Plasma Hepatic Lipase Activity Research Articles

The Proline 7 Substitution in the Preproneuropeptide Y Is Associated with Higher Hepatic Lipase Activity In Vivo.

Hepatic lipase (HL) functions as a lipolytic enzyme that hydrolyzes triglycerides and phospholipids present in circulating plasma lipoproteins. Plasma HL activity is known to be regulated by hormonal and metabolic factors, but HL responsiveness to insulin as well as its role in modulating atherosclerotic risk is still controversial. We investigated on the influence of a known polymorphism in the neurotransmitter neuropeptide Y (NPY) on HL activity in two different cohorts consisting of diabetic and nondiabetic patients. HL activity was 24% and 34% higher on nondiabetic and diabetic subjects in the presence of the 7Pro allele in NPY, respectively. The presence of the 7Pro allele was an independent predictor of HL activity in multivariate analyses in both cohorts. These data suggest a regulatory effect of NPY on HL activity. Among carriers of the 7Pro allele, we also found a statistically significant lower absolute number of infarctions compared to noncarriers (p < 0.05) and a nonsignificant trend towards less myocardial infarction in the 7Pro allele diabetic carriers (p = 0.085). In conclusion, the common 7Pro allele in NPY was associated with higher HL activity in nondiabetic and diabetic subjects and its presence seems to coincide with a lower frequency of certain cardiovascular events.

Role of SN1 Lipases on Plasma Lipids in Metabolic Syndrome and Obesity

To assess the phospholipase activity of endothelial (EL) and hepatic lipase (HL) in postheparin plasma of subjects with metabolic syndrome (MS)/obesity and their relationship with atherogenic and antiatherogenic lipoproteins. Additionally, to evaluate lipoprotein lipase (LPL) and HL activity as triglyceride (TG)-hydrolyses to complete the analyses of SN1 lipolytic enzymes in the same patient. Plasma EL, HL, and LPL activities were evaluated in 59 patients with MS and 36 controls. A trend toward higher EL activity was observed in MS. EL activity was increased in obese compared with normal weight group (P=0.009) and was negatively associated with high-density lipoprotein-cholesterol (P=0.014 and P=0.005) and apolipoprotein A-I (P=0.045 and P=0.001) in control and MS group, respectively. HL activity, as TG-hydrolase, was increased in MS (P=0.025) as well as in obese group (P=0.017); directly correlated with low-density lipoprotein-cholesterol (P=0.005) and apolipoprotein B (P=0.003) and negatively with high-density lipoprotein-cholesterol (P=0.021) in control group. LPL was decreased in MS (P<0.001) as well as in overweight and obese compared with normal weight group (P=0.015 and P=0.004, respectively); inversely correlated %TG-very low-density lipoproteins (P=0.04) and TG/apolipoprotein B index (P=0.013) in control group. These associations were not found in MS. We describe for the first time EL and HL activity as phospholipases in MS/obesity, being both responsible for high-density lipoprotein catabolism. Our results elucidate part of the remaining controversies about SN1 lipases activity in MS and different grades of obesity. The impact of insulin resistance on the activity of the 3 enzymes determines the lipoprotein alterations observed in these states.

Low molecular weight heparin-induced increase in chylomicron-remnants clearance, is associated with decreased plasma TNF-α level and increased hepatic lipase activity

The acute effect of heparin on lipoprotein clearance is well characterized. Yet, the effect of prolonged low-molecular-weight-heparin (LMWH) administration on post-prandial lipemia has remained so far unexplored. Recent reports suggest that LMWH could modify lipid and carbohydrate metabolism by diminishing TNFα-mediated inflammatory response. This, together with the known negative effect of TNF-α on insulin sensitivity, prompted us to hypothesize that LMWH would favorably affect post-prandial lipoprotein disposal. Twenty four patients were given a vitamin A-fat loading meal at the end of 6-week enoxaparin treatment and after 3-month washout period. Post-prandial lipemia was assessed by measuring retinyl-palmitate (RP) during 8hours following the meal. Insulin sensitivity index (ISI), plasma lipolytic activity and plasma TNF-α were measured. Enoxaparin did not impact fasting plasma lipids and lipoproteins levels. Enoxaparin increased RP clearance in the chylomicron remnant (CMR) fraction by 32% (P<0.01). Additionally, enoxaparin decreased plasma TNF-α by 22% (P<0.01), increased hepatic lipase (HL) activity by 81% (P<0.01), along with a 2-fold increase in ISI (P<0.01). The decrease in CMR correlated with the reduction in TNFα and the increase in ISI and HL activity (R=0.48, -0.68, -0.56, respectively, p<0.05). Significant correlations were also found between the reduction in TNFα and both the increase in ISI and increase in HL activity (R=-0.43, -0.54, respectively, P<0.05). The association of the effect on post-prandial metabolism, plasma TNFα level and HL activity during prolonged enoxaparin treatment may support the hypothesis that the beneficial outcome of enoxaparin may possibly be linked to anti-inflammatory and lipase-potentiating impact.

Upregulation of fatty acid synthesis and the suppression of hepatic triglyceride lipase as a direct cause of hereditary postprandial hypertriglyceridemia in rabbits

Rabbits with hereditary postprandial hypertriglyceridemia exhibit central obesity and are regarded as a reliable model for metabolic syndrome. This study was performed to gain insight into the affected process of lipid metabolism and into the causative genes of the postprandial hypertriglyceridemia rabbits. Eleven genes that play key roles in lipid metabolism were selected, their mRNA levels were assessed by quantitative PCR, and their expressions were compared among postprandial hypertriglyceridemia rabbits using Japanese white rabbits as the control. Two genes appeared to be in causal connection with postprandial hypertriglyceridemia, and these were regarded as likely candidates for the pathogenesis. One was the fatty acid synthase gene, which had an expression constitutively higher in postprandial hypertriglyceridemia rabbits than in Japanese white rabbits during the fasting state and reached quite high levels after feeding. The other was the gene for hepatic triglyceride lipase with an expression that was approximately one order lower than that found in the Japanese white rabbits. The low plasma hepatic triglyceride lipase activities were consistent with the low levels of the transcript in the livers of the postprandial hypertriglyceridemia rabbits. Thus, elevated fatty acid synthesis and defected lipid hydrolysis together would cause the postprandial hypertriglyceridemia in postprandial hypertriglyceridemia rabbits.

Hepatic lipase activity is decreased in Japanese patients with type III hyperlipoproteinemia

BackgroundType III hyperlipoproteinemia (HLP), a disorder associated with a high incidence of premature cardiovascular diseases, is characterized by the accumulation of remnant lipoproteins in the plasma. The primary genetic defect in patients with type III HLP is the presence of apolipoprotein E2 (apoE2), an isoform of apoE, and accumulation of remnant lipoproteins in the plasma has been thought to be attributable to the presence of apoE2, which bind poorly to low density lipoprotein receptors, resulting in defective remnant lipoprotein clearance. On the other hand, the activity of hepatic lipase (HL), the enzyme that plays a pivotal role in the removal of remnant lipoproteins, in type III HLP has not been investigated. MethodsWe examined post-heparin plasma lipoprotein lipase (LPL) and HL activities in 7 patients with type III HLP. The activities of HL and LPL in post-heparin plasma were measured separately by an immunochemical method using antiserum specifically directed against HL. ResultsThe post-heparin plasma HL activity was significantly reduced, while the LPL activity was normal. ConclusionsReduced HL activity may account, at least in part, for the accumulation of remnant lipoproteins in the plasma, a characteristic feature of type III HLP.

Determination of lipoprotein lipase activity using a novel fluorescent lipase assay

A novel, real-time, homogeneous fluorogenic lipoprotein lipase (LPL) assay was developed using a commercially available substrate, the EnzChek lipase substrate, which is solubilized in Zwittergent. The triglyceride analog substrate does not fluoresce, owing to apposition of fluorescent and fluorescent quenching groups at the sn-1 and sn-2 positions, respectively, fluorescence becoming unquenched upon release of the sn-1 BODIPY FA derivative following hydrolysis. Increase in fluorescence intensity at 37°C was proportional to LPL concentration. The assay was more sensitive than a similar assay using 1,2-O-dilauryl-rac-glycero-3-glutaric acid-(6-methylresorufin ester) and was validated in biological samples, including determination of LPL-specific activity in postheparin mouse plasma. The simplicity and reproducibility of the assay make it ideal for in vitro, high-throughput screening for inhibitors and activators of LPL, thus expediting discovery of drugs of potential clinical value.

MS407 REDUCED MYOCARDIAL GLUCOSE UTILIZATION AFTER FASTING AND HEPARIN INJECTION IN RATS

Type III hyperlipoproteinemia (HLP), a disorder associated with a high incidence of premature cardiovascular diseases, is characterized by the accumulation of remnant lipoproteins in the plasma. The primary genetic defect in patients with type III HLP is the presence of apolipoprotein E2 (apoE2), an isoform of apoE, and accumulation of remnant lipoproteins in the plasma has been thought to be attributable to the presence of apoE2, which bind poorly to low density lipoprotein receptors, resulting in defective remnant lipoprotein clearance. On the other hand, the activity of hepatic lipase (HL), the enzyme that plays a pivotal role in the removal of remnant lipoproteins, in type III HLP has not been investigated.We examined post-heparin plasma lipoprotein lipase (LPL) and HL activities in 7 patients with type III HLP. The activities of HL and LPL in post-heparin plasma were measured separately by an immunochemical method using antiserum specifically directed against HL.The post-heparin plasma HL activity was significantly reduced, while the LPL activity was normal.Reduced HL activity may account, at least in part, for the accumulation of remnant lipoproteins in the plasma, a characteristic feature of type III HLP.

Acrolein consumption induces systemic dyslipidemia and lipoprotein modification

Aldehydes such as acrolein are ubiquitous pollutants present in automobile exhaust, cigarette, wood, and coal smoke. Such aldehydes are also constituents of several food substances and are present in drinking water, irrigation canals, and effluents from manufacturing plants. Oral intake represents the most significant source of exposure to acrolein and related aldehydes. To study the effects of short-term oral exposure to acrolein on lipoprotein levels and metabolism, adult mice were gavage-fed 0.1 to 5 mg acrolein/kg bwt and changes in plasma lipoproteins were assessed. Changes in hepatic gene expression related to lipid metabolism and cytokines were examined by qRT-PCR analysis. Acrolein feeding did not affect body weight, blood urea nitrogen, plasma creatinine, electrolytes, cytokines or liver enzymes, but increased plasma cholesterol and triglycerides. Similar results were obtained with apoE-null mice. Plasma lipoproteins from acrolein-fed mice showed altered electrophoretic mobility on agarose gels. Chromatographic analysis revealed elevated VLDL cholesterol, phospholipids, and triglycerides levels with little change in LDL or HDL. NMR analysis indicated shifts from small to large VLDL and from large to medium-small LDL with no change in the size of HDL particles. Increased plasma VLDL was associated with a significant decrease in post-heparin plasma hepatic lipase activity and a decrease in hepatic expression of hepatic lipase. These observations suggest that oral exposure to acrolein could induce or exacerbate systemic dyslipidemia and thereby contribute to cardiovascular disease risk.

Increased Expression and Activity of Hepatic Lipase in the Liver of Morbidly Obese Adult Patients in Relation to Lipid Content

The types and sources of lipid deposition in the liver of most patients with morbid obesity, as well as the effects of bariatric surgery, are discussed. In 26 patients with morbid obesity who underwent bariatric surgery, we analyzed different kinds of lipids and hepatic lipase (HL) from both plasma and liver biopsies performed 12-18 months after surgery. The HL activity and HL-mRNA in morbidly obese (MO) livers were high (258 +/- 17 mU/g, and 4.5-fold, respectively); after surgery, the activity decreased (137 +/- 15 mU/g, p < 0.001) but not the levels of HL-mRNA (4.3-fold). Plasma HL activity was also high (4.31 +/- 0.94 mU/mL plasma), and it decreased during weight loss (2.01 +/- 0.29 mU/mL, p < 0.01); moreover, it correlated (r = 0.3694, p < 0.05) with decreased liver HL activity. Adrenocorticotropic hormone in MO was higher (27 +/- 3 pg/mL) than after surgery (13 +/- 1 pg/mL, p < 0.001). All hepatic and plasma lipids were significantly increased in MO patients, but, after bariatric surgery, most of those parameters recovered or normalized. Liver HL activity correlated with total and esterified cholesterol (r = 0.4399, p < 0.001 and r = 0.4395, p < 0.01, respectively). High HL in MO patients could allow for liver intake of cholesterol that could be re-exported to steroidogenic organs to synthesize steroidal hormones. A decrease of plasma HL during weight loss could be a good index for improvement of liver disease.

PO2-30 APO A-I ISOFORMS DISPLAY DIFFERENT EFFICIENCIES IN INDUCING ABCA1-DEPENDENT CHOLESTEROL EFFLUX FROM MOUSE PERITONEAL MACROPHAGES

The sequence of alterations in the concentration and composition of different plasma lipoproteins following alcohol intake is not known. We therefore monitored the concentrations of cholesterol, triglycerides, phospholipids, and proteins in the major lipoprotein fractions (VLDL, LDL, HDL2, and HDL3) in ten nonalcoholic healthy male volunteers who were given 5.5 g of alcohol per kilogram of body weight during 212days (a weekend). In addition, lipoprotein lipase activity was measured in post-heparin plasma and in adipose tissue and hepatic lipase activity was measured in post-heparin plasma before and after the experiment. In a separate control experiment, the same subjects received meals and liquids without alcohol. Blood alcohol levels remained below 1.5 g/L. Alcohol caused a progressive increase in the fasting VLDL triglyceride and phospholipid concentrations, both of which were doubled during the experiment (P < 0.001). In contrast, the VLDL cholesterol levels remained unchanged until the third morning, when there was a slight increase. The LDL triglyceride and phospholipid concentrations also rose without simultaneous changes in the LDL cholesterol concentration. Consistent with these changes, the HDL cholesterol concentration showed no response to alcohol during the experiment, but the HDL phospholipid level rose from 76 to 99 mg/dL (P < 0.001). This was reflected as an increase in the HDL2 concentration from 124 to 158 mg/dL (P < 0.01), whereas no change occurred in the HDL3 level. The increment of HDL2 concentration was due to a rise of its triglycerides, phospholipids, and apoproteins A-I and A-II but not to a rise of cholesterol. Thus, the VLDL, LDL and HDL2 fractions all became relatively depleted of cholesterol during alcohol intake. Alcohol potentiated the postprandial rise of plasma triglycerides with an increase in triglyceride concentrations in all lipoprotein fractions. During alcohol intake the HDL2 concentration increased postprandially (P < 0.05) whereas the HDL3 concentration decreased slightly, the fall being accounted for by a decrease in the HDL3 cholesterol level. The lipoprotein lipase activity of adipose tissue increased by an average of 2.3-fold (P < 0.01) over the alcohol-intake period, whereas the postheparin plasma hepatic lipase activity fell by 28% (P < 0.01). The results support the hypothesis that alcohol initially stimulates the secretion of VLDL particles that contain less cholesterol than “normal” VLDL. As a consequence of this and of a concomitant induction of lipoprotein lipase, alcohol intake is followed by an accelerated transfer of the VLDL catabolic products to HDL and by a subsequent rise in the levels of HDL2 triglycerides, phospholipids, and apoproteins but not of cholesterol. The suppression of hepatic lipase activity by alcohol may contribute further to the rise of HDL2 phospholipids. It thus appears that the increase of HDL cholesterol is a late phenomenon being expressed only after more prolonged use of alcohol.

PO2-33 THE INCREASE OF APOA-V DURING POSTPRANDIAL LIPEMIA FOLLOWS THE RESPONSE OF TRIGLYCERIDE-RICH LIPOPROTEINS (TRL) IN TYPE 2 DIABETES

The sequence of alterations in the concentration and composition of different plasma lipoproteins following alcohol intake is not known. We therefore monitored the concentrations of cholesterol, triglycerides, phospholipids, and proteins in the major lipoprotein fractions (VLDL, LDL, HDL2, and HDL3) in ten nonalcoholic healthy male volunteers who were given 5.5 g of alcohol per kilogram of body weight during 212days (a weekend). In addition, lipoprotein lipase activity was measured in post-heparin plasma and in adipose tissue and hepatic lipase activity was measured in post-heparin plasma before and after the experiment. In a separate control experiment, the same subjects received meals and liquids without alcohol. Blood alcohol levels remained below 1.5 g/L. Alcohol caused a progressive increase in the fasting VLDL triglyceride and phospholipid concentrations, both of which were doubled during the experiment (P < 0.001). In contrast, the VLDL cholesterol levels remained unchanged until the third morning, when there was a slight increase. The LDL triglyceride and phospholipid concentrations also rose without simultaneous changes in the LDL cholesterol concentration. Consistent with these changes, the HDL cholesterol concentration showed no response to alcohol during the experiment, but the HDL phospholipid level rose from 76 to 99 mg/dL (P < 0.001). This was reflected as an increase in the HDL2 concentration from 124 to 158 mg/dL (P < 0.01), whereas no change occurred in the HDL3 level. The increment of HDL2 concentration was due to a rise of its triglycerides, phospholipids, and apoproteins A-I and A-II but not to a rise of cholesterol. Thus, the VLDL, LDL and HDL2 fractions all became relatively depleted of cholesterol during alcohol intake. Alcohol potentiated the postprandial rise of plasma triglycerides with an increase in triglyceride concentrations in all lipoprotein fractions. During alcohol intake the HDL2 concentration increased postprandially (P < 0.05) whereas the HDL3 concentration decreased slightly, the fall being accounted for by a decrease in the HDL3 cholesterol level. The lipoprotein lipase activity of adipose tissue increased by an average of 2.3-fold (P < 0.01) over the alcohol-intake period, whereas the postheparin plasma hepatic lipase activity fell by 28% (P < 0.01). The results support the hypothesis that alcohol initially stimulates the secretion of VLDL particles that contain less cholesterol than “normal” VLDL. As a consequence of this and of a concomitant induction of lipoprotein lipase, alcohol intake is followed by an accelerated transfer of the VLDL catabolic products to HDL and by a subsequent rise in the levels of HDL2 triglycerides, phospholipids, and apoproteins but not of cholesterol. The suppression of hepatic lipase activity by alcohol may contribute further to the rise of HDL2 phospholipids. It thus appears that the increase of HDL cholesterol is a late phenomenon being expressed only after more prolonged use of alcohol.

The hepatic lipase gene C‐480T polymorphism in the development of early coronary atherosclerosis: the Helsinki Sudden Death Study

The T allele of the hepatic lipase (HL) C-480T polymorphism was previously found to be associated with lower post-heparin plasma HL activity, atherosclerosis and risk of coronary artery disease. We studied the association of HL C-480T polymorphism with the extent of atherosclerosis at vessel-wall level in an autopsy series of middle-aged men. An autopsy cohort of 700 Caucasian Finnish men aged 33-70 years (mean 53 years), which comprised two autopsy series, collected 10 years apart during 1981-82 and 1991-92, were analysed. Areas of coronary wall covered with fatty streaks and fibrotic and complicated lesions were measured using computer-assisted planimetry and related to HL C-480T genotypes (CC, CT, and TT). There was a significant age-by-genotype interaction on the mean percentage area of fatty streaks (P = 0.01). The HL C-480T polymorphism was a significant explanatory factor for fatty streak area in men under 53 years of age with or without age, body mass index, hypertension, diabetes, smoking, alcohol consumption, apolipoprotein E genotype, and series number as covariates. Men carrying the TT genotype had two times larger areas of fatty streaks compared to the CC carriers (8.8% vs. 4.3%, P = 0.009). However, this association disappeared in men over 53 years. The areas of more advanced atherosclerotic lesions did not vary significantly among the genotype groups. Our results suggest that the HL C-480T polymorphism affects the formation of early coronary atherosclerotic lesions in men in their early middle age.

Low Plasma Adiponectin Levels Are Associated With Increased Hepatic Lipase Activity In Vivo: Response to Schneider et al.

Recently, close attention has been given to the relationships between plasma adiponectin levels and lipolytic enzymes such as hepatic lipase and lipoprotein lipase activities in an effort to understand the possible mechanism of hyperlipidemia in low adiponectin. The cross-sectional study by Schneider et al. (1) has concluded that postheparin plasma hepatic lipase activity is inversely associated with plasma …

Low Plasma Adiponectin Levels Are Associated With Increased Hepatic Lipase Activity In Vivo

Recently, close attention has been given to the relationships between plasma adiponectin levels and lipolytic enzymes such as hepatic lipase and lipoprotein lipase activities in an effort to understand the possible mechanism of hyperlipidemia in low adiponectin. The cross-sectional study by Schneider et al. (1) has concluded that postheparin plasma hepatic lipase activity is inversely associated with plasma …

Opposite Contributions of Trunk and Leg Fat Mass with Plasma Lipase Activities: The Hoorn Study

Lipoprotein lipase (LPL) and hepatic lipase (HL) are essential in hydrolysis of triglyceride-rich lipoproteins. LPL activity is negatively, whereas HL activity is positively, associated with total body fat. We determined the associations of trunk and leg fat mass with plasma LPL and HL activities in a cross-sectional study. LPL and HL activities were determined in post-heparin plasma in a sample of 197 men and 209 women, 60 to 87 years of age. A total body DXA scan was performed to determine trunk and leg fat mass. In women, but not in men, trunk fat mass was negatively associated with LPL activity, whereas leg fat mass was positively associated, after mutual adjustment and adjustment for age. Standardized betas (95% confidence interval) for trunk and leg fat mass were -0.24 (-0.41; -0.08) and 0.14 (-0.02; 0.31), respectively (interaction by sex, p = 0.03). Larger trunk fat mass was associated with higher HL activity in men [0.48 (0.28; 0.68)] and women [0.40 (0.24; 0.56)]. A negative association of leg fat mass and HL activity was observed in men, although not statistically significant [-0.13 (-0.33; 0.06)], and in women [-0.28 (-0.38; -0.18)]. Abdominal fat is associated with unfavorable and femoral fat with favorable LPL and HL activities in plasma.

Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I

Obese mice without leptin (ob/ob) or the leptin receptor (db/db) have increased plasma HDL levels and accumulate a unique lipoprotein referred to as LDL/HDL1. To determine the role of apolipoprotein A-I (apoA-I) in the formation and accumulation of LDL/HDL1, both ob/ob and db/db mice were crossed onto an apoA-I-deficient (apoA-I(-/-)) background. Even though the obese apoA-I(-/-) mice had an expected dramatic decrease in HDL levels, the LDL/HDL1 particle persisted. The cholesterol in this lipoprotein range was associated with both alpha- and beta-migrating particles, confirming the presence of small LDLs and large HDLs. Moreover, in the obese apoA-I(-/-) mice, LDL particles were smaller and HDLs were more negatively charged and enriched in apoE compared with controls. This LDL/HDL1 particle was rapidly remodeled to the size of normal HDL after injection into C57BL/6 mice, but it was not catabolized in obese apoA-I(-/-) mice even though plasma hepatic lipase (HL) activity was increased significantly. The finding of decreased hepatic scavenger receptor class B type I (SR-BI) protein levels may explain the persistence of LDL/HDL1 in obese apoA-I(-/-) mice. Our studies suggest that the maturation and removal of large HDLs depends on the integrity of a functional axis of apoA-I, HL, and SR-BI. Moreover, the presence of large HDLs without apoA-I provides evidence for an apoA-I-independent pathway of cholesterol efflux, possibly sustained by apoE.

Low Plasma Adiponectin Levels Are Associated With Increased Hepatic Lipase Activity In Vivo

Hepatic lipase plays a key role in hydrolyzing triglycerides and phospholipids present in circulating plasma lipoproteins. Plasma hepatic lipase activity is known to be regulated by several hormonal and metabolic factors, but hepatic lipase responsiveness to insulin is still controversial. Hypoadiponectinemia is known to be associated with insulin resistance, diabetes, and obesity. These conditions are often characterized by high plasma triglyceride and low HDL cholesterol levels, and they have been shown to be associated with high plasma hepatic lipase activity. We therefore raised the question whether adiponectin may be associated with plasma hepatic lipase activity in vivo. We measured plasma adiponectin and postheparin hepatic lipase activity in 206 nondiabetic men and in a second group of 110 patients with type 2 diabetes. The correlation of these parameters with markers of insulin resistance and systemic inflammation was investigated. In nondiabetic patients, adiponectin levels were significantly inversely correlated with plasma hepatic lipase activity (r = -0.4, P < 0.01). These results were confirmed in the group of patients with type 2 diabetes (r = -0.32, P = 0.004). Multivariate analysis revealed that adiponectin was the strongest factor influencing hepatic lipase activity. The association was independent of age, sex, BMI, plasma triglycerides, insulin, HDL cholesterol, and high-sensitivity C-reactive protein and accounted for approximately 10 and 12% of the variation in hepatic lipase activity in the two different patient cohorts, respectively. These results demonstrate for the first time a significant inverse association between adiponectin and postheparin plasma hepatic lipase activity that is independent of other factors such as markers of insulin resistance or inflammation. Therefore, adiponectin, rather than insulin, may represent an important factor contributing to the regulation of hepatic lipase activity in both nondiabetic individuals and patients with type 2 diabetes. The effect of adiponectin on hepatic lipase activity may also help to explain the HDL cholesterol-elevating action of adiponectin.

Epistatic interaction between two nonstructural loci on chromosomes 7 and 3 influences hepatic lipase activity in BSB mice

BSB mice exhibit a wide range of obesity despite being produced by a backcross of lean C57BL/6J (B) x lean Mus spretus (SPRET/Pt) F1 animals x B. Previous linkage studies identified a quantitative trait locus (QTL) on mouse chromosome 7 with coincident peaks for hepatic lipase activity, obesity, and plasma cholesterol. However, these mice were not analyzed for gene x gene epistasis. Hepatic lipase activity is correlated with obesity and plasma cholesterol levels. In this study, we identified QTLs for plasma hepatic lipase activity with three statistical mapping methods: maximum likelihood interval mapping, Bayesian nonepistatic mapping, and Bayesian epistatic mapping. Bayesian epistatic mapping detected not only the QTL on chromosome 7 but also an additional QTL on chromosome 3, which has a weak main effect but a strong interaction with chromosome 7. SPRET/Pt alleles of the QTL on each chromosome promote hepatic lipase activity. The proportion of phenotypic variance explained by the epistatic effect is higher than that explained by the main effect of the QTL on chromosome 7.

Hepatic Lipase mRNA, Protein, and Plasma Enzyme Activity Is Increased in the Insulin-Resistant, Fructose-Fed Syrian Golden Hamster and Is Partially Normalized by the Insulin Sensitizer Rosiglitazone

Postheparin plasma hepatic lipase (HL) activity has been shown to correlate with features of the metabolic syndrome and type 2 diabetes in humans. We examined HL postheparin plasma enzyme activity, hepatocyte mRNA, and protein mass in the insulin-resistant, fructose-fed Syrian golden hamster, and the response of the insulin-sensitizing peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. Male Syrian golden hamsters were treated for 5 weeks with 1) normal diet (DIET group), 2) 60% fructose diet (FRUC group), or 3) 60% fructose and rosiglitazone (20 mmol . kg(-1) . day(-1)) (FRUC+RSG group). Hepatocyte HL mRNA, protein mass, and postheparin plasma HL activity were increased in FRUC compared with DIET hamsters. FRUC+RSG hamsters had partial normalization of HL mRNA, mass, and activity. There was a shift in the size of LDL particles from large to small in FRUC animals and a shift back to large LDL size in FRUC+RSG. This is the first demonstration that HL hepatocyte mRNA, mass, and plasma enzymatic activity increase concomitantly with induction of an insulin-resistant state and can be partially normalized by treatment with an insulin sensitizer. The increase in HL in insulin-resistant states may play an important role in the typical dyslipidemia of these conditions, and reduction of HL could explain some of the beneficial effects of insulin sensitizers on the plasma lipid profile.

Reciprocal hemizygosity analysis of mouse hepatic lipase reveals influence on obesity.

We previously demonstrated coincident quantitative trait loci (QTLs) for percentage body fat, plasma hepatic lipase (HL) activity, and plasma cholesterol on mouse chromosome 7. In the present study, we investigated whether hepatic lipase (Lipc) is an obesity gene, whether Lipc interacts with an unknown gene on chromosome 7, and how HL activity is linked to the chromosome 7 locus. BSB mice are a model of complex obesity due to interactions among genes from C57BL/6J and Mus spretus (SPRET) in (C57BL/6J x SPRET) x C57BL/6J backcross mice. Five crosses tested the impact on obesity of combinations of inactive (knockout) and wild-type Lipc alleles from C57BL/6J or SPRET in a reciprocal hemizygosity analysis. The combined data from this allelic series suggest that Lipc alleles, and not alleles from a gene linked to Lipc, influence obesity. No interaction between Lipc and chromosome 7 was demonstrated. We confirmed the chromosome 7 QTLs for obesity, HL activity, and cholesterol. Because obesity and HL activity are not consistently associated in the BSB model, linkage of HL activity to chromosome 7 is not secondary to obesity per se. We also report, for the first time to our knowledge, a QTL in mammals for food intake. This use of reciprocal hemizygosity analysis in mammals, which, to our knowledge, is the first reported, reveals its power to detect previously unknown effects of Lipc on obesity.