A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women

Carr, Maria; Hokanson, John E.; Deeb, Samir S.; Purnell, Jonathan Q.; Mitchell, Ellen Siobhan; Brunzell, John D.

doi:10.1161/01.atv.19.11.2701

Cited by 67 publications

(49 citation statements)

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“…In this study we found that both IAF and adiponectin were major correlates of plasma lipoproteins, in particular of LDL buoyancy (Rf) and HDL cholesterol concentrations, in keeping with other reports [31,34,64]. These relationships could be mediated by effects of adiponectin on hepatic lipase activity, which is increased in central obesity and insulin resistance states associated with the metabolic syndrome [65,66]. While hepatic lipase does not seem to be acutely regulated by insulin [67], it could be increased by reduced adiponectin concentrations.…”

Section: Discussionsupporting

confidence: 91%

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

et al. 2003

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Aims/hypothesis. Increased intra-abdominal fat is associated with insulin resistance and an atherogenic lipoprotein profile. Circulating concentrations of adiponectin, an adipocyte-derived protein, are decreased with insulin resistance. We investigated the relationships between adiponectin and leptin, body fat distribution, insulin sensitivity and lipoproteins. Methods. We measured plasma adiponectin, leptin and lipid concentrations, intra-abdominal and subcutaneous fat areas by CT scan, and insulin sensitivity index (S I ) in 182 subjects (76 M/106F). Results. Adiponectin concentrations were higher in women than in men (7.4±2.9 vs 5.4±2.3 µg/ml, p<0.0001) as were leptin concentrations (19.1±13.7 vs 6.9±5.1 ng/ml, p<0.0001). Women were more insulin sensitive (S I : 6.8±3.9 vs 5.9±4.4×10 −5 min −1 /(pmol/l), p<0.01) and had more subcutaneous (240±133 vs 187±90 cm 2 , p<0.01), but less intra-abdominal fat (82±57 vs 124±68 cm 2 , p<0.0001). By simple regression, adiponectin was positively correlated with age (r=0.227, p<0.01) and S I (r=0.375, p<0.0001), and negatively correlated with BMI (r=−0.333, p<0.0001), subcutaneous (r=−0.168, p<0.05) and intra-abdominal fat (r=−0.35, p<0.0001). Adiponectin was negatively correlated with triglycerides (r=−0.281, p<0.001) and positively correlated with HDL cholesterol (r=0.605, p<0.0001) and Rf, a measure of LDL particle buoyancy (r=0.474, p<0.0001). By multiple regression analysis, adiponectin was related to age (p<0.0001), sex (p<0.005) and intra-abdominal fat (p<0.01). S I was related to intraabdominal fat (p<0.0001) and adiponectin (p<0.0005). Both intra-abdominal fat and adiponectin contributed independently to triglycerides, HDL cholesterol and Rf. Conclusion/interpretation. These data suggest that adiponectin concentrations are determined by intra-abdominal fat mass, with additional independent effects of age and sex. Adiponectin could link intra-abdominal fat with insulin resistance and an atherogenic lipoprotein profile. [Diabetologia (2003) 46:459-469] Keywords Adiponectin, Acrp30, adipoQ, central obesity, subcutaneous fat, intra-abdominal fat, insulin sensitivity, lipids, hepatic lipase, cardiovascular disease, leptin. It is well recognized that obesity and insulin resistance are closely related [1,2,3,4]. Android body fat distribution is associated with insulin resistance more than is a gynoid body fat distribution [5], with the site of abdominal fat distribution being an additional determinant of insulin sensitivity [6,7,8,9,10,11]. We found in both lean and obese subjects that the intraabdominal fat (IAF) depot is a stronger determinant of insulin sensitivity than the subcutaneous fat (SCF) depot [11], while SCF is the main determinant of the plasma concentration of leptin [11], an adipocyte-derived hormone regulating energy metabolism [12,13].

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Section: Discussionsupporting

confidence: 91%

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

et al. 2003

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“…Consistent with this is the fact that HL activity is higher overall in men than in women (4) and is higher with central obesity (11,12). HL is produced primarily by the liver and is located on the luminal surface of sinusoidal endothelial cells.…”

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confidence: 62%

Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk

Herbst¹,

Amory²,

Brunzell³

et al. 2003

American Journal of Physiology-Endocrinology and Metabolism

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. Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk. Am J Physiol Endocrinol Metab 284: E1112-E1118, 2003; 10.1152/ ajpendo.00524.2002.-Testosterone administration to men is known to decrease high-density lipoprotein cholesterol (HDL-C) and the subclasses HDL 2 and HDL3. It also might increase the number of small, dense, low-density lipoprotein cholesterol (LDL-C) particles in hypogonadal men. The decrease in HDL-C and in LDL-C size is potentially mediated by hepatic lipase activity, which hydrolyzes lipoprotein phospholipids and triacylglycerol. To determine how HDL-C and LDL-C particles are affected by testosterone administration to eugonadal men, testosterone was administered as a supraphysiological dose (600 mg/wk) for 3 wk to elderly, obese, eugonadal men before elective hip or knee surgery, and lipids were measured by routine methods and by density gradient ultracentrifugation. Hepatic lipase activity increased Ͼ60% above baseline levels, and HDL-C, HDL 2, and HDL3 significantly declined in 3 wk. In addition, the LDL-C peak particle density and the amount of LDL-C significantly increased. Testosterone is therefore a potent stimulator of hepatic lipase activity, decreasing HDL-C, HDL 2, and HDL3 as well as increasing LDL particle density changes, all associated with increased cardiovascular risk.androgen; lipoprotein particle density TESTOSTERONE (T) administration to men is known to decrease HDL-cholesterol (HDL-C) (6-8, 25, 39), although not necessarily in hypogonadal men (27,30,42). When HDL-C declines with T administration in both eugonadal and hypogonadal men, it is unclear whether this decrease is in the subclasses HDL 2 (22) or HDL 3 (32-34) or both. That HDL-C decreases with T administration might be important for long-term use of T in men, because low HDL-C, including low HDL 2 and low HDL 3 , is associated with an increased risk for cardiovascular disease (3,14,26).The decrease in HDL-C with T administration is likely mediated by an increase in hepatic lipase (HL) activity. Consistent with this is the fact that HL activity is higher overall in men than in women (4) and is higher with central obesity (11,12). HL is produced primarily by the liver and is located on the luminal surface of sinusoidal endothelial cells. It catalyzes the hydrolysis of triacylglycerols and phospholipids, mediating the removal of lipoproteins from plasma (23). This hydrolysis converts the more buoyant HDL 2 to the smaller, denser HDL 3 , which can be taken up by the liver, thereby decreasing HDL-C. In addition, HL by the same mechanism converts large, buoyant LDL to small, dense LDL (41), the latter also being a risk factor for cardiovascular disease (2,24,31). One study demonstrated an increase in one population of small, dense LDL particles with T administration to hypogonadal men (32), but a cross-sectional study demonstrated an inverse association between serum T levels and small, dense LDL (29), although the T levels in that study have been called into questi...

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“…In this model, the cholesterol concentration in the fractions corresponding to VLDL (fractions 31-38), IDL (fractions 29 and 30), buoyant LDL (fractions [12][13][14], dense LDL (fractions 7-9), and HDL (fractions 1-5) was associated with IAF, whereas S I made no additional contribution to any of the fractions. In a third model, we included BMI as an independent variable together with IAF, S I , and SCF, and found that the cholesterol concentration in the fractions corresponding to VLDL (fractions [31][32][33][34][35][36][37][38], IDL (fraction 30), and dense LDL (fractions 8 -10) was associated with IAF, whereas S I again made no additional contribution. Thus IAF, but not S I , had independent effects to determine the cholesterol concentration beyond those of SCF and BMI.…”

Section: Dj Nieves and Associatesmentioning

confidence: 99%

“…Thus an increase in the waist-to-hip ratio (WHR) has been found to be associated with small dense LDL particles (26), as has been an increase in IAF mass (27,28) or insulin sensitivity (29,30). This pattern of central fat distribution has also been associated with an increase in VLDL and intermediate-density lipoprotein (IDL) (26,31) and a decrease in HDL 2 cholesterol (26,32,33). Although these analyses strongly suggest that central fat distribution and/or insulin resistance is an important determinant of adverse changes in lipoprotein profile, we believed that a critical examination of this issue in a large number of apparently healthy subjects was required to determine the impact of differences in body fat distribution and insulin sensitivity on plasma lipids.…”

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confidence: 99%

The Atherogenic Lipoprotein Profile Associated With Obesity and Insulin Resistance Is Largely Attributable to Intra-Abdominal Fat

et al. 2003

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Obesity and insulin resistance are both associated with an atherogenic lipoprotein profile. We examined the effect of insulin sensitivity and central adiposity on lipoproteins in 196 individuals (75 men and 121 women) with an average age of 52.7 years. Subjects were subdivided into three groups based on BMI and their insulin sensitivity index (S I ): lean insulin sensitive (n ‫؍‬ 65), lean insulin resistant (n ‫؍‬ 73), and obese insulin resistant (n ‫؍‬ 58). This categorization revealed that both obesity and insulin resistance determined the lipoprotein profile. In addition, the insulin-resistant groups had increased central adiposity. Increasing intra-abdominal fat (IAF) area, quantified by computed tomography scan and decreasing S I , were important determinants of an atherogenic profile, marked by increased triglycerides, LDL cholesterol, and apolipoprotein B and decreased HDL cholesterol and LDL buoyancy (Rf). Density gradient ultracentrifugation (DGUC) revealed that in subjects who had more IAF and were more insulin resistant, the cholesterol content was increased in VLDL, intermediate-density lipoprotein (IDL), and dense LDL fractions whereas it was reduced in HDL fractions. Multiple linear regression analysis of the relation between the cholesterol content of each DGUC fraction as the dependent variable and IAF and S I as independent variables revealed that the cholesterol concentration in the fractions corresponding to VLDL, IDL, dense LDL, and HDL was associated with IAF, and that S I additionally contributed independently to VLDL, but not to IDL, LDL, or HDL. Thus an atherogenic lipoprotein profile appears to be the result primarily of an increase in IAF, perhaps via insulin resistance.

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A Hepatic Lipase Gene Promoter Polymorphism Attenuates the Increase in Hepatic Lipase Activity With Increasing Intra-abdominal Fat in Women

Cited by 67 publications

References 61 publications

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex

Testosterone administration to men increases hepatic lipase activity and decreases HDL and LDL size in 3 wk

The Atherogenic Lipoprotein Profile Associated With Obesity and Insulin Resistance Is Largely Attributable to Intra-Abdominal Fat

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