Decreased Lipoprotein Lipase Research Articles

PFOS-induced dyslipidemia and impaired cholinergic neurotransmission in developing zebrafish: Insight into its mechanisms

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant that has been widely detected in the environment and is known to accumulate in organisms, including humans. The study investigated dose-dependent mortality, hatching rates, malformations, lipid accumulation, lipid metabolism alterations, and impacts on cholinergic neurotransmission. Increasing PFOS concentration led to higher mortality, hindered hatching, and caused concentration-dependent malformations, indicating severe abnormalities in developing zebrafish. The results also demonstrated that PFOS exposure led to a significant increase in total lipids, triglycerides, total cholesterol, and LDL in a concentration-dependent manner, while HDL cholesterol levels were significantly decreased. Additionally, PFOS exposure led to a significant decrease in glucose levels. The study identified TGs, TCHO, and glucose as the most sensitive biomarkers in assessing lipid metabolism alterations. The study also revealed altered expression of genes involved in lipid metabolism, including upregulation of fasn, acaca, and hmgcr and downregulation of ldlr, pparα, and abca1, as well as decreased lipoprotein lipase (LPL) and increased fatty acid synthase (FAS) activity,suggesting an impact on fatty acid synthesis, cholesterol uptake, and lipid transport. Additionally, PFOS exposure led to impaired cholinergic neurotransmission, evidenced by a concentration-dependent inhibition of acetylcholinesterase activity, altered gene expressions related to neural development and function, and reduced Na+/K+-ATPase activity. STRING network analysis highlighted two distinct gene clusters related to lipid metabolism and cholinergic neurotransmission, with potential interactions through the pparα-creb1 pathway. Overall, this study provide important insights into the potential health risks associated with PFOS exposure, including dyslipidemia, cardiovascular disease, impaired glucose metabolism, and neurotoxicity. Further research is needed to fully elucidate the underlying mechanisms and potential long-term effects of PFOS exposure.

Plasma concentrations of apolipoproteins C3 and C2 do not explain differences in insulin-stimulated endothelial-bound lipoprotein lipase activity in insulin resistant humans

Elevated circulating triglycerides (i.e., dyslipidemia) is a hallmark of insulin resistance and is generally caused by decrease in lipoprotein lipase (LPL) activity. LPL hydrolyzes triglycerides (TG) into free fatty acids in plasma for use and/or storage in tissues (i.e., adipose, skeletal muscle). Plasma apolipoproteins (Apos) C3 and C2 interact with LPL to modulate its function by activating or inhibiting LPL. Previous research shows, in the metabolic environment of insulin resistance, the concentration of ApoC3 is increased in plasma while that of ApoC2 is decreased. Thus, Apos are considered key factors in regulating plasma lipid metabolism via modulation of LPL function. The purpose of this study was to investigate the concentrations of ApoC3 and ApoC2 in plasma and along endothelial-bound LPL activity in insulin resistant and healthy/non-insulin resistant individuals. We evaluated insulin resistance (IR)/insulin sensitivity (IS) using an oral glucose tolerance test (i.e., Matsuda index calculation) in subjects between ages 19 and 45 years old. Subjects were placed in the following two groups: 1) IR, if Matsuda index <4.0 (N=6; 4 males, 2 females; BMI: 23-45 kg/m2), or 2) IS, if Matsuda index >7.0 (N=11, 9 males, 2 females; BMI: 18-26 kg/m2). Subjects received an intravenous insulin infusion (0.5 mU/kg/min) for 30 minutes to resemble increased postprandial plasma insulin response. To release whole-body endothelial-bound LPL, subjects received an injection of intravenous heparin (75 UI/kg). Plasma samples were collected 10 minutes after the heparin infusion and analyzed for LPL concentration and activity, and ApoC3 and ApoC2 concentrations using ELISA. Differences between IS and IR subjects were determined using a t-test, and the P value was set at P < 0.05. Plasma LPL concentrations were not different between groups (IR = 457 ± 17 ng/ml, IS = 453 ± 27 ng/ml, P > 0.05), but plasma LPL activity was higher in the IR subjects (IR = 665 ± 113 nmol/min/ml, IS = 365 ± 59 nmol/min/ml, P = 0.02). IR subjects had higher concentrations of plasma ApoC3 (IR = 3.6 ± 0.5 mg/dl, IS = 2.7 ± 0.2 mg/dl, P=0.03) but ApoC2 was not different between groups (IR = 0.15 ± 0.03 mg/dl, IS = 0.11 ± 0.01 mg/dl, P = 0.11). The ratio of circulating LPL to circulating ApoC3 (IR = 145 ± 22, IS = 176 ± 15) or circulating ApocC2 (IR = 4104 ± 844, IS = 4391 ± 483) were not different between groups (P > 0.05). We conclude that interactions of LPL with APOC3 and ApoC2 may not be main determinants regulating differential whole-body plasma LPL activity under plasma insulin-stimulated conditions in insulin resistant humans. American Diabetes Association Grant #7-12-CT-40 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Mechanism, clinical consequences, and management of dyslipidemia in children with nephrotic syndrome

Dyslipidemia in nephrotic syndrome (NS) is often characterized by marked increases in the levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol, and other lipoproteins, such as very low-density lipoprotein, intermediate-density lipoprotein, and lipoprotein(a). It has been suggested that impaired catabolism of lipoproteins and cholesterol is mainly due to decreased lipoprotein lipase and hepatic lipase activity, and increased biosynthesis of lipoproteins in the liver. The management strategies for dyslipidemia in patients with NS consist of lifestyle modification, lipid-lowering agents represented by statins, second-line agents such as fibrates and bile acid sequestrants, and lipid apheresis. Compared with dyslipidemia in adult NS patients, whose risks of atherosclerotic disease and progressive renal injury are considered high, clinical data on dyslipidemia in pediatric NS patients are limited. Therefore, it is necessary to pay more attention to the evaluation and management of dyslipidemia in pediatric patients with NS in clinical practice.

Changes in lipidomic profile by anti-retroviral treatment regimen: An ACTG 5257 ancillary study.

High cardiovascular disease risk in people living with HIV is partly attributed to antiretroviral therapy (ART). Lipid response to ART has been extensively studied, yet, little is known how small molecule lipids respond to Integrase inhibitor-based (INSTI-based) compared to Protease inhibitor-based (PI-based) ART regimens.Ancillary study to a phase 3, randomized, open-label trial [AIDS Clinical Trial Group A5257 Study] in treatment-naive HIV-infected patients randomized in a 1:1:1 ratio to receive ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r) (both PI-based), or raltegravir with Tenofovir Disoproxil Fumarate-TDF plus emtricitabine (RAL, INSTI-based).We examined small molecule lipid response in a subcohort of 75 participants. Lipidomic assays of plasma samples collected pre- and post-ART treatment (48 weeks) were conducted using ultra-performance liquid chromatography coupled to time-of-flight mass spectrometry. The effect of ART regimens was regressed on lipid species response adjusting for the baseline covariates (lipids, age, sex, race, CD4 level, BMI, and smoking). Results were validated in the Centers for AIDS Research Network of Integrated Clinical Systems study (N = 16).Out of 417 annotated lipids, glycerophospholipids (P = .007) and sphingolipids (P = .028) had a higher response to ATV/r and DRV/r compared to RAL. The lysophosphatidylcholine (LPCs(16:1),(17:1),(20:3)) and phosphophatidylcholine species (PCs(40:7),(38:4)) had an opposite response to RAL versus ATV/r in the discovery and validation cohort. The INSTI-based regimen had an opposite response of ceramide species ((d38:1), (d42:2)), PCs((35:2), (38:4)), phosphatidylethanolamines (PEs(38:4), (38:6)), and sphingomyelin(SMd38:1) species compared with the PI-based regimens. There were no differences observed between 2 PI-based regimens.We observed differences in response of small molecule lipid species by ART regimens in treatment-naive people living with HIV.

Angiopoietin-like protein 4 regulates breast muscle lipid metabolism in broilers

The objective of this study was to determine the effects of angiopoietin-like protein 4 (ANGPTL4) on breast muscle lipid metabolism in broilers. In experiment 1, 36 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 6 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of His-SUMO-ANGPTL4 at the dose of 0 (injection of normal saline [NS]), 20, 100, 500, 2,500, or 12,500 ng/kg BW, respectively. The results showed that broilers at 30 min after His-SUMO-ANGPTL4 at the level of 12,500 ng/kg BW intravenous injection had higher (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, higher (P < 0.05) adipose triglyceride lipase and carnitine palmitoyltransferase 1 mRNA expression in the breast muscle, but lower (P < 0.05) lipoprotein lipase (LPL) mRNA expression in the breast muscle. In experiment 2, 18 thirty-five-day-old male Arbor Acres broilers were randomly allocated into 3 treatment groups with 6 birds in a completely randomized design. The broilers were subjected to intravenous injection of NS, His-SUMO, or His-SUMO-ANGPTL4 (12,500 ng/kg BW) in order to rule out the effect of His-SUMO tag. It's confirmed that ANGPTL4 could increase (P < 0.05) concentrations of triglyceride and non-esterified fatty acid in the serum, enhance (P < 0.05) adipose triglyceride lipase mRNA expression in the breast muscle, and decrease (P < 0.05) LPL mRNA expression in the breast muscle. In experiment 3 and 4, co-culture experiments of chicken primary myoblasts and NS, His-SUMO, or His-SUMO-ANGPTL4 (250 pg/mL, physiological dose) were set up to monitor the cytotoxicity of ANGPTL4 and the changes of lipid metabolism-related genes expression. It was found that cell viability was not affected but LPL mRNA expression in chicken primary myoblasts was highly reduced (P < 0.05) by ANGPTL4. In conclusion, ANGPTL4 could promote lipodieresis and inhibit LPL in the breast muscle of broilers.

Effects of dietary fat source and green tea (Camellia sinensis) extract on genes associated with lipid metabolism and inflammatory responses in female broiler chickens

This study was aimed to investigate the effects of dietary fat sources and green tea extract (GTE) on gene expression associated with lipid metabolism and inflammation in broiler chicken. A total of 300 female Ross 308 broiler chicks were allocated to six dietary treatments in a completely randomised design with a factorial arrangement of two levels of GTE (0 and 500 mg/kg diet) × three levels of fat inclusion [without fat (control group), soybean oil (SO) and tallow (Ta)]. Liver fat (LF), liver methallothionin (LMT) content, and lipoprotein lipase (LPL), adipose triglyceride lipase (ATGL), tumour necrosis factor α (TNF-α), and interleukin (IL-6)] genes expression were investigated. Relative expression and statistical analyses of genes expression were assessed using REST software. The effect of added dietary fats was significant and improved performance parameters compared to the control group (p < .05). The highest abdominal fat and blood triglyceride, and the lowest carcase yield, were achieved in chicks fed SO-supplemented diet (p < .05). Chicks fed a diet supplemented with SO showed an overexpression and a decrease of LPL and ATGL compared to the Ta-supplemented and control groups, respectively (p < .05). GTE supplementation was effective on LPL and ATGL expression and ameliorated the effect of SO on abdominal fat percentage. TNF-α expression, LMT content, and relative weight of lymphoid organs were affected neither by GTE nor by the fat sources. There was no detection of IL-6 gene expression in adipose tissue. The results of this study demonstrated that diets rich in SO were capable increase fat deposition by an increase and decrease in LPL and ATGL gene expression, respectively. However inclusion of GTE in broiler diets alleviated the LPL-increasing and ATGL-reducing effects of SO and ameliorated the effect of SO on abdominal fat mass. Highlights Diets supplemented with SO increased abdominal fat mass by changes in LPL and ATGL gene expression. Obesity was not effective in the expression of inflammatory genes (TNF-α and IL-6), indicating a lack of connection between inflammation and obesity in broiler chicken. GTE (500 mg/kg diet) addition to the diets supplemented with SO ameliorated the effect of SO on LPL and ATGL gene expression and abdominal fat mass.

Fasting induces ANGPTL4 and reduces LPL activity in human adipose tissue

ObjectiveStudies in mice have shown that the decrease in lipoprotein lipase (LPL) activity in adipose tissue upon fasting is mediated by induction of the inhibitor ANGPTL4. Here, we aimed to validate this concept in humans by determining the effect of a prolonged fast on ANGPTL4 and LPL gene and protein expression in human subcutaneous adipose tissue. MethodsTwenty-three volunteers ate a standardized meal at 18.00 h and fasted until 20.00 h the next day. Blood was drawn and periumbilical adipose tissue biopsies were collected 2 h and 26 h after the meal. ResultsConsistent with previous mouse data, LPL activity in human adipose tissue was significantly decreased by fasting (−60%), concurrent with increased ANGPTL4 mRNA (+90%) and decreased ANGPTL8 mRNA (−94%). ANGPTL4 protein levels in adipose tissue were also significantly increased by fasting (+46%), whereas LPL mRNA and protein levels remained unchanged. In agreement with the adipose tissue data, plasma ANGPTL4 levels increased upon fasting (+100%), whereas plasma ANGPTL8 decreased (−79%). Insulin, levels of which significantly decreased upon fasting, downregulated ANGPTL4 mRNA and protein in primary human adipocytes. By contrast, cortisol, levels of which significantly increased upon fasting, upregulated ANGPTL4 mRNA and protein in primary human adipocytes as did fatty acids. ConclusionANGPTL4 levels in human adipose tissue are increased by fasting, likely via increased plasma cortisol and free fatty acids and decreased plasma insulin, resulting in decreased LPL activity.This clinical trial was registered with identifier NCT03757767.

The Long Noncoding RNA Metastasis-Associated Lung Adenocarcinoma Transcript-1 Regulates CCDC80 Expression by Targeting miR-141-3p/miR-200a-3p in Vascular Smooth Muscle Cells.

Our previous study showed that Coiled-Coil Domain Containing 80 (CCDC80) accelerates the development of atherosclerosis by decreasing lipoprotein lipase (LPL) expression and activity in apoE knockout mice. However, the regulatory mechanism for CCDC80 expression is unclear. This study was designed to evaluate whether noncoding RNAs involved the regulation of CCDC80 expression in vascular smooth muscle cells. Bioinformatics prediction and luciferase reporter gene results showed that miR-141-3p/200a-3p bound to the 3'UTR of CCDC80. Furthermore, miR-141-3p/200a-3p mimics decreased the expression of CCDC80 but increased LPL expression. Opposite results were observed with miR-141-3p/200a-3p inhibitors. We also found that lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) interacted with the sequences of miR-141-3p/200a-3p and decreased their expression. RT-qPCR and western blotting results showed that MALAT1 overexpression increased CCDC80 expression and decreased LPL expression, while MALAT1 knockdown displayed an opposite phenotype. The effects of both MALAT1 overexpression and knockdown were blocked by miR-141-3p/200a-3p mimics or inhibitors. Thus, we demonstrated that lncRNA MALAT1 regulates CCDC80 and LPL expression through miR-141-3p/200a-3p.

Dyslipidemia and cardiovascular health in childhood nephrotic syndrome.

Children with steroid-resistant nephrotic syndrome (SRNS) are exposed to multiple cardiovascular risk factors predisposing them to accelerated atherosclerosis. This risk is negligible in steroid-sensitive nephrotic syndrome, but a substantial proportion of children with SRNS progress to chronic kidney disease, exacerbating the already existing cardiovascular risk. While dyslipidemia is an established modifiable risk factor for cardiovascular disease in adults with NS, it is uncertain to what extent analogous risks exist for children. There is increasing evidence of accelerated atherosclerosis in children with persistently high lipid levels, especially in refractory NS. Abnormalities of lipid metabolism in NS include hypertriglyceridemia and hypercholesterolemia due to elevated apolipoprotein B-containing lipoproteins, decreased lipoprotein lipase and hepatic lipase activity, increased hepatic PCSK9 levels, and reduced hepatic uptake of high-density lipoprotein. Existing guidelines for the management of dyslipidemia in children may be adapted to target lower lipid levels in children with NS, but they will most likely require both lifestyle modifications and pharmacological therapy. While there is a lack of data from randomized controlled trials in children with NS demonstrating the benefit of lipid-lowering drugs, therapies including statins, bile acid sequestrants, fibrates, ezetimibe, and LDL apheresis have all been suggested and/or utilized. However, concerns with the use of lipid-lowering drugs in children include unclear side effect profiles and unknown long-term impacts on neurological development and puberty. The recent introduction of anti-PCSK9 monoclonal antibodies and other therapies targeted to the molecular mechanisms of lipid transport disrupted in NS holds promise for the future treatment of dyslipidemia in NS.

Coiled-coil domain-containing 80 accelerates atherosclerosis development through decreasing lipoprotein lipase expression via ERK1/2 phosphorylation and TET2 expression

Recent studies showed that coiled-coil domain-containing 80 (CCDC80) has a positive link with atherosclerosis and that plasma CCDC80 levels are positively correlated with the levels of fasting plasma triglycerides (TG) in obese individuals. The underlying mechanisms, however, are unclear. Using Hematoxylin-eosin (H&E) and Oil Red O staining, we found that CCDC80 overexpression in vivo significantly increased plasma lipid contents, decreased the expression and activity of lipoprotein lipase (LPL), and accelerated the development of atherosclerosis. Conversely, knockdown of CCDC80 decreased plaque lesions area. In vitro, qRT-PCR and western blot results showed that CCDC80 overexpression significantly decreased, while CCDC80 knockdown increased, LPL expression in cultured vascular smooth muscle cells (VSMCs). Further, we found that CCDC80 reduced LPL expression via inhibiting the phosphorylation of extracellular regulated protein kinase 1/2 (ERK1/2) and also increased the methylation of LPL promoter via down-regulating Tet methylcytosine dioxygenase 2 (TET2). Our results also revealed that CCDC80 significantly down-regulated TET2 expression through decreasing the phosphorylation of ERK1/2. In addition, we found that CCDC80 decreased binding of TET2 to forkhead box O3 (FOXO3a) but had no effect on FOXO3a expression. On the other hand, and that FOXO3a was partially involved in TET2-regulated LPL expression. CCDC80 down-regulated ERK1/2 phosphorylation and decreased expression of TET2 and its interaction with FOXO3a, leading to a reduction of LPL expression and acceleration of atherosclerosis.

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment.

Nephrotic syndrome is a highly prevalent disease that is associated with high morbidity despite notable advances in its treatment. Many of the complications of nephrotic syndrome, including the increased risk of atherosclerosis and thromboembolism, can be linked to dysregulated lipid metabolism and dyslipidaemia. These abnormalities include elevated plasma levels of cholesterol, triglycerides and the apolipoprotein B-containing lipoproteins VLDL and IDL; decreased lipoprotein lipase activity in the endothelium, muscle and adipose tissues; decreased hepatic lipase activity; and increased levels of the enzyme PCSK9. In addition, there is an increase in the plasma levels of immature HDL particles and reduced cholesterol efflux. Studies from the past few years have markedly improved our understanding of the molecular pathogenesis of nephrotic syndrome-associated dyslipidaemia, and also heightened our awareness of the associated exacerbated risks of cardiovascular complications, progressive kidney disease and thromboembolism. Despite the absence of clear guidelines regarding treatment, various strategies are being increasingly utilized, including statins, bile acid sequestrants, fibrates, nicotinic acid and ezetimibe, as well as lipid apheresis, which seem to also induce partial or complete clinical remission of nephrotic syndrome in a substantial percentage of patients. Future potential treatments will likely also include inhibition of PCSK9 using recently-developed anti-PCSK9 monoclonal antibodies and small inhibitory RNAs, as well as targeting newly identified molecular regulators of lipid metabolism that are dysregulated in nephrotic syndrome.

Comparative analysis of effects of dietary arachidonic acid and EPA on growth, tissue fatty acid composition, antioxidant response and lipid metabolism in juvenile grass carp,Ctenopharyngodon idellus

Four isonitrogenous and isoenergetic purified diets containing free arachidonic acid (ARA) or EPA (control group), 0·30 % ARA, 0·30 % EPA and 0·30 % ARA+EPA (equivalent) were designed to feed juvenile grass carp (10·21 (sd 0·10) g) for 10 weeks. Only the EPA group presented better growth performance compared with the control group (P<0·05). Dietary ARA and EPA were incorporated into polar lipids more than non-polar lipids in hepatopancreas but not intraperitoneal fat (IPF) tissue. Fish fed ARA and EPA showed an increase of serum superoxide dismutase and catalase activities, and decrease of glutathione peroxidase activity and malondialdehyde contents (P<0·05). The hepatopancreatic TAG levels decreased both in ARA and EPA groups (P<0·05), accompanied by the decrease of lipoprotein lipase (LPL) activity in the ARA group (P<0·05). Fatty acid synthase (FAS), diacylglycerol O-acyltransferase and apoE gene expression in the hepatopancreas decreased in fish fed ARA and EPA, but only the ARA group exhibited increased mRNA level of adipose TAG lipase (ATGL) (P<0·05). Decreased IPF index and adipocyte sizes were found in the ARA group (P<0·05). Meanwhile, the ARA group showed decreased expression levels of adipogenic genes CCAAT enhancer-binding protein α, LPL and FAS, and increased levels of the lipid catabolic genes PPAR α, ATGL, hormone-sensitive lipase and carnitine palmitoyltransferase 1 (CPT-1) in IPF, whereas the EPA group only increased PPAR α and CPT-1 mRNA expression and showed less levels than the ARA group. Overall, dietary EPA is beneficial to the growth performance, whereas ARA is more potent in inducing lipolysis and inhibiting adipogenesis, especially in IPF. Meanwhile, dietary ARA and EPA showed the similar preference in esterification and the improvement in antioxidant response.

Long-term effects of angiotensin-(1–7) on lipid metabolism in the adipose tissue and liver

The angiotensin (Ang) converting enzyme 2/Ang-(1–7)/Mas axis has been described to have a beneficial role on metabolic disorders. In the present study, the use of a transgenic rat model that chronically overexpresses Ang-(1–7) enabled us to investigate the chronic effects of this peptide on lipid accumulation in the liver and adipose tissue. The transgenic group showed a marked tendency toward increased expression of peroxisome proliferator-activated receptor-γ (PPARγ) and decreased lipoprotein lipase (LPL) expression and activity in epididymal adipose tissue. We also showed that Mas receptor-knockout mice had decreased PPARγ expression in adipose tissue, accompanied by an increase in LPL activity. These results confirm the regulation of adipose tissue LPL activity by Ang-(1–7) and suggest that this occurs independent of PPARγ expression. The reduced adiposity index of transgenic rats, due to the effect of Ang-(1–7), was accompanied by a decrease in lipogenesis. These findings suggest a direct effect of Ang-(1–7) on lipogenesis, independent of the stimulatory effect of insulin. Furthermore, the decreased concentration of triacylglycerol in the liver of transgenic rats may result from increased activity of cytosolic lipases and decreased fatty acid uptake from the adipose tissue, determined from fatty acid-binding protein expression, and hepatic de novo fatty acid synthesis, evaluated by fatty acid synthase expression. The data clearly show that Ang-(1–7) regulates lipid metabolism in the adipose tissue and liver.

The heterozygous N291S mutation in the lipoprotein lipase gene impairs whole-body insulin sensitivity and affects a distinct set of plasma metabolites in humans

Mutations in the lipoprotein lipase gene causing decreased lipoprotein lipase activity are associated with surrogate markers of insulin resistance and the metabolic syndrome in humans. We investigated the hypothesis that a heterozygous lipoprotein lipase mutation (N291S) induces whole-body insulin resistance and alterations in the plasma metabolome. In 6 carriers of a heterozygous lipoprotein lipase mutation (N291S) and 11 age-matched and weight-matched healthy controls, we examined insulin sensitivity and substrate metabolism by euglycemic-hyperinsulinemic clamps combined with indirect calorimetry. Plasma samples were taken before and after the clamp (4hours of physiological hyperinsulinemia), and metabolites were measured enzymatically or by gas chromatography-mass spectrometry. Compared with healthy controls, heterozygous carriers of a defective lipoprotein lipase allele had elevated fasting plasma levels triglycerides (P<.006), and markedly impaired insulin-stimulated glucose disposal rates (P<.024) and nonoxidative glucose metabolism (P<.015). Plasma metabolite profiling demonstrated lower circulating levels of pyruvic acid and α-tocopherol in the N291S carriers than in controls both before and after stimulation with insulin (all >1.5-fold change and P<.05). Heterozygous carriers with a defective lipoprotein lipase allele are less insulin sensitive and have increased plasma levels of nonesterified fatty acids and triglycerides. The heterozygous N291S carriers also have a distinct plasma metabolomic signature, which may serve as a diagnostic tool for deficient lipoprotein lipase activity and as a marker of lipid-induced insulin resistance.

TNF-α decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4

Lipoprotein lipase (LPL) hydrolyzes lipids in plasma lipoproteins so that the fatty acids can be taken up and used by cells. The activity of LPL changes rapidly in response to changes in nutrition, physical activity and other conditions. Angiopoietin-like protein 4 (ANGPTL4) is an important controller of LPL activity. Both LPL and ANGPTL4 are produced and secreted by adipocytes. When the transcription blocker Actinomycin D was added to cultures of 3T3-L1 adipocytes, LPL activity in the medium increased several-fold. LPL mRNA decreased moderately during 5h, while ANGPTL4 mRNA and protein declined rapidly, explaining that LPL activity was increased. TNF-α is known to reduce LPL activity in adipose tissue. We have shown that TNF-α increased ANGPTL4 both at the mRNA and protein level. Expression of ANGPTL4 is known to be under control of Foxo1. Use of the Foxo1-specific inhibitor AS1842856, or knockdown of ANGPTL4 by RNAi, resulted in increased LPL activity in the medium. Both with ActD and with the Foxo1 inhibitor the cells became unresponsive to TNF-α. This study shows that TNF-α, by a Foxo1 dependent pathway, increases the transcription of ANGPTL4 which is secreted by the cells and causes inactivation of LPL.

Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia.

Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)). Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.

Severe pulmonary hypertension is associated with altered right ventricle metabolic substrate uptake.

In severe pulmonary hypertension (SPH), prior studies have shown an increase in right ventricle (RV) uptake of glucose, but it is unclear whether there is a change in the relative utilization of fatty acids. We hypothesized that in the RV in SPH, as in left ventricular (LV) failure, there is altered substrate utilization, with increased glucose uptake and decreased fatty acid uptake. SPH was induced in rats by treatment with the VEGF receptor inhibitor SU5416 and 3 wk of hypoxia (10% FiO2 ), followed by an additional 4 wk of normoxia (SU-Hx group). Control rats were treated with carboxymethylcellulose vehicle and 7 wk of normoxia (CMC-Nx group). The rodents then underwent positron emission tomography with sequential administration of two radiotracers, 2-deoxy-2-[(18)F]fluoroglucose ((18)F-FDG) and 14-(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid ((18)F-FTHA), analogs of glucose and fatty acid, respectively. Five CMC-Nx and 3 SU-Hx rats completed the entire experimental protocol. In the RV, there was a mild increase in (18)F-FDG uptake (1.35-fold, P = 0.085) and a significant decrease in (18)F-FTHA uptake (-2.1-fold, P < 0.05) in the SU-Hx rats relative to the CMC-Nx rats. In the LV, SU-Hx rats had less uptake of both radiotracers compared with CMC-Nx rats. Less RV fatty acid uptake in SPH was corroborated by decreased fatty acid transporters and enzymes in the RV tissue, and specifically a decrease in lipoprotein lipase. In the RV in rats with SPH, there is a major shift in metabolic substrate preference, largely due to decreased fatty acid uptake.

Lipolysis, and not hepatic lipogenesis, is the primary modulator of triglyceride levels in streptozotocin-induced diabetic mice.

Diabetic hypertriglyceridemia is thought to be primarily driven by increased hepatic de novo lipogenesis. However, experiments in animal models indicated that insulin deficiency should decrease hepatic de novo lipogenesis and reduce plasma triglyceride levels. To address the discrepancy between human data and genetically altered mouse models, we investigated whether insulin-deficient diabetic mice had triglyceride changes that resemble those in diabetic humans. Streptozotocin-induced insulin deficiency increased plasma triglyceride levels in mice. Contrary to the mouse models with impaired hepatic insulin receptor signaling, insulin deficiency did not reduce hepatic triglyceride secretion and de novo lipogenesis-related gene expression. Diabetic mice had a marked decrease in postprandial triglycerides clearance, which was associated with decreased lipoprotein lipase and peroxisome proliferator-activated receptor α mRNA levels in peripheral tissues and decreased lipoprotein lipase activity in skeletal muscle, heart, and brown adipose tissue. Diabetic heterozygous lipoprotein lipase knockout mice had markedly elevated fasting plasma triglyceride levels and prolonged postprandial triglycerides clearance. Insulin deficiency causes hypertriglyceridemia by decreasing peripheral lipolysis and not by an increase in hepatic triglycerides production and secretion.

Association between serum lipoprotein lipase level and dyslipidemia in patients with obstructive sleep apnea syndrome

To explore the association between serum lipoprotein lipase (LPL) level and dyslipidemia in patients with obstructive sleep apnea syndromes (OSAS). Overnight polysomnography (PSG) was performed for 158 patients with snoring at our Sleep Center from June 2011 to April 2013. Based on the results of apnea-hypopnea index (AHI) assessment, they were divided into 4 groups: primary snoring (AHI<5/h, n = 26), mild (5/h ≤ AHI ≤ 15/h, n = 23), moderate (15/h < AHI ≤ 30/h, n = 31) and severe (AHI>30/h, n = 78) OSAS. According to body mass index (BMI), primary snoring group was further divided into normal BMI and overweight (obese) groups. The level of LPL was determined by enzyme-linked immunosorbent assay (ELISA) and the correlations were observed with OSAS, blood total cholesterol (TC), triglyceride (TG), high density lipoprotein (HDL), low density lipoprotein (LDL) and very low density lipoprotein (VLDL).In normal weight OSAS patients, the relationship was analyzed between different conditions, plasma lipid and serum LPL.In 49 OSAS groups, the level of LPL was observed after 6-month continuous positive airflow pressure (CPAP). From a comparison of four groups, it was found that AHI, night blood lowest oxygen saturation (L-SaO2) and time ratio of lowest SaO2<90% (TS90%) had statistical significance (all P < 0.01). The serum LPL gradually decreased in four groups. Compared with primary snoring group, there was a significant increase of serum LPL level in severe OSAS group ((37 ± 15) vs (45 ± 17) µg/L, P = 0.022). And severe OSAS group had significantly higher serum levels of TC, TG and LDL (P = 0.025,0.001,0.049).HDL of OSAS group was significantly lower than that of primary snoring group (all P < 0.05). Additionally, after adjustment for BMI and age, serum LPL levels showed significant negative correlations with TC and LDL (r = 0.221,0.199) .Serum LPL level was negative correlated with AHI and TS90 % and oxygen decrease index (ODI) (r = 0.231,0.228,0.184). Compared with normal BMI patients, there was a significant increase of VLDL ((0.77 ± 0.30) vs (0.46 ± 0.23) mmol/L, P = 0.034) and decrease of LPL ((37 ± 10) vs (523 ± 23) µg/L, P = 0.047) in weight (obesity) in primary snoring group. Compared with primary snoring group in normal BMI groups, there was a significant increase of TG,VLDL and decrease of LPL, HDL in OSAS group (all P < 0.05). The level of LPL significantly increased after 6-month CPAP ((60 ± 6) vs (38 ± 3) µg/L, P = 0.001). Serum LPL and plasma lipid decrease in OSAS patients. And serum LPL level is correlated significantly with the severity of OSAS and nocturnal hypoxia. Thus LPL may play some roles in dyslipidemia of OSAS patients.

Dietary walnut oil modulates liver steatosis in the obese Zucker rat

PurposeNon-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. We aimed to clarify the impact of dietary walnut oil versus animal fat on hepatic steatosis, representing the initial step of multistage pathogenesis of NAFLD, in Zucker obese rats.MethodsZucker lean ad libitum (a.l.), Zucker obese a.l. or Zucker obese pair fed (p.f.) to the lean received isocaloric diets containing 8 % walnut oil (W8), W14 or 14 % lard (L14) (n = 10/group). Body weight, clinical serology, liver weight, lipid content and fatty acid composition and hepatic lipid metabolism-related transcripts were evaluated.ResultsCompared to lean, Zucker obese a.l. and p.f. showed hepatic triacylglyceride (TAG) accumulation. In Zucker obese p.f., W14 compared to W8 and L14 reduced liver lipids, TAG as well as hepatic omega-6 (n-6)/n-3 ratio and SCD activity index [(C18:0 + C18:1)/C18:0 ratio] paralleled by decreased lipoprotein lipase mRNA in obese p.f. and elevated microsomal triglyceride transfer protein mRNA in lean and obese. Further, W14 elevated the fasting blood TAG and reduced cholesterol levels in obese.ConclusionsIn our model, consumption of W14 inhibited hepatic lipid accumulation along with modulated hepatic gene expression implicated in hepatic fatty acid influx or lipoprotein assembly. These results provide first indication that dietary lipids from walnut oil are modulators of hepatic steatosis as the initial step of progressive NAFLD pathogenesis.