NIDD subjects have a defect in heparin releasable lipoprotein lipase activity, which is reversed with improved glycemic control.(ABSTRACT TRUNCATED AT 250 WORDS)

Levels of lipoprotein(a), apolipoprotein B, and lipoprotein cholesterol distribution in IDDM. Results from follow-up in the Diabetes Control and Complications Trial.

Levels of lipoprotein(a) [Lp(a)], apolipoprotein (apo) B, and lipoprotein cholesterol distribution using density-gradient ultracentrifugation were measured as part of a cross-sectional study at the final follow-up examination (mean 6.2 years) in the Diabetes Control and Complications Trial. Compared with the subjects in the conventionally treated group (n = 680), those subjects receiving intensive diabetes therapy (n = 667) had a lower level of Lp(a) (Caucasian subjects only, median 10.7 vs 12.5 mg/dl, respectively; P = 0.03), lower apo B (mean 83 vs. 86 mg/dl, respectively; P = 0.01), and a more favorable distribution of cholesterol in the lipoprotein fractions as measured by density-gradient ultracentrifugation with less cholesterol in the very-low-density lipoprotein and the dense low-density lipoprotein fractions and greater cholesterol content of the more buoyant low-density lipoprotein. Compared with a nondiabetic Caucasian control group (n = 2,158), Lp(a) levels were not different in the intensive treatment group (median 9.6 vs. 10.7 mg/dl, respectively; NS) and higher in the conventional treatment group (9.6 vs. 12.5 mg/dl, respectively; P < 0.01). No effect of renal dysfunction as measured by increasing albuminuria or reduced creatinine clearance on Lp(a) levels could be demonstrated in the diabetic subjects. Prospective follow-up of these subjects will determine whether these favorable lipoprotein differences in the intensive treatment group persist and whether they influence the onset of atherosclerosis in insulin-dependent diabetes.

Analysis of the ileal bile acid transporter gene, SLC10A2, in subjects with familial hypertriglyceridemia.

Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na(+)/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5' flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2.

Contribution of hepatic lipase, lipoprotein lipase, and cholesteryl ester transfer protein to LDL and HDL heterogeneity in healthy women.

Hepatic lipase (HL) and cholesteryl ester transfer protein (CETP) have been independently associated with low density lipoprotein (LDL) and high density lipoprotein (HDL) size in different cohorts. These studies have been conducted mainly in men and in subjects with dyslipidemia. Ours is a comprehensive study of the proposed biochemical determinants (lipoprotein lipase, HL, CETP, and triglycerides) and genetic determinants (HL gene [LIPC] and Taq1B) of small dense LDL (sdLDL) and HDL subspecies in a large cohort of 120 normolipidemic, nondiabetic, premenopausal women. HL (P<0.001) and lipoprotein lipase activities (P=0.006) were independently associated with LDL buoyancy, whereas CETP (P=0.76) and triglycerides (P=0.06) were not. The women with more sdLDL had higher HL activity (P=0.007), lower HDL2 cholesterol (P<0.001), and lower frequency of the HL (LIPC) T allele (P=0.034) than did the women with buoyant LDL. The LIPC variant was associated with HL activity (P<0.001), HDL2 cholesterol (P=0.034), and LDL buoyancy (P=0.03), whereas the Taq1B polymorphism in the CETP gene was associated with CETP mass (P=0.002) and HDL3 cholesterol (P=0.039). These results suggest that HL activity and HL gene promoter polymorphism play a significant role in determining LDL and HDL heterogeneity in healthy women without hypertriglyceridemia. Thus, HL is an important determinant of sdLDL and HDL2 cholesterol in normal physiological states as well as in the pathogenesis of various disease processes.

Relationship of insulin sensitivity and ApoB levels to intra-abdominal fat in subjects with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age- and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.