Hepatic Lipase Activity Research Articles

Effects of Huanglian Jiedu Decoction on blood lipid metabolism and its related gene expressions in rats with hyperlipidemia

To observe the effects of Huanglian Jiedu Decoction (HJD), a compound traditional Chinese herbal medicine, on lipid metabolism and its related gene expressions in rats with hyperlipidemia. Fifty SD rats were randomly divided into normal control group, untreated group, Lipitor (atorvastatin) group, and low- and high-dose HJD groups. Except the normal control group, rats in the other groups were fed with high-fat diet to induce hyperlipidemia. Then the rats were administered with corresponding drugs for 8 weeks. After treatment, the serum levels of total cholesterol (TC), triacylglycerol (TAG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were assayed. The activities of lipoprotein lipase (LPL) and hepatic lipase (HL) in liver tissues were measured. Low-density lipoprotein receptor (LDLR) and peroxisome proliferator-activated receptor gamma (PPARgamma) mRNA expressions in liver tissues were determined by reverse transcription-polymerase chain reaction. Compared with the normal control group, the levels of serum TC, TAG and LDL-C in the untreated group were increased and the level of serum HDL-C was reduced. The activities of LPL and HL and expressions of LDLR and PPARgamma mRNAs in the untreated group were lower than those in the normal control group. After treatment, high-dose HJD significantly improved hyperlipemia by decreasing TC, TAG and LDL-C and increasing HDL-C. The activities of LPL and HL and expression levels of LDLR and PPARgamma mRNAs in liver tissues were also markedly enhanced in the high-dose HJD group as compared with those in the untreated group. HJD can activate the activity of lipid metabolism enzyme, and enhance the expressions of LDLR and PPARgamma mRNAs to modulate the lipid metabolic disorders in rats with hyperlipidemia.

Protective effects of diosgenin in the hyperlipidemic rat model and in human vascular endothelial cells against hydrogen peroxide-induced apoptosis

Hyperlipidemia is a major cause of atherosclerosis and atherosclerosis-associated conditions in cardiovascular diseases. Oxidative stress, as a main risk factor causes vascular endothelial cell apoptosis, which is implicated in the pathogenesis of cardiovascular disorders. Diosgenin, an aglycone of steroidal saponins, has been reported to exert anti-proliferative and proapoptotic actions on cancer cells widely. In this study, we propose that diosgenin can protect the hyperlipidemic rats and prevent endothelial apoptosis under oxidative stress. We investigated the hypolipidemic and antioxidative effects of diosgenin on rats fed with high cholesterol and high fat diet for 6 weeks. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), glutathione peroxidase (GSH-PX), nitric oxide synthase (NOS), hepatic malondialdehyde (MDA), lipoprotein lipase (LPL), hepaticlipase (HL) and superoxide dismutase (SOD) activities were evaluated. Then we explored the effects and mechanism of diosgenin against hydrogen peroxide-induced apoptosis of human vein endothelium cells (HUVECs). Intracellular reactive oxygen species (ROS), glutathione (GSH), nitric oxide (NO), DNA fragment formation and mitochondrial membrane potentials (DeltaPsim) were determined. Diosgenin treatment increased LPL, HL, SOD, GSH-PX and NOS activities, thus attenuated oxygen free radicals, decreased MDA, TC, TG and LDL-C levels in hyperlipidemic rats. Diosgenin pretreatment significantly attenuated H(2)O(2)-induced apoptosis in HUVECs, intracellular ROS, GSH depletion, DNA fragment formation, and restored NO, DeltaPsim. These results suggested that diosgenin is a very useful compound to control hyperlipidemia by both improving the lipid profile and modulating oxidative stress and prevent H(2)O(2)-induced apoptosis of HUVECs, in partly through regulating mitochondrial dysfunction pathway.

Polymorphisms in the hepatic lipase gene affect plasma HDL-cholesterol levels in a Turkish population

We investigated the effects of single nucleotide polymorphisms (SNPs) of the hepatic lipase gene (LIPC) on plasma HDL-cholesterol (HDL-C) levels in Turks, a population with low levels of HDL-C. All exons and six evolutionarily conserved regions from 28 Turkish subjects were sequenced. We found 51 SNPs, nine of which were novel. Those 51 SNPs and SNPs from the National Center for Biotechnology Information dbSNP were evaluated by bioinformatics approaches. The population frequencies and linkage disequilibrium among SNPs from HapMap were combined with results from transcriptional factor prediction tools and the literature to select SNPs for genotyping. We found that five tagging LIPC SNPs, two reported here for the first time, were significantly associated with plasma HDL-C levels in both men and women (n = 2,612). These results were replicated in a separate Turkish cohort (n = 1,164). Plasma HDL-C levels were higher in subjects homozygous for the minor alleles of rs4775041, rs1800588 (-514C>T), and rs11858164 and lower in subjects homozygous for the minor alleles of rs11856322 and rs2242061. These SNPs seemed to have independent and additive effects on plasma HDL-C levels (1.5-5.2 mg/dl). Hepatic lipase activity in a subset (n = 260) of the main cohort was also significantly associated with all five SNPs. Thus, five LIPC SNPs, two novel, are associated with plasma HDL-C levels and hepatic lipase activity in two cohorts of Turkish subjects.

A Case of Adolescent Hyperlipoproteinemia with Xanthoma and Acute Pancreatitis, Associated with Decreased Activities of Lipoprotein Lipase and Hepatic Triglyceride Lipase

Lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) enhance the hydrolysis of triglycerides (TG) transported by chylomicron (CM) and very-low-density lipoprotein (VLDL). We report a case of severe hyperchylomicronemia with high levels of remnant lipoprotein and total cholesterol (T-Chol) in a 15-year-old boy. Precise examination of the lipid profile showed decreased activities of both LPL and HTGL, although the protein mass for LPL and HTGL were maintained. In addition, bezafibrate treatment effectively ameliorated hypertriglyceridemia in this case. This is the first case of hyperchylomicronemia with decreased activities and unaffected protein masses for both LPL and HTGL, without overt immuno-dysfunction.

Prazosin Stimulates the Release of Hepatic Triacylglycerole Lipase Caused from Primary-culture Rat Hepatocytes

Prazosin is an alpha 1 adrenoceptor antagonist, and it is used as an antihypertensive agent. The effects of prazosin on the activity of hepatic triacylglycerole lipase (HTGL) are not fully understood. In this study, we demonstrated that prazosin stimulates the release of HTGL activity from primary cultures of rat hepatocytes in a time- and dose-dependent manner. U-73122, a phopholipase C (PLC) inhibitor, suppresses prazosin's stimulation of the release of HTGL activity. Moreover, prazosin stimulated the increase of PLC activity in the hepatocytes in a time- and dose-dependent manner. In addition, the prazosin-stimulated release of HTGL activity was reduced by Quin2/AM (an intracellular Ca2+-chelator), W-7 (a Calmodulin inhibitor), and KN-93 [an inhibitor of Ca2+/Calmodulin dependent protein kinase (CaMK)-II]. These results suggest that the prazosin-stimulated release of HTGL activity is partly due to the activation of CaMK-II that is associated with the elevation of PLC activity in the hepatocytes.

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.

Effects of dietary lipid levels on growth, survival and lipid metabolism during early ontogeny of Pelteobagrus vachelli larvae

A feeding trial was conducted to investigate the effect of dietary lipid level on darkbarbel catfish ( Pelteobagrus vachelli) larvae during ontogeny with regard to growth, survival and lipid utilization. Larvae were fed, from mouth opening to 20 days after hatching (DAH), with five isonitrogenous microdiets containing different lipid levels (58, 74, 111, 151 and 199 g kg − 1 diet). Live prey (newly hatched Artemia, unenriched) was used as the control diet. The activities of lipoprotein lipase (LPL), hepatic lipase (HL), pancreatic lipase (PL) and LPL gene expression at 3 DAH (mouth opening), 6 DAH, 11 DAH and 20 DAH were examined. The results showed that dietary lipid significantly affected survival and growth of darkbarbel catfish larvae. At the end of the feeding trial, larvae fed diets containing 111 to 151 g lipid kg − 1 had significantly higher survival. Specific growth rate (SGR) of larvae fed the diet containing the highest dietary lipid (199 g kg − 1 ) was significantly ( P < 0.05) lower while no significant differences were observed among other groups fed formulated diets. LPL mRNA level generally increased first with increasing dietary lipid levels and then reached a plateau at different sampling ages. A similar pattern was observed for LPL activity only at 6 DAH and 20 DAH. High dietary lipid increased HL activity at 20 DAH. At 6 DAH, highest PL activity was observed at 199 g lipid kg − 1 diet. Higher dietary lipid resulted in earlier elevated activities of LPL, PL and HL. The specific activities of the above three enzymes and LPL mRNA expression were detected at mouth opening and were significantly influenced by age. The activities of these enzymes increased first and then decreased or reached a plateau during development. The results suggest that dietary lipid could modify lipid utilization during ontogeny of darkbarbel catfish larvae.

Application of GC/MS-based metabonomic profiling in studying the lipid-regulating effects of Ginkgo biloba extract on diet-induced hyperlipidemia in rats

To evaluate the lipid-regulating effects of extract from Ginkgo biloba leaves (EGB) using pharmacological methods and metabonomic profiling in a rat model of diet-induced hyperlipidemia. EGB was orally administered at a dose level of 40 mg/kg in both the EGB-prevention and -treatment groups. All rat samples obtained were examined for known and potential biomarkers and enzyme activity using commercial assay kits and GC/MS-based metabonomic profiling coupled with principal component analysis (PCA). The data obtained from the assay kits indicated that EGB reduced total cholesterol and low density lipoprotein cholesterol levels and increased high density lipoprotein cholesterol levels in rat plasma obtained from both the EGB-prevention and -treatment groups compared with those of the diet-induced hyperlipidemia group. EGB also increased the activities of lipoprotein lipase and hepatic lipase and excretion of fecal bile acid in rats from the EGB-prevention and-treatment groups. Using GC/MS-based metabonomic analysis, more than 40 endogenous metabolites were identified in rat plasma. PCA of rat plasma samples obtained using GC/MS produced a distinctive separation of the four treatment groups and sampling points within each group. Metabolic changes during hyperlipidemia formation and improvement resulting from EGB treatment were definitively monitored with PCA score plots. Furthermore, elevated levels of sorbitol, tyrosine, glutamine and glucose, and decreased levels of citric acid, galactose, palmitic acid, arachidonic acid, acetic acid, cholesterol, butyrate, creatinine, linoleate, ornithine and proline, were observed in the plasma of rats treated with EGB. EGB exerts multi-directional lipid-lowering effects on the rat metabonome, including limitation of the absorption of cholesterol, inactivation of HMGCoA and favorable regulation of profiles of essential polyunsaturated fatty acid (EFA). Further experiments are warranted to explore the mechanisms of action underlying the lipid-regulating effects of EGB against hyperlipidemia.

Ciprofibrate increases cholesteryl ester transfer protein gene expression and the indirect reverse cholesterol transport to the liver

BackgroundCETP is a plasma protein that modulates atherosclerosis risk through its HDL-cholesterol reducing action. The aim of this work was to examine the effect of the PPARα agonist, ciprofibrate, on the CETP gene expression, in the presence and absence of apolipoprotein (apo) CIII induced hypertriglyceridemia, and its impact on the HDL metabolism.ResultsMice expressing apo CIII and/or CETP and non-transgenic littermates (CIII, CIII/CETP, CETP, non-Tg) were treated with ciprofibrate during 3 weeks. Drug treatment reduced plasma triglycerides (30-43%) and non-esterified fatty acids (19-47%) levels. Cholesterol (chol) distribution in plasma lipoprotein responses to ciprofibrate treatment was dependent on the genotypes. Treated CIII expressing mice presented elevation in VLDL-chol and reduction in HDL-chol. Treated CETP expressing mice responded with reduction in LDL-chol whereas in non-Tg mice the LDL-chol increased. In addition, ciprofibrate increased plasma post heparin lipoprotein lipase activity (1.3-2.1 fold) in all groups but hepatic lipase activity decreased in treated CETP and non-Tg mice. Plasma CETP activity and liver CETP mRNA levels were significantly increased in treated CIII/CETP and CETP mice (30-100%). Kinetic studies with 3H-cholesteryl ether (CEt) labelled HDL showed a 50% reduction in the 3H-CEt found in the LDL fraction in ciprofibrate treated compared to non-treated CETP mice. This means that 3H-CEt transferred from HDL to LDL was more efficiently removed from the plasma in the fibrate treated mice. Accordingly, the amount of 3H-CEt recovered in the liver 6 hours after HDL injection was increased by 35%.ConclusionTogether these data showed that the PPARα agonist ciprofibrate stimulates CETP gene expression and changes the cholesterol flow through the reverse cholesterol transport, increasing plasma cholesterol removal through LDL.

Energy reserves and metabolic status affect the acclimation of gilthead sea bream ( Sparus aurata) to cold

During winter, low temperatures induce a direct metabolic depression in gilthead sea bream, without any significant compensatory effect below 13 °C. The present study therefore focused on how to improve response to cold in these fish, looking specifically at the two factors of diet (high energy, HiE, and low energy, LoE) and activity (normal, − SW, and sustained activity, + SW) prior to exposure to cold. Following a preparatory period of 75 days water was adjusted to 10 °C and kept for 40 days. Enzymatic activities and store deposition revealed that the HiE−SW group had acquired an energy surplus whilst the LoE+SW group exhibited an energy deficit. Liver enzyme activities evidenced diet dependence: LoE groups showed greater glucose-6-phosphate dehydrogenase activity and HiE groups showed greater lipoprotein lipase and hepatic lipase activities. Moreover, the HiE−SW group's lower citrate synthase/cytochrome- c-oxidase ratio reflected the energy surplus available. Perivisceral fat mobilisation caused by cold stress affected liver integrity, resulting in a pre-steatotic condition for the HE−SW group. The differences in liver enzyme activities produced by pre-cold conditions disappeared at low temperatures and enzymatic activities did not compensate. Therefore any improvement that would enable gilthead sea bream to face up to winter must be achieved prior to the appearance of low temperatures.

Adipocyte Differentiation, Mitochondrial Gene Expression and Fat Distribution: Differences between Zidovudine and Tenofovir after 6 Months

Abnormal lipid metabolism and cell oxidative mechanisms are reported in patients on antiretroviral treatment. We compared the expression of several key adipocyte genes in HIV-infected patients randomized to antiretroviral regimens containing zidovudine (AZT) or tenofovir disoproxil fumarate (TDF). Subcutaneous fat was sampled from 32 HIV-positive treatment-naive patients before and 6 months after randomization to AZT/lamivudine/efavirenz (n=15) or TDF/emtricitabine/efavirenz (n=17) plus 15 HIV-negative matched controls. Expression of genes involved in adipocyte differentiation, lipid metabolism, mitochondrial function and glucocorticoid generation were profiled using real-time PCR. Lipoprotein lipase and hepatic lipase activity were assessed. Before treatment, 11beta-hydroxysteroid dehydrogenase expression was down-regulated compared with controls. Following 6 months treatment with AZT, there was a significant increase in visceral adipose tissue (VAT; P=0.02) and the ratio of VAT to subcutaneous adipose tissue (P=0.008), down-regulation of cytochrome B (P=0.003) and cytochrome oxidase (COX)-3 gene expression (P=0.03), up-regulation of NADH dehydrogenase (P=0.008) and nuclear-encoded COX-4 (complex IV) gene expression (P=0.012). Genes involved with adipocyte cortisol generation, fatty acid metabolism and the tricarboxylic acid cycle were up-regulated. In the TDF-treated patients, there was no significant change in regional body fat or mitochondrial genes compared with pretreatment values. Changes in the expression of genes involved with cortisol and fatty acid metabolism were less marked with TDF. Interference with the mitochondrial electron transport chain appears to occur early in an AZT-containing regimen and occurs at a time when there is increased visceral fat and up-regulation of genes involved with adipocyte differentiation and fatty acid flux.

Effects of Weight Loss on Lipid Transfer Proteins in Morbidly Obese Women

Obesity is associated with lipid abnormalities leading to an increased morbidity and mortality from atherosclerotic disease. Lipid transfer proteins such as Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP), and lipases such as lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in the pathogenesis of the obesity associated proatherogenic dyslipidemia. Nineteen severely obese female subjects undergoing laparosopic gastric banding participated in this prospective study. Subjects were examined with respect to body composition, lipid profile, CETP, PLTP, LPL and HL before and 1 year after surgical treatment. Mean weight loss was 22.2 kg, mainly due to losses in the fat depots. Triglycerides decreased and HDL(2)-C increased significantly. In respect to transfer proteins mean CETP mass decreased from 1.82 to 1.71 microg mL(-1) (P = 0.043) and mean PLTP activity was reduced from 7.15 to 6.12 micromol mL(-1) h(-1) (P = 0.002), in parallel. In addition, both mean LPL activity and mean HL activity tended to decrease from 297 to 248 nmol mL(-1) h(-1) for LPL (P = 0.139) and from 371 to 319 nmol mL(-1) h(-1) for HL (P = 0.170), respectively. We conclude that weight loss induced by bariatric surgery is associated with the amelioration of the obesity-associated dyslipidemic state. This improvement may be attributable to decreased mass and action of the adipocyte tissue derived lipid transfer proteins CETP and PLTP.

Long term hemodialysis aggravates lipolytic activity reduction and very low density, low density lipoproteins composition in chronic renal failure patients

BackgroundDyslipidemia, particularly hypertriglyceridemia is common in uremia, and represents an independent risk factor for atherosclerosis.MethodsTo investigate the effects of hemodialysis (HD) duration on very low density lipoprotein (VLDL) and low density lipoprotein (LDL) compositions and lipopolytic activities, 20 patients on 5 to 7 years hemodialysis were followed-up during 9 years. Blood samples were drawn at T0 (beginning of the study), T1 (3 years after initiating study), T2 (6 years after initiating study) and T3 (9 years after initiating study). T0 was taken as reference.ResultsTriacylglycerols (TG) values were correlated with HD duration (r = 0.70, P < 0.05). An increase of total cholesterol was noted at T2 and T3. Lowered activity was observed for lipoprotein lipase (LPL) (-44%) at T3 and hepatic lipase (HL) (-29%) at T1, (-64%) at T2 and (-73%) at T3. Inverse relationships were found between HD duration and LPL activity (r = -0.63, P < 0.05), and HL activity (r = -0.71, P < 0.01). At T1, T2 and T3, high VLDL-amounts and VLDL-TG and decreased VLDL-phospholipids values were noted. Increased LDL-cholesteryl esters values were noted at T1 and T2 and in LDL-unesterified cholesterol at T2 and T3.ConclusionDespite hemodialysis duration, VLDL-LDL metabolism alterations are aggravated submitting patients to a greater risk of atherosclerosis.

Tacrolimus-Induced Elevation in Plasma Triglyceride Concentrations After Administration to Renal Transplant Patients Is Partially Due to a Decrease in Lipoprotein Lipase Activity and Plasma Concentrations

Hyperlipidemia is a frequent and persistent complication in solid organ transplant recipients, leading to the high occurrence of cardiovascular disease in this patient population. Lipid abnormalities including increased total cholesterol, triglycerides (TG), and low-density lipoprotein-cholesterol have been reported frequently in transplantation patients and a variety of immunosuppressive therapies seem to be one of the main factors that influence posttransplant lipidemic profiles. For many years, tacrolimus (TAC) has been used as an immunosuppressive drug in transplantation. The aim of our investigation was to determine the effect of TAC administration on the plasma lipid profile and some key regulatory proteins of plasma lipid metabolism including cholesterol ester transfer protein, hepatic lipase and lipoprotein lipase (LPL) within renal transplant patients. Twenty-five renal transplant patients were recruited and received TAC therapy, of which nine of these patients were treated with statin therapy for dyslipidemia. The effects of TAC on plasma total cholesterol, TG, HDL-C, low-density lipoprotein-cholesterol, cholesterol ester transfer protein, hepatic lipase and LPL concentration and activity were determined from patients plasma samples collected before the transplant surgery (baseline), and weekly for four consecutive weeks after surgery and TAC administration. We observed that TAC significantly increases plasma TG concentrations and reduces LPL plasma concentration and activity in renal transplant patients, independent of any lipid lowering drug treatment patients received. Taken together, these findings suggest that the reduction in LPL activity, partly due to the decrease of plasma LPL concentration after TAC administration may be an explanation for hypertriglyceridemia observed in patients administered TAC.

Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apolipoprotein A-II metabolism

This study was designed to establish the mechanism responsible for the increased apolipoprotein (apo) A-II levels caused by the cholesteryl ester transfer protein inhibitor torcetrapib. Nineteen subjects with low HDL cholesterol (<40 mg/dl), nine of whom were also treated with 20 mg of atorvastatin daily, received placebo for 4 weeks, followed by 120 mg of torcetrapib daily for the next 4 weeks. Six subjects in the nonatorvastatin cohort participated in a third phase, in which they received 120 mg of torcetrapib twice daily for 4 weeks. At the end of each phase, subjects underwent a primed-constant infusion of [5,5,5-(2)H(3)]L-leucine to determine the kinetics of HDL apoA-II. Relative to placebo, torcetrapib significantly increased apoA-II concentrations by reducing HDL apoA-II catabolism in the atorvastatin (-9.4%, P < 0.003) and nonatorvastatin once- (-9.9%, P = 0.02) and twice- (-13.2%, P = 0.02) daily cohorts. Torcetrapib significantly increased the amount of apoA-II in the alpha-2-migrating subpopulation of HDL when given as monotherapy (27%, P < 0.02; 57%, P < 0.003) or on a background of atorvastatin (28%, P < 0.01). In contrast, torcetrapib reduced concentrations of apoA-II in alpha-3-migrating HDL, with mean reductions of -14% (P = 0.23), -18% (P < 0.02), and -18% (P < 0.01) noted during the atorvastatin and nonatorvastatin 120 mg once- and twice-daily phases, respectively. Our findings indicate that CETP inhibition increases plasma concentrations of apoA-II by delaying HDL apoA-II catabolism and significantly alters the remodeling of apoA-II-containing HDL subpopulations.

Two novel mutations and functional analyses of the CETP and LIPC genes underlying severe hyperalphalipoproteinemia

Previous studies have shown that CETP and LIPC mutations contribute to hyperalphalipoproteinemia (HALP) in some populations. We investigated whether activities in cholesteryl ester transfer protein (CETP) and hepatic lipase (HL) contribute to HALP in the Thai population and performed genetic analyses of the CETP and LIPC genes. We recruited 38 individuals with high-density lipoprotein cholesterol (HDL-C) levels of at least 2.59 mmol/L (100 mg/dL) (HALP group) and an equal number of individuals with normal serum HDL-C levels (control group). The CETP and HL activities were determined in both groups. Genetic analyses covering all the coding regions and exon-intron junctions of the CETP and LIPC genes were performed in subjects who had low CETP activity and HL activity, respectively. The mean CETP and HL activities were significantly lower in the HALP group than in the control group (34 ± 4 vs 44 ± 3 pmol/[ μL h], P = .04 and 150 ± 17 vs 227 ± 16 nmol free fatty acid/[mL min] P = .002, respectively). Of the 38 individuals with HALP, 19 and 16 were found to have low CETP activity and HL activity, respectively. Of the 19 subjects with low CETP activity, 6 subjects were found to be heterozygous for a known functionally relevant c.1325A>G (D442G) mutation. The other subject was found to be heterozygous for a novel deletion mutation, c.734_737delTCCC mutation. Of the 16 subjects with low HL activity, 8 and 2 subjects were found to be heterozygous for known variants, c.283 G>A (V73M) and c.1068A>C (L334F), respectively. These variants have previously been shown not to be associated with HALP. Another subject was found to be heterozygous for a novel missense mutation, c.421G>A (G119S). Its amino acid change, absence in controls, evolutionary conservation, occurrence in functionally important domain, and predicted damaging function suggested that the G119S mutation is functionally relevant. Two novel mutations in the CETP and LIPC genes found in this study are likely to be the causes of low enzyme activities and elevated HDL-C levels.

Lipoprotein lipase activity and mass, apolipoprotein C-II mass and polymorphisms of apolipoproteins E and A5 in subjects with prior acute hypertriglyceridaemic pancreatitis

BackgroundSevere hypertriglyceridaemia due to chylomicronemia may trigger an acute pancreatitis. However, the basic underlying mechanism is usually not well understood. We decided to analyze some proteins involved in the catabolism of triglyceride-rich lipoproteins in patients with severe hypertriglyceridaemia.MethodsTwenty-four survivors of acute hypertriglyceridaemic pancreatitis (cases) and 31 patients with severe hypertriglyceridaemia (controls) were included. Clinical and anthropometrical data, chylomicronaemia, lipoprotein profile, postheparin lipoprotein lipase mass and activity, hepatic lipase activity, apolipoprotein C II and CIII mass, apo E and A5 polymorphisms were assessed.ResultsOnly five cases were found to have LPL mass and activity deficiency, all of them thin and having the first episode in childhood. No cases had apolipoprotein CII deficiency. No significant differences were found between the non-deficient LPL cases and the controls in terms of obesity, diabetes, alcohol consumption, drug therapy, gender distribution, evidence of fasting chylomicronaemia, lipid levels, LPL activity and mass, hepatic lipase activity, CII and CIII mass or apo E polymorphisms. However, the SNP S19W of apo A5 tended to be more prevalent in cases than controls (40% vs. 23%, NS).ConclusionPrimary defects in LPL and C-II are rare in survivors of acute hypertriglyceridaemic pancreatitis; lipase activity measurements should be restricted to those having their first episode during chilhood.

Novel roles of hepatic lipase and phospholipid transfer protein in VLDL as well as HDL metabolism

Objective Elevated plasma phospholipid transfer protein (PLTP) expression may increase atherosclerosis in mice by reducing plasma HDL and increasing hepatic VLDL secretion. Hepatic lipase (HL) is a lipolytic enzyme involved in several aspects of the same pathways of lipoprotein metabolism. We investigated whether the effects of elevated PLTP activity are compromised by HL deficiency. Methods and results HL deficient mice were crossbred with PLTP transgenic (PLTPtg) mice and studied in the fasted state. Plasma triglycerides were decreased in HL deficiency, explained by reduced hepatic triglyceride secretion. In PLTPtg mice, a redistribution of HL activity between plasma and tissue was evident and plasma triglycerides were also decreased. HL deficiency mitigated or even abolished the stimulatory effect of elevated PLTP activity on hepatic triglyceride secretion. HL deficiency had a modest incremental effect on plasma HDL, which remained present in PLTP transgenic/HL −/− mice, thereby partially compensating the decrease in HDL caused by elevation of PLTP activity. HDL decay experiments showed that the fractional turnover rate of HDL cholesteryl esters was delayed in HL deficient mice, increased in PLTPtg mice and intermediate in PLTPtg mice in an HL −/− background. Conclusions HL affects hepatic VLDL. Elevated PLTP activity lowers plasma HDL-cholesterol by stimulating the plasma turnover and hepatic uptake of HDL cholesteryl esters. HL is not required for the increase in hepatic triglyceride secretion or for the lowering of HDL-cholesterol induced by PLTP overexpression.

The thyromimetic T-0681 protects from atherosclerosis

This report describes studies in hyperlipidemic New Zealand White (NZW) rabbits investigating the impact of the liver-selective thyromimetic T-0681 on lipoprotein metabolism and the development of atherosclerosis. Prolonged treatment with T-0681 increased the hepatic expression of both LDL receptor and scavenger receptor class B, type I without affecting cholesteryl ester transfer protein activity. Upregulation of hepatic lipoprotein receptors was accompanied by a marked decrease of apolipoprotein B-containing lipoproteins, reflected by a 60% reduction of plasma cholesterol and a >70% reduction of plasma triglyceride levels. Most importantly, T-0681 reduced the development of atherosclerosis by 80% in NZW rabbits on high-cholesterol chow. Our data suggest that liver-selective thyromimetics, such as T-0681, may prove to be useful therapeutic agents against the development of atherosclerosis in humans.

Diagnostic value of post-heparin lipase testing in detecting common genetic variants in the LPL and LIPC genes

Post-heparin lipoprotein lipase and hepatic lipase activities are used to identify primary disorders of triglyceride and HDL-cholesterol metabolism. Their ability to identify common variants in the lipoprotein lipase (LPL) and hepatic lipase (LIPC) genes is unclear. To investigate the ability of lipase testing to detect common lipase gene variants, we included 183 patients who had undergone post-heparin lipase testing and genotyped the LPL D9N, N291S, PvuII, HindIII, and S447X and the LIPC-514CT, V73M, V133V, and N193S polymorphisms. Allele frequencies were compared with 163 controls. Polymorphisms with different allele frequencies in patients and controls or influencing lipids, were analyzed further. The diagnostic value of post-heparin lipase testing was assessed using logistic regression and receiver operating characteristic curves. We found that lipase activities did not predict the LPL D9N and N291S polymorphisms, but predicted the LPL S447X and LIPC-514CT polymorphisms. Adjusted for covariates, the area under the receiver operating characteristic curves was 0.643, 0.478, 0.686, and 0.657 for LPL D9N, N291S S447X and LIPC-514CT, respectively. On the basis of these findings, we conclude that high-LPL and low-HL activities associate with the LPL S447X and LIPC-514CT polymorphisms, but low-LPL activity was not related to LPL polymorphisms. Overall, the discriminative ability of post-heparin lipase tests in identifying carriers of common variants in the LPL and LIPC genes was limited. This indicates that conclusions on the genetic causes of lipase activities outside of the normal range should be drawn with caution.