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Purpose of Review: To provide a comprehensive overview of hypertriglyceridemia (HTG) in youth, identifying gaps in categorizing triglyceride (TG) levels and management strategies, and exploring new therapies for TG reduction. Recent Findings: Non-fasting TG levels as important cardiovascular (CV) risk indicators, with HTG's pathophysiology involving genetic and secondary factors affecting TG metabolism. Emerging treatments, including those affecting the lipoprotein lipase complex and inhibiting proteins like apoC3 and ANGPTL3, show promise. Summary: The review highlights the need for specific management approaches for youth, the significance of non-fasting TG levels, and the potential of new therapies in reducing CV and pancreatitis risks, advocating for further research on these treatments' efficacy and safety. [ABSTRACT FROM AUTHOR]

GPIHBP1 is a membrane protein of endothelial cells that transports lipoprotein lipase (LPL), the key enzyme in plasma triglyceride metabolism, from the interstitial space to its site of action on the capillary lumen. An intrinsically disordered highly negatively charged N-terminal domain of GPIHBP1 contributes to the interaction with LPL. In this work, we investigated whether the plethora of heparin-binding proteins with positively charged regions found in human plasma affect this interaction. We also wanted to know whether the role of the N-terminal domain is purely non-specific and supportive for the interaction between LPL and full-length GPIHBP1, or whether it participates in the specific recognition mechanism. Using surface plasmon resonance, affinity chromatography, and FRET, we were unable to identify any plasma component, besides LPL, that bound the N-terminus with detectable affinity or affected its interaction with LPL. By examining different synthetic peptides, we show that the high affinity of the LPL/N-terminal domain interaction is ensured by at least ten negatively charged residues, among which at least six must sequentially arranged. We conclude that the association of LPL with the N-terminal domain of GPIHBP1 is highly specific and human plasma does not contain components that significantly affect this complex. [ABSTRACT FROM AUTHOR]

Cyperus rotundus rhizomes have been used in longevity remedies in Thailand for nourishing good health, which led us to investigate the effect on energy homeostasis, especially glucose utilization in myotubes and adipocytes, and on inhibition of lipogenesis in adipocytes. The results showed that an ethyl acetate extract of C. rotundus rhizomes (ECR) containing 1.61%w/w piceatannol, with a half-maximal concentration of 17.76 ± 0.03 μg/mL in 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, caused upregulation and cell-membrane translocation of glucose transporters GLUT4 and 1 in L6 myotubes but downregulation and cytoplasmic localization of GLUT4 expression in 3T3-L1 adipocytes and was related to the p-Akt/Akt ratio in both cells, especially at 100 μg/mL. Moreover, ECR (25–100 μg/mL) significantly inhibited lipid accumulation via Adenosine Monophosphate-Activated Protein Kinase (AMPK), Acetyl CoA Carboxylase (ACC), and Glycogen Synthase Kinase (GSK) pathways. Its immunoblot showed increased expression of p-AMPKα/AMPKα and p-ACC/ACC but decreased expression of p-Akt/Akt and p-GSK3β/GSK3β in 3T3-L1 adipocytes. Moreover, the decreased expression of the adipogenic effectors, perilipin1 and lipoprotein lipase, in ECR-incubated adipocytes (50 and 100 μg/mL) indicated reduced de novo lipogenesis. Our study elucidated mechanisms of C. rotundus that help attenuate glucose tolerance in skeletal muscle and inhibit lipid droplet accumulation in adipose tissue. [ABSTRACT FROM AUTHOR]

The present study was designed to evaluate the anti-obesity and anti-hyperglycemic activity of Thymoquinone (ThyQ) isolated from Nigella sativa seeds. Male Wistar rats were randomly divided into five groups and fed either normal pellet diet or high-fat diet (HFD) for 18 weeks and water ad-libitum. Group I: normal pellet diet (NPD)-fed, Group II: high-fat diet (HFD)-fed, Group III: HFD-fed-ThyQ (20 mg)-treated, Group IV: HFD-fed-ThyQ (40 mg)-treated and Group V: HFD-fed-Orlistat (5 mg)-treated group. Intervention with ThyQ started from 12th week onwards to HFD-fed rats of group III and IV. ThyQ administration significantly (p < 0.01) mitigated body weight gain, blood glucose, insulin level, serum and liver lipids (except HDL) and improved glucose tolerance and insulin sensitivity as evaluated by oral glucose tolerance test (OGTT), homeostasis model assessment—insulin resistance (HOMA-IR) and insulin tolerance test (ITT). Furthermore, ThyQ significantly (p < 0.01) diminished serum aspartate transaminase (AST), alanine transaminase (ALT), acetyl-CoA carboxylase (ACC), plasma leptin, resistin and visfatin levels but enhanced lipoprotein lipase (LPL) and adiponectin levels. RT-PCR analysis demonstrated down-regulated mRNA expression of sterol regulatory element-binding proteins-1c (SREBP-1c), CCAAT/enhancer-binding protein—α (C/EBP-α) and fatty acid synthase (FAS) but upregulation of Insulin receptor substrate-1 (IRS-1).Western blot analysis displayed phosphorylation of adenosine monophosphate activated protein kinase (AMPK) in ThyQ-treated rats. Liver microtome sections of HFD-fed rats showed degenerated hepatocytes with high lipid stores while that of adipose tissue sections displayed large, fat-laden adipocytes, however, these histological changes were considerably attenuated in ThyQ-treated groups. Together these findings demonstrate that ThyQ can be a valuable therapeutic compound to potentially alleviate diet-induced obesity, hyperglycemia and insulin resistance. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL) functions as a marker of adipocyte differentiation in mammals, but little is known about its role in fish adipogenesis. The aim of this research is to investigate the function of Lpl in adipocyte differentiation in fish. In this paper, we isolated and characterized lipoprotein lipase a (lpla) and lipoprotein lipase b (lplb) from grass carp (Ctenopharyngodon idellus). The complete coding sequence of lpla and lplb was 1524 bp and 1503 bp in length, coding for 507 amino acids and 500 amino acids, respectively. Both lpla and lplb mRNA were expressed in a great number of tissues. During adipogenesis, the level of lpla mRNA reached its maximum at day 2 and then dropped gradually, while the level of lplb mRNA had no significant changes, indicating that lpla and lplb may have different function in the differentiation of grass carp adipocyte. Furthermore, inhibition of lpla by inhibitor of LPL(GSK264220A) at early time points most clearly reduced adipogenesis, whereas these effects were less pronounced at later stages, suggesting that lpla predominantly affects early adipogenesis rather than late adipogenesis. Based on these findings, it can be inferred that lpla and lplb in grass carp may have distinct roles in the differentiation of grass carp adipocyte, and lpla may play an important role in the early adipogenesis rather than late adipogenesis in grass carp. [ABSTRACT FROM AUTHOR]

People with HIV remain at greater risk for both infectious and non-infectious pulmonary diseases even after antiretroviral therapy initiation and CD4 cell count recovery. These clinical risks reflect persistent HIV-mediated defects in innate and adaptive immunity, including in the alveolar macrophage, a key innate immune effector in the lungs. In this proof-of-concept pilot study, we leveraged paired RNA-seq and ATAC-seq analyses of human alveolar macrophages obtained with research bronchoscopy from people with and without HIV to highlight the potential for recent methodologic advances to generate novel hypotheses about biological pathways that may contribute to impaired pulmonary immune function in people with HIV. In addition to 35 genes that were differentially expressed in macrophages from people with HIV, gene set enrichment analysis identified six gene sets that were differentially regulated. ATAC-seq analysis revealed 115 genes that were differentially accessible for people with HIV. Data-driven integration of the findings from these complementary, high-throughput techniques using xMWAS identified distinct clusters involving lipoprotein lipase and inflammatory pathways. By bringing together transcriptional and epigenetic data, this analytic approach points to several mechanisms, including previously unreported pathways, that warrant further exploration as potential mediators of the increased risk of pulmonary disease in people with HIV. [ABSTRACT FROM AUTHOR]

Background: Diabetes is a serious metabolic disorder and many medicinal plants are used in traditional medicine to manage it. This study aimed to evaluate the therapeutic effects of Vernonia calvoana (V. calvoana) extract fractions on streptozotocin-induced diabetic rat models. In this study, we first investigated the binding affinity of ligands from extracts of V. calvoana crystal structure proteins using a molecular docking approach. Furthermore, the in silico predictions were validated by in vitro and in vivo biochemical evaluations to ascertain the efficacy of these extract fractions. The in vitro antioxidant activity of the fractions was evaluated using DPPH, FRAP, SOD, and LPx scavenging. For biological activity, extract fractions of V. calvoana and metformin (400 mg and 500 mg/kg body weight, respectively) were administered to diabetic rats for 21 days after induction and confirmation of diabetes. Results: The radical scavenger activities of the fractions showed a good dose-dependent reaction activity. A significant reduction in hyperglycemia, hyperlipidemia, nephrotoxicity, and hepatotoxicity was observed in all experimental treated groups. Improved hematological and histopathological changes were also observed. Conclusion: The In silico analyses revealed that all the compounds from extract fractions of V. calvoana have varying binding affinity for PFK and lipoprotein lipase, with some showing higher affinity than the standard drug, further validating the biological activity of the plant. The results of this study indicated that V. calvoana extracts might have potential value in treating complications arising from diabetes mellitus. [ABSTRACT FROM AUTHOR]

Fenofibrate (FEN) is an antilipidemic drug that increases the activity of the lipoprotein lipase enzyme, thus enhancing lipolysis; however, it may cause myopathy and rhabdomyolysis in humans. Coenzyme Q10 (CoQ10) is an endogenously synthesized compound that is found in most living cells and plays an important role in cellular metabolism. It acts as the electron carrier in the mitochondrial respiratory chain. This study aimed to elucidate FEN-induced skeletal muscle changes in rats and to evaluate CoQ10 efficacy in preventing or alleviating these changes. Forty adult male rats were divided equally into four groups: the negative control group that received saline, the positive control group that received CoQ10, the FEN-treated group that received FEN, and the FEN + CoQ10 group that received both FEN followed by CoQ10 daily for 4 weeks. Animals were sacrificed and blood samples were collected to assess creatine kinase (CK). Soleus muscle samples were taken and processed for light and electron microscopic studies. This study showed that FEN increased CK levels and induced inflammatory cellular infiltration and disorganization of muscular architecture with lost striations. FEN increased the percentage of degenerated collagen fibers and immune expression of caspase-3. Ultrastructurally, FEN caused degeneration of myofibrils with distorted cell organelles. Treatment with CoQ10 could markedly ameliorate these FEN-induced structural changes and mostly regain the normal architecture of muscle fibers due to its antifibrotic and antiapoptotic effects. In conclusion, treatment with CoQ10 improved muscular structure by suppressing oxidative stress, attenuating inflammation, and inhibiting apoptosis. [ABSTRACT FROM AUTHOR]

Background: Angiopoietin-like 4 (ANGPTL4) belongs to the angiopoietin-like protein family and mediates the inhibition of lipoprotein lipase activity. Emerging evidence suggests that ANGPTL4 has pleiotropic functions with anti- and pro-inflammatory properties. Methods: A thorough search on PubMed related to ANGPTL4 and inflammation was performed. Results: Genetic inactivation of ANGPTL4 can significantly reduce the risk of developing coronary artery disease and diabetes. However, antibodies against ANGPTL4 result in several undesirable effects in mice or monkeys, such as lymphadenopathy and ascites. Based on the research progress on ANGPTL4, we systematically discussed the dual role of ANGPTL4 in inflammation and inflammatory diseases (lung injury, pancreatitis, heart diseases, gastrointestinal diseases, skin diseases, metabolism, periodontitis, and osteolytic diseases). This may be attributed to several factors, including post-translational modification, cleavage and oligomerization, and subcellular localization. Conclusion: Understanding the potential underlying mechanisms of ANGPTL4 in inflammation in different tissues and diseases will aid in drug discovery and treatment development. [ABSTRACT FROM AUTHOR]

Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms for ER proteins and aggregates, respectively; however, the crosstalk between these two pathways under physiological settings remains unexplored. Using adipocytes as a model system, here we report that SEL1L-HRD1 protein complex of ERAD degrades misfolded ER proteins and limits ER-phagy and that, only when SEL1L-HRD1 ERAD is impaired, the ER becomes fragmented and cleared by ER-phagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL, a key lipolytic enzyme and an endogenous SEL1L-HRD1 substrate) and certain ER chaperones. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process influenced by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a sequence of events centered around SEL1L-HRD1 ERAD to dispose of misfolded proteins in the ER of adipocytes, highlighting the profound cellular adaptability to misfolded proteins in the ER in vivo. Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two central degradative mechanisms in the ER. Here the authors describe the sequence of events underlying the disposition of misfolded ER proteins by ERAD and ER-phagy. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL), a crucial gene in lipid metabolism, has a significant role in the progression of malignant tumors. The purpose of this research was to investigate the impact of rs15285 found in the LPL gene's 3'UTR region on the risk, biological behavior, and gastric cancer (GC) prognosis as well as to examine its potential function. Genotyping of rs15285 in 888 GC cases and 874 controls was conducted by SNaPshot technology. We used bioinformatics analysis and in vitro experiments to study the role of rs15285. First, this study revealed for the first time that polymorphism rs15285 increases the risk of GC (OR = 1.48, 95%CI = 1.16–1.89, P = 0.002). Although no relationship was found between rs12585 and the pathological features of GC, the prognosis of individuals with the rs12585 TT genotype was poorer than that of patients with the CC or CC+CT genotype (HR = 2.39 for TT vs. CC, P = 0.025; HR = 2.38 for TT vs. CC+CT, P = 0.025). In addition, bioinformatics analysis showed rs12585 may affect the binding of miRNAs to LPL, resulting in an increase of LPL expression to promote cancer progression. Ultimately, in vitro tests revealed that the rs15285 T allele increased LPL expression on the mRNA as well as the protein levels, promoting GC cell proliferation, invasion, and metastasis. The LPL rs12528 TT genotype increased the risk of GC and predicted a poor prognosis. Mechanistically, the rs15285 T allele could improve the expression of LPL, and thus promotes the malignant phenotype of GC. Therefore, our study may provide new biological predictors and a theoretical basis for the prognosis and customized therapy of stomach cancer patients. Key points: • Rs15285 polymorphism is a risk factor for GC. • Rs12585 TT genotype predicts a bad outcome in GC individuals. • Rs15285 T allele enhances GC cells malignant biological behavior. [ABSTRACT FROM AUTHOR]

Nonalcoholic fatty liver disease (NAFLD) is a condition that affects about 24% of people worldwide. Increased liver fat, inflammation, and, in the most severe cases, cell death are all characteristics of NAFLD. However, NAFLD pathogenesis and therapy are still not clear enough. Thus, this study aimed to determine the effect of a high-cholesterol diet (HCD) inducing NAFLD on lipolytic gene expression, liver function, lipid profile, and antioxidant enzymes in rabbits and the modulatory effects of probiotic Lactobacillus acidophilus (L. acidophilus) on it. A total of 45 male New Zealand white rabbits, eight weeks old, were randomly divided into three groups of three replicates (5 rabbits/replicate). Rabbits in group I were given a basal diet; rabbits in group II were given a high-cholesterol diet that caused NAFLD; and rabbits in group III were given a high-cholesterol diet as well as probiotics in water for 8 weeks. The results showed that a high-cholesterol diet caused hepatic vacuolation and upregulated the genes for lipoprotein lipase (LPL), hepatic lipase (HL), and cholesteryl ester transfer protein (CETP). Downregulated low-density lipoprotein receptor (LDLr) gene, increased liver enzymes [alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), lactate dehydrogenase (LDH)], cholesterol, triglycerides (TG), low-density lipoprotein (LDL), glucose, and total bilirubin. On the other hand, it decreased high-density lipoprotein (HDL), total protein, albumin, and liver antioxidants [glutathione peroxidase (GPx), catalase (CAT), reduced glutathione (GSH), and superoxide dismutase (SOD)]. Supplementing with probiotics helped to return all parameters to normal levels. In conclusion, probiotic supplementation, especially L. acidophilus, protected against NAFLD, and restored lipolytic gene expression, liver functions, and antioxidants to normal levels. [ABSTRACT FROM AUTHOR]

Background: Primary hypertriglyceridemia (HTG) is a very rare autosomal recessive disorder caused by the mutations of the genes related with triglyceride metabolism, including apolipoproteins and lipoprotein lipase (LPL) among others. Germline mutations in the LPL gene cause familial LPL deficiency with an incidence of about 1:1,000,000. It is often diagnosed in childhood and consanguinity is common. Case presentation: We present here a LPL nonsense variant in an infant with heterozygous carriers (parents) of one of each variation detected in the infant. The infant presented with recurrent vomiting, diarrhoea, and haematochezia at 1 month of age. A diagnosis of familial HTG in the infant was made from the clinical manifestations and observation of a lipemic blood sample. Next-generation sequencing identified two pairs of variants in the LPL gene in the patient: chr8:g.19961024G>A; c.1263G>A; p.Trp421Ter and chr8:g.19962221T>G; c.1427+2T>G which were confirmed and validated by Sanger sequencing. The nonsense variant in exon 8 (chr8:g.19961024G>A (HET); c.1263G>AC; p.Trp421Ter) of the LPL gene was detected only in the father, while the 5ʹ splice site variant in intron 9 (chr8:g.19962221T>G (HET); c.1427+2T>G) was detected only in the mother. Thus, the infant manifesting HTG inherited one recessive gene from each of the carrier parents. There were no de novo mutations in the index patient. Based on the clinical findings and genetic test results, it was concluded that the infant suffers from compound heterozygous familial HTG. Conclusions: The current case of the infant with germline mutations in the LPL gene resulting in very severe HTG highlights the importance of genetic counseling. Genetic identification of the pathogenic variants is essential to strategize genetic therapy whenever feasible. The consanguineous nature of the parents is the most probable identified risk factor for the germline mutation in the LPL gene. [ABSTRACT FROM AUTHOR]

We studied the effect of an indolinone derivative GRS on the development of experimental atherosclerosis in C57BL/6 mice. Atherosclerosis was modeled by intraperitoneal administration of endothelial lipoprotein lipase inhibitor Kolliphor P 407 micro Geismar over 5 months. GRS was administered orally in a dose of 10 mg/kg once a day throughout the experiment. In 5 months, the levels of total cholesterol, LDL, and triglycerides in blood serum, as well as histological composition of the ascending aorta were studied. In mice with experimental atherosclerosis, we observed pronounced dyslipidemia with an increase in serum cholesterol, LDL, and triglycerides and accumulation of xanthoma cells in the aorta wall. Repeat administration of GRS did not eliminate dyslipidemia, but prevented an increase in the number of xanthoma cells in the aorta wall (p<0.05). The stimulator of soluble guanylate cyclase GRS did not exhibit hypolipidemic activity, but restored impaired endothelial function in the atherosclerosis model and prevented atherosclerotic damage to blood vessels and vascular wall remodeling. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL) hydrolyzes the triglyceride core of lipoproteins and also functions as a bridge, allowing for lipoprotein and cholesterol uptake. Transgenic mice expressing LPL in adipose tissue under the control of the adiponectin promoter (AdipoQ-LPL) have improved glucose metabolism when challenged with a high fat diet. Here, we studied the transcriptional response of the adipose tissue of these mice to acute high fat diet exposure. Gene set enrichment analysis (GSEA) provided mechanistic insight into the improved metabolic phenotype of AdipoQ-LPL mice. First, the cholesterol homeostasis pathway, which is controlled by the SREBP2 transcription factor, is repressed in gonadal adipose tissue AdipoQ-LPL mice. Furthermore, we identified SND1 as a link between SREBP2 and CCL19, an inflammatory chemokine that is reduced in AdipoQ-LPL mice. Second, GSEA identified a signature for pancreatic β-cells in adipose tissue of AdipoQ-LPL mice, an unexpected finding. We explored whether β-cell function is improved in AdipoQ-LPL mice and found that the first phase of insulin secretion is increased in mice challenged with high fat diet. In summary, we identify two different mechanisms for the improved metabolic phenotype of AdipoQ-LPL mice. One involves improved adipose tissue function and the other involves adipose tissue—pancreatic β-cell crosstalk. [ABSTRACT FROM AUTHOR]

The major cause of death worldwide is atherosclerosis-related cardiovascular disease (ACD). Myrtenal was studied to determine control rats were given standard diets and a high-fat diet was given to AS model groups. Atherosclerosis-related cardiovascular disease (ACD) is globally attributed to being a predominant cause of mortality. While the beneficial effects of Myrtenal, the monoterpene from natural compounds, are increasingly being acknowledged, its anti-atherosclerotic activity has not been demonstrated clearly. The present study is proposed to determine the anti-atherosclerotic activity of Myrtenal in high-fat diet-induced atherosclerosis (AS) rat models. Control groups were maintained with standard diets, the AS model rats were provided a high-fat diet, two of the experimental groups fed with a high-fat diet were treated with Myrtenal (50 mg/kg and 100 mg/kg), and one experimental group on high-fat diet was treated with simvastatin (10 mg/kg) for 30 days. The levels of inflammatory cytokines were analyzed using kits. The lipoproteins and the lipid profile were estimated using an auto-analyzer. The atherogenic index and marker enzyme activities were also determined. Serum concentrations of 6-keto-prostaglandin F1α (6-keto-PGF1α), thromboxaneB2 (TXB2), endothelin (ET), and nitric oxide (NO) were measured. The AS model groups indicated altered lipid profile, lipoprotein content, atherogenic index, calcium levels, HMG-CoA reductase activity, collagen level, and mild mineralization indicating atherosclerosis, while the AS-induced Myrtenal-treated groups demonstrated anti-atherogenic activity. The Myrtenal-treated groups exhibited a decreased TC, TG, and LDLc levels; increased HDLc levels; and a decline in the inflammatory cytokines such as CRP, IL-1β, IL-8, and IL-18 when compared to the untreated AS rats. Furthermore, Myrtenal decreased ET, TXB2, and 6-keto-PGF1α levels indicating its anti-atherosclerotic activity. The study results thus indicate that Myrtenal modulates the lipid metabolic pathway to exert its anti-atherosclerotic activity. [ABSTRACT FROM AUTHOR]

Purpose of Review: Elevated low-density lipoprotein cholesterol (LDL-C) and triglyceride-rich lipoproteins (TRLs) or remnants are important risk factors for the development of atherosclerotic cardiovascular disease (ASCVD). The ongoing challenge of not being able to achieve recommended LDL-C targets despite maximally tolerated lipid-lowering therapy (LLT) has led to the development of novel therapeutic agents including angiopoietin-like 3 (ANGPTL3) inhibitors. Recent Findings: ANGPTL3 is a glycoprotein produced by the liver that inhibits lipoprotein lipase and endothelial lipase. Data from genetic and clinical studies have shown that a lower ANGPTL3 level is associated with lower plasma LDL-C, triglyceride (TG), and other lipoproteins. Pharmacological inactivation of ANGPTL3 with the monoclonal antibody, evinacumab, results in a 50% reduction in LDL-C, even in patients with homozygous familial hypercholesterolemia (HoFH). The safe and effective targeted delivery of nucleic acid–based therapies will shape the future of the lipid arena. Summary: ANGPTL3 is a novel target in lipoprotein metabolism, targeting not only LDL-C via an LDL-receptor (LDLR) independent mechanism but also TRLs and carries a significant promise for further ASCVD risk reduction. [ABSTRACT FROM AUTHOR]

LncRNA HDAC11-AS1 (HDAC11-AS1) is the natural antisense transcript of HDAC11, a key enzyme for DNA histone deacetylation. We evaluated the role of HDAC11-AS1 in atherosclerosis. In this research, we found that HDAC11-AS1 ameliorated blood lipid levels and atherosclerosis in high fat-dieted apoE−/− mice by regulating HDAC11 negatively. The change in blood lipid levels is related to the expression of LPL, which is enhanced by HDAC11-AS1 through regulating adropin histone deacetylation in vitro and in vivo. In conclusion, HDAC11-AS1 plays an anti-atherogenic role through adropin to induce LPL expressions, thereby enhancing TG metabolism. The results are valuable for the further development of HDAC11-AS1 and its clinical applications. It provides a new clinical therapeutic target for cardiovascular disease treatment. [ABSTRACT FROM AUTHOR]

Dysbiosis of the oral microbiota plays an important role in the progression of periodontitis, which is characterized by chronic inflammation and alveolar bone loss, and associated with systemic diseases. Bacterial extracellular vesicles (EVs) contain various bioactive molecules and show diverse effects on host environments depending on the bacterial species. Recently, we reported that EVs derived from Filifactor alocis, a Gram-positive periodontal pathogen, had osteoclastogenic activity. In the present study, we analysed the osteoclastogenic potency and immunostimulatory activity of EVs derived from the Gram-negative periodontal pathogens Porphyromonas gingivalis and Tannerella forsythia, the oral commensal bacterium Streptococcus oralis, and the gut probiotic strain Lactobacillus reuteri. Bacterial EVs were purified by density gradient ultracentrifugation using OptiPrep (iodixanol) reagent. EVs from P. gingivalis, T. forsythia, and S. oralis increased osteoclast differentiation and osteoclstogenic cytokine expression in osteoclast precursors, whereas EVs from L. reuteri did not. EVs from P. gingivalis, T. forsythia, and S. oralis preferentially activated Toll-like receptor 2 (TLR2) rather than TLR4 or TLR9, and induced osteoclastogenesis mainly through TLR2. The osteoclastogenic effects of EVs from P. gingivalis and T. forsythia were reduced by both lipoprotein lipase and polymyxin B, an inhibitor of lipopolysaccharide (LPS), while the osteoclastogenic effects of EVs from S. oralis were reduced by lipoprotein lipase alone. These results demonstrate that EVs from periodontal pathogens and oral commensal have osteoclastogenic activity through TLR2 activation by lipoproteins and/or LPS. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is one of the leading causes of death worldwide. CVD includes coronary artery diseases such as angina, myocardial infarction, and stroke. "Lipid hypothesis" which is also known as the cholesterol hypothesis proposes the linkage of plasma cholesterol level with the risk of developing CVD. Conventional management involves the use of statins to reduce the serum cholesterol levels as means for CVD prevention or treatment. The regulation of serum cholesterol levels can potentially be regulated with biological interventions like monoclonal antibodies. Phage display is a powerful tool for the development of therapeutic antibodies with successes over the recent decade. Although mainly for oncology, the application of monoclonal antibodies as immunotherapeutic agents could potentially be expanded to CVD. This review focuses on the concept of phage display for antibody development and discusses the potential target antigens that could potentially be beneficial for serum cholesterol management. [ABSTRACT FROM AUTHOR]

Human metallothionein-2A (MT2A) protein participates in metal homeostasis, detoxification, oxidative stress reduction, and immune defense. It decreases heavy metal ions and reactive oxygen species (ROS) during injury of cells and tissues. The single nucleotide polymorphisms at the MT2A gene have been associated in various human diseases including cancer. The current study aimed to elucidate associations between MT2A genotypes with the clinical, biochemical, and molecular characteristics that potentially related to lowered MT2A ex-pression. One hundred and forty-one healthy Taiwanese subjects were enrolled from Changhua Show-Chwan Memorial Hospital. Clinical, biochemical and molecular characteristics including the frequent minor allele SNPs, rs28366003 and rs10636, within the MT2A gene were determined. The genotype distribution of MT2A rs10636 fits the Hardy–Weinberg equilibrium. The significant associations with gradually decline of mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were identified with MT2A rs10636 and rs28366003 using analysis of variance (ANOVA) with Tukey's analysis as a post hoc test. We further validated the correlations between the expressions of genes in erythropoiesis, cholesterol synthesis, platelet synthesis, insulin with MT2A using the web-based Gene Expression Profiling Interactive Analysis (GEPIA) databases. The results revealed that hypoxia-inducible factor 1α (HIF-1α), erythropoietin (EPO), lipoprotein lipase (LPL), and lecithin-cholesterol acyltransferase (LCAT) mRNA ex-pression are significantly correlated with MT2A mRNA expression. In conclusion, these results suggested that genetic variations of MT2A rs10636 and rs28366003 might be an important risk factor for erythropoiesis in the Taiwanese general population. [ABSTRACT FROM AUTHOR]

Purpose: Polysorbates (PS) are excipients used in the biotech industry to stabilize monoclonal antibody (mAb) protein products. However, PS in drug product formulations can be degraded during storage and lead to particle formation because of the limited solubility of the free fatty acids released through the enzymatic hydrolysis of PS—a process driven by residual host cell proteins, especially lipases, that are co-purified with the drugs. When multiple lipases are present, it is very difficult to know the cause for PS degradation. In this study, we aim to determine the cause of PS degradation from two lipases, lysosomal acid lipase (LAL) and lipoprotein lipase (LPL). Methods: PS degradation pattern of the drug product was compared with those induced by recombinant lipases. Correlations between the concentration of LPL or LAL and PS20 loss were compared. Specific inhibitors, LAL inhibitor lalistat2 and LPL inhibitor GSK264220A, were used to differentiate their degradation of PS in the drug products. Results: The complete inhibition of PS20 degradation by lalistat2 suggested that LAL, rather than LPL, was responsible for the PS20 degradation. In addition, LAL was more strongly correlated than LPL with the percentage of PS20 degradation. No PS20 degradation was observed for several mAbs containing similar levels of LPL (0.5–1.5 ppm) in the absence of LAL, suggesting that LPL concentrations below 1.5 ppm does not degrade PS20 in drug products. Conclusions: LAL was determined to be the cause of the PS20 degradation. This study provides a practical strategy to determine the root cause of PS degradation. [ABSTRACT FROM AUTHOR]

Purpose of Review: Hypertriglyceridemia (HTG) is common and is a significant contributor to atherosclerosis and pancreatitis risk. Specific HTG treatments have had variable success in reducing atherosclerosis risk. Novel therapies for severe HTG treatment and pancreatitis risk reduction are likely to be available soon. These novel therapies are expected to have broader applications for more moderate HTG and atherosclerosis risk reduction as well. Recent Findings: NHANES 2012 data has confirmed a reduction in average triglyceride (TG) levels in the US population. Dietary modification and weight reduction when needed remain the core treatment elements for all individuals with HTG, while statin therapy is a foundational pharmacologic care for atherosclerotic cardiovascular disease (ASCVD) event risk reduction. In addition, the REDUCE-IT study provides evidence for additional benefit from the use of high-dose icosapent ethyl (IPE) on top of background medical therapy in adults with moderate HTG and ASCVD or type 2 diabetes mellitus (T2D) and additional ASCVD risk factors. However, treatment with eicosapentaenoic acid (EPA) combined with docosahexanoic acid (DHA) did not reduce ASCVD in a similar population studied in the STRENGTH trial. Furthermore, novel therapeutics targeting PPAR-ɑ, as well as ApoC-III and AngPTL3, effectively lower TG levels in individuals with moderate and severe HTG, respectively. These treatments may have applicability for reducing risk from ASCVD among individuals with chylomicronemia; in addition, ApoC-III and AngPTL3 treatments may have a role in treating individuals with the rare monogenic familial chylomicronemia syndrome (FCS) at risk for acute pancreatitis (AP). Summary: Residual ASCVD risk in individuals treated with contemporary care may be due in part to non-LDL lipid abnormalities including HTG. The findings from REDUCE-IT, but not STRENGTH, confirm that consumption of high-dose EPA may reduce ASCVD risk, while combination therapy of EPA plus DHA does not reduce ASCVD in a similar population. TG lowering likely reduces ASCVD risk in individuals with HTG, but ASCVD risk is multifactorial; the added benefit of IPE to contemporary preventive therapy is the consequence of differential non-TG biologic properties between the two fatty acids. Acute pancreatitis is more difficult to study prospectively since it is less common; however, TG lowering is likely critical for the care of at-risk individuals. Additional benefit from novel therapy that has an impact on this otherwise refractory condition is anticipated. [ABSTRACT FROM AUTHOR]

It is well known that carnivorous fish cannot use plant-proteins efficiently. They affect lipid metabolism of fish and cause serious problems to fish health. The reasons for this deficiency of fish metabolism are not known well. Chinese perch, a carnivorous fish, can accept artificial diet after domestication and is also considered as a novel model of fish for nutrition studies. Therefore, the aim of this study was to explore the effect of fish meal replacement by low- or high-rapeseed meal on lipid and glucose metabolism of Chinese perch. Three experimental diets were formulated with 0, 10%, and 30% rapeseed meal, named as Control, RSL, and RSH groups, respectively. After 8-weeks of the feeding trial, the inhibition of growth and fat deposition were observed in Chinese perch fed with rapeseed meal diets compared to the control group. Fish fed with RSL diets showed decreased food intake, serum low density lipoprotein (LDL), phosphorylated Grb10 (P < 0.05), inhibited fatty acid (FA) transport (lipoprotein lipase (LPL)), and glycerol synthesis (phosphoenol pyruvate carboxykinase (PEPCK)) in the liver. In addition, fish fed with RSL diets were also inhibited FA synthesis (fatty acid synthase (FAS), sterol regulatory element binding protein 1 (SREBP1), and Acetyl-CoA carboxylase (ACC1)), lipid uptake (hepatic lipase (HL)), β-oxidation (carnitine palmitoyltransferase I (CPT1)), and glycerol synthesis (PEPCK) in the visceral adipose tissue. Fish fed with RSH diets showed phosphorylated AMPK, inhibited FA synthesis (SREBP1, ACC1, and FAS), while enhanced lipolysis (hormone-sensitive lipase (HSL)), and then reduced Acetyl-CoA pool. In turn, β-oxidation (peroxisome proliferator-activated receptor-a (PPARα) and CPT1) was inhibited, while glycolysis (glucose-6-phosphatase (G6PD) and pyruvate carboxylase (PC)) were enhanced, consequently the lipid accumulation was decreased in the liver. Fish were also inhibited lipid uptake (LPL), that caused inhibiting of FA synthesis (SREBP1), β-oxidation (CPT1), glycerol synthesis (PEPCK), and in turn improved lipolysis (HSL) in the visceral adipose tissue. Our study suggested that both RSL and RSH diets decreased lipid accumulation in Chinese perch; however, the mechanism of lipid metabolism was different. Fish accepted less diet in RSL group, which inhibited lipid metabolism in the liver and in the visceral adipose tissues, while fish in RSH group activated AMPK pathway, inhibited FA synthesis, and enhanced lipolysis, which reduced Acetyl-CoA pool in the liver. Subsequently, lipid uptake and metabolism were inhibited in the visceral adipose tissue of RSH fish. [ABSTRACT FROM AUTHOR]

Human endothelial progenitor cells (EPCs) were isolated from cord blood samples and enriched by magnetic activated cell sorting method based on the CD133 marker. Cells were incubated with different doses of bacterial lipopolysaccharide, ranging from 2, 5, 10, 50, 100, 200, 250, 500, to 1000 µg/ml, for 48 h. The cell survival rate was determined by using MTT assay. To confirm activation of the toll-like receptor signaling pathway, PCR array analysis was performed. Protein levels of ERK1/2, p-ERK1/2, NF-ƙB and TRIF proteins were measured using western blotting. The content of TNF-α and lipoprotein lipase activity were analyzed by immunofluorescence imaging. Flow cytometric analysis of CD31 was performed to assess the maturation rate. Cell migration was studied by the Transwell migration assay. The expression of genes related to exosome biogenesis was measured using real-time PCR analysis. In vivo gel plug angiogenesis assay was done in nude mice. Lipopolysaccharide changed endothelial progenitor cells' survival in a dose-dependent manner with maximum viable cells in groups treated with 2 µg/ml. PCR array analysis showed the activation of toll-like signaling pathways after exposure to LPS (p<0.05). Western blotting analysis indicated an induction of p-ERK1/2 and Erk1/2, NF-kB and TRIF in LPS-treated EPCs compared with the control (p<0.05). Immunofluorescence staining showed an elevation of TNF-α and lipoprotein lipase activity after lipopolysaccharide treatment (p<0.05). Lipopolysaccharide increased EPC migration and expression of exosome biogenesis-related genes (p<0.05). In vivo gel plug analysis revealed enhanced angiogenesis in cells exposed to bacterial lipopolysaccharide. Data highlighted the close relationship between the toll-like receptor signaling pathway and functional activity in EPCs. [ABSTRACT FROM AUTHOR]

Introduction: Overexpression of lipoprotein lipase (LPL) protects against high-fat-diet (HFD)-induced obesity and insulin resistance in transgenic rabbits; however, the molecular mechanisms remain unclear. Skeletal muscle is a major organ responsible for insulin-stimulated glucose uptake and energy expenditure. Objectives: The main purpose of the current study was to examine the effects of the overexpression of LPL on the skeletal muscle metabolomic profiles to test our hypothesis that the mitochondrial oxidative metabolism would be activated in the skeletal muscle of LPL transgenic rabbits and that the higher mitochondrial oxidative metabolism activity would confer better phenotypic metabolic outcomes. Methods: Under a HFD, insulin resistance index was measured using the intravenous glucose tolerance test, and total energy expenditure (TEE) was measured by doubly-labeled water in control and LPL transgenic rabbits (n = 12, each group). Serum lipids, such as triglycerides and free fatty acid, were also measured. The skeletal muscle metabolite profile was analyzed using capillary electrophoresis time-of flight mass spectrometry in the two groups (n = 9, each group). A metabolite set enrichment analysis (MSEA) with muscle metabolites and a false discovery rate q < 0.2 was performed to identify significantly different metabolic pathways between the 2 groups. Results: The triglycerides and free fatty acid levels and insulin resistance index were lower, whereas the TEE was higher in the LPL transgenic rabbits than in the control rabbits. Among 165 metabolites detected, the levels of 37 muscle metabolites were significantly different between the 2 groups after false discovery rate correction (q < 0.2). The MSEA revealed that the TCA cycle and proteinogenic amino acid metabolism pathways were significantly different between the 2 groups (P < 0.05). In the MSEA, all four selected metabolites for the TCA cycle (2-oxoglutaric acid, citric acid, malic acid, fumaric acid), as well as eight selected metabolites for proteinogenic amino acid metabolism (asparagine, proline, methionine, phenylalanine, histidine, arginine, leucine, isoleucine) were consistently increased in the transgenic rabbits compared with control rabbits, suggesting that these two metabolic pathways were activated in the transgenic rabbits. Some of the selected metabolites, such as citric acid and methionine, were significantly associated with serum lipids and insulin resistance (P < 0.05). Conclusion: The current results suggest that the overexpression of LPL may lead to increased activities of TCA cycle and proteinogenic amino acid metabolism pathways in the skeletal muscle, and these enhancements may play an important role in the biological mechanisms underlying the anti-obesity/anti-diabetes features of LPL overexpression. [ABSTRACT FROM AUTHOR]

Catharanthus roseus L. (C. roseus) is one of the medicinal plants used to treat diabetes. In this study, 3T3-L1 preadipocyte cell lines which are fully differentiated into adipocytes were utilized and these were treated with extracts derived from above ground part of C. roseus. The effect of these extracts on obesity and inflammation markers in cells was examined at the transcriptional level. Adipocyte lipid contents were measured by Oil Red O staining. Analyses, including changes related to adiposity and inflammation, were evaluated by measuring the relative mRNA expression levels of the genes of interest by the Real Time Reverse Transcription-Polymerase Chain Reaction (RT-PCR) method. The appropriate dose and durations for C. roseus were determined to be 12.5 μg/mL and 24- and 48 h respectively. The expression of the inflammation marker Interleukin-6 (Il-6) was decreased when C. roseus extract was administered to fully differentiated 3T3-L1 cells according to the determined dose and durations. Lipoprotein lipase (Lpl) and Fatty acid synthase (Fasn) gene expressions in fully differentiated cells decreased compared to the control after 24 h however, this effect was not observed after 48 h. Collagen V, has also been shown to be affected by treatment of fully differentiated 3T3-L1 cells with plant extracts in both 24- and 48-h periods. [ABSTRACT FROM AUTHOR]

Ibrutinib-based therapy represents a recent success in managing high-risk CLL patients with 17p/TP53 deletion. However, a subset of CLL patients are resistant to therapy. Deletion of lipoprotein lipase (LPL) has been postulated as a potential evasion mechanism to ibrutinib-based therapy. In this study, we assessed for LPL deletion by fluorescence in situ hybridization in 176 consecutive CLL patients with 17p/TP53 deletion. LPL deletion was detected in 35 (20%) of CLL patients. Patients with LPL deletion (del) showed a higher frequency of CD38 expression but have comparable frequencies of somatic hypermutation and ZAP-70 expression compared with patients with normal (nml) LPL. Gene mutation analysis showed that TP53 was mutated in 68% of LPL-del versus 91% of LPL-nml patients. The overall response to ibrutinib-based therapy was 57%, including 37% complete remission (CR) and 20% partial remission (PR) in patients with LPL-del versus 90% (56% CR and 34% PR) in patients with LPL-nml (p < 0.001). LPL-del patients also showed a poorer overall survival (OS) compared with patients with LPL-nml (median OS, 236 months versus undefined, p < 0.001). In summary, the data presented establish an association between LPL deletion, resistance to ibrutinib-based therapy, and poorer overall survival in TP53-deleted CLL patients. We suggest that LPL deletion might be utilized as a biomarker for risk stratification and to predict therapeutic response in this high-risk group of CLL patients. [ABSTRACT FROM AUTHOR]

The present study was aimed to evaluate the restorative efficacy of asiatic acid (AA), an active constituent in Centella asiatica (L.) in streptozotocin (STZ)-nicotinamide (NAD)-induced diabetic rats. Male Wistar albino rats were made diabetic with STZ-NAD administration and assessed the effect of AA (20, 30, and 40 mg/kg body weight per day, for 45 days) on body weight, glucose, insulin, insulin resistance, lipid metabolic parameters in plasma and tissue (liver and kidney), and histopathology of liver in control and experimental diabetic rats. A significant (p < 0.05) increase in the concentrations of plasma and tissue lipids cholesterol, triglycerides, free fatty acids, and phospholipids and low-density and very low-density lipoproteins, and a decrease in the concentration of high-density lipoproteins were observed in diabetic rats. A significant elevation in the activity and expression of 3-hydroxy 3-methylglutaryl coenzyme A reductase in plasma and tissue and a concomitant decline in the activity of plasma lipoprotein lipase and lecithin cholesterol acyl transferase were observed in diabetic rats. The pathological abnormalities in plasma and tissues of diabetic rats were significantly ameliorated by AA supplementation for a period of 45 days and offered great support to the biochemical findings. AA also reduced the fat accumulation in the liver and protected from the hepatic steatosis. In conclusion, AA exhibited antidiabetic potential through extenuating hyperglycemic status, changing insulin resistance by alleviating metabolic dysregulation of lipid profile in both plasma and tissues. [ABSTRACT FROM AUTHOR]

BALB/cJ mice exhibit considerable phenotypic differences with other BALB/c substrains. Some of these traits involve the liver, including persistent postnatal expression of genes that are normally expressed only in the fetal liver and reduced expression of major urinary proteins. These traits are due to a mutation that dramatically reduces expression of the gene encoding the transcription factor Zinc fingers and homeoboxes 2 (Zhx2). BALB/cJ mice also exhibit reduced serum lipid levels and resistance to atherosclerosis compared to other mouse strains when placed on a high-fat diet. This trait is also due, at least in part, to the Zhx2 mutation. Microarray analysis identified many genes affecting lipid homeostasis, including Lipoprotein lipase, that are dysregulated in BALB/cJ liver. This led us to investigate whether hepatic lipid levels would be different between BALB/cJ and BALB/c mice when placed on a normal chow or a high-fat chow diet. On the high-fat chow, BALB/cJ mice had increased weight gain, increased liver:body weight ratio, elevated hepatic lipid accumulation and markers of liver damage when compared to BALB/c mice. These traits in BALB/cJ mice were only partially reversed by a hepatocyte-specific Zhx2 transgene. These data indicate that Zhx2 reduces liver lipid levels and is hepatoprotective in mice on a high-fat diet, but the partial rescue by the Zhx2 transgene suggests a contribution by both parenchymal and non-parenchymal cells. A model to account for the cardiovascular and liver phenotype in mice with reduced Zhx2 levels is provided. [ABSTRACT FROM AUTHOR]

Diabetes mellitus is a hereditary predisposed multifactorial disease. However, the genetic mechanisms of its development have not been fully revealed yet. We conducted a search for associations of polymorphic variants of the LEPR (rs1137100), LRP5 (rs3736228), and LPL (rs320) genes involved in the development of obesity with the development of type 2 diabetes mellitus. The association with development of the disease was established for the T allele of the LRP5 locus (rs3736228) (p = 0.029, OR = 1.46). The rs1137100 locus (p = 0.032) of the LEPR gene was shown to be associated with the body mass index (BMI), but it was not connected with the presence of type 2 diabetes mellitus. Risk markers of development of type 2 diabetes included the T allele of the rs3736228 locus of the LRP5 gene (OR = 1.74, p = 0.012) and the G allele of the rs320 locus of the LPL gene (OR = 1.39, p = 0.027). Statistically significant association was only found in the group of nonobese patients. A decrease in the level of low-density lipoprotein was observed in individuals with the TT genotype of the LPL locus (rs320) (p = 0.04). Individuals with the GT and GG genotypes of this locus had a lower cholesterol level (p = 0.027). A decrease in the level of BMI (p = 0.012) and a decrease in the concentration of triglycerides in the blood (p = 0.00000004) were detected in carriers of the CC genotype of the LRP5 rs3736228 locus. [ABSTRACT FROM AUTHOR]

Purpose: We studied effects of diet-induced postmenopausal weight loss on gene expression and activity of proteins involved in lipogenesis and lipolysis in adipose tissue.Methods: Fifty-eight postmenopausal women with overweight (BMI 32.5 ± 5.5) were randomized to eat an ad libitum Paleolithic-type diet (PD) aiming for a high intake of protein and unsaturated fatty acids or a prudent control diet (CD) for 24 months. Anthropometry, plasma adipokines, gene expression of proteins involved in fat metabolism in subcutaneous adipose tissue (SAT) and lipoprotein lipase (LPL) activity and mass in SAT were measured at baseline and after 6 months. LPL mass and activity were also measured after 24 months.Results: The PD led to improved insulin sensitivity (P < 0.01) and decreased circulating triglycerides (P < 0.001), lipogenesis-related factors, including LPL mRNA (P < 0.05), mass (P < 0.01), and activity (P < 0.001); as well as gene expressions of CD36 (P < 0.05), fatty acid synthase, FAS (P < 0.001) and diglyceride acyltransferase 2, DGAT2 (P < 0.001). The LPL activity (P < 0.05) and gene expression of DGAT2 (P < 0.05) and FAS (P < 0.05) were significantly lowered in the PD group versus the CD group at 6 months and the LPL activity (P < 0.05) remained significantly lowered in the PD group compared to the CD group at 24 months.Conclusions: Compared to the CD, the PD led to a more pronounced reduction of lipogenesis-promoting factors in SAT among postmenopausal women with overweight. This could have mediated the favorable metabolic effects of the PD on triglyceride levels and insulin sensitivity. [ABSTRACT FROM AUTHOR]

It has long been established that maternal nutritional condition and fatty acid intake during pregnancy and/or lactation may influence the modifications in the individual risk for developing metabolic diseases throughout life, but little is known about the possible role of maternal nutrition before conception. The aim of this study was to investigate the effect of maternal supplementation with olive oil on offspring lipid metabolism under obesogenic conditions. Female Wistar rats were fed control or cafeteria diet which were either supplemented or not supplemented with olive oil (5%) for 2 months before and during gestation. Pregnant rats and their offspring were also fed on similar diet. After overnight fasting, offspring were sacrificed at 1 and 3 month of life. Cafeteria diet led to higher body weight, hyperglycemia and hyperlipidemia, LDL cholesterol, serum Lecithin-cholesterol acyltransferase activity and tissues lipoprotein lipase and hormone-sensitive lipase in offspring. In contrast, adult obese offspring had a lower HDL cholesterol. Olive oil rich-CAF diet decreased plasma lipids, increased HDL cholesterol and up-regulated lipolytic enzyme activities at weaning until adulthood. These data suggest that maternal olive oil may an effective strategy to improving metabolic alterations related to cafeteria diet in offspring. [ABSTRACT FROM AUTHOR]

Three members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3, ANGPTL4 and ANGPTL8, are known regulators of plasma triacylglycerol levels. Recently, these three proteins have garnered considerable interest as potential targets for therapeutically reducing plasma triacylglycerol levels and improving cardiovascular outcomes. In this issue of Diabetologia, Janssen et al (10.1007/s00125-018-4583-5) and Vatner et al (10.1007/s00125-018-4579-1) show that reducing levels of ANGPTL4 and ANGPTL8, respectively, could have the added benefit of improving glucose tolerance. Interestingly, the improvements in glucose tolerance observed in both studies, both done in rodents, were coupled with increased fat mass. These findings suggest that funnelling lipids to adipose tissue and away from ectopic sites could be beneficial and strengthen the argument for pursuing the therapeutic targeting of ANGPTL proteins. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Targeting regulators of adipose tissue lipoprotein lipase could enhance adipose lipid clearance, prevent ectopic lipid accumulation and consequently ameliorate insulin resistance and type 2 diabetes. Angiopoietin-like 8 (ANGPTL8) is an insulin-regulated lipoprotein lipase inhibitor strongly expressed in murine adipose tissue. However, Angptl8 knockout mice do not have improved insulin resistance. We hypothesised that pharmacological inhibition, using a second-generation antisense oligonucleotide (ASO) against Angptl8 in adult high-fat-fed rodents, would prevent ectopic lipid accumulation and insulin resistance by promoting adipose lipid uptake.Methods: ANGPTL8 expression was assessed by quantitative PCR in omental adipose tissue of bariatric surgery patients. High-fat-fed Sprague Dawley rats and C57BL/6 mice were treated with ASO against Angptl8 and insulin sensitivity was assessed by hyperinsulinaemic-euglycaemic clamps in rats and glucose tolerance tests in mice. Factors mediating lipid-induced hepatic insulin resistance were assessed, including lipid content, protein kinase Cε (PKCε) activation and insulin-stimulated Akt phosphorylation. Rat adipose lipid uptake was assessed by mixed meal tolerance tests. Murine energy balance was assessed by indirect calorimetry.Results: Omental fat ANGPTL8 mRNA expression is higher in obese individuals with fatty liver and insulin resistance compared with BMI-matched insulin-sensitive individuals. Angptl8 ASO prevented hepatic steatosis, PKCε activation and hepatic insulin resistance in high-fat-fed rats. Postprandial triacylglycerol uptake in white adipose tissue was increased in Angptl8 ASO-treated rats. Angptl8 ASO protected high-fat-fed mice from glucose intolerance. Although there was no change in net energy balance, Angptl8 ASO increased fat mass in high-fat-fed mice.Conclusions/interpretation: Disinhibition of adipose tissue lipoprotein lipase is a novel therapeutic modality to enhance adipose lipid uptake and treat non-alcoholic fatty liver disease and insulin resistance. In line with this, adipose ANGPTL8 is a candidate therapeutic target for these conditions. [ABSTRACT FROM AUTHOR]

Lipoprotein lipase (LPL) mediates hydrolysis of triglycerides (TGs) to supply free fatty acids (FFAs) to tissues. Here, we show that LPL activity is also required for hematopoietic stem progenitor cell (HSPC) maintenance. Knockout of Lpl or its obligatory cofactor Apoc2 results in significantly reduced HSPC expansion during definitive hematopoiesis in zebrafish. A human APOC2 mimetic peptide or the human very low-density lipoprotein, which carries APOC2, rescues the phenotype in apoc2 but not in lpl mutant zebrafish. Creating parabiotic apoc2 and lpl mutant zebrafish rescues the hematopoietic defect in both. Docosahexaenoic acid (DHA) is identified as an important factor in HSPC expansion. FFA-DHA, but not TGDHA, rescues the HSPC defects in apoc2 and lpl mutant zebrafish. Reduced blood cell counts are also observed in Apoc2 mutant mice at the time of weaning. These results indicate that LPL-mediated release of the essential fatty acid DHA regulates HSPC expansion and definitive hematopoiesis. [ABSTRACT FROM AUTHOR]

To investigate the effects of fasting on lipid metabolism in spotted seabass muscle and liver tissues, we analyzed mRNA levels and enzyme activities of lipoprotein lipase (LPL), hormone-sensitive lipase (HSL) and fatty acid synthetase (FAS), and the relationship among fat content, mRNA level, and enzyme activity during fasting of 35 days. The results showed that expressions of all the three genes were ubiquitous. During the fasting experiment, the hepatosomatic index (HSI) and fat content of muscle and liver tissues significantly decreased before 5 days of fasting (P < 0.05). mRNA levels of LPL increased significantly after 5 days of fasting in liver and 7 days in muscle. Abundance of HSL transcripts increased significantly after 14 days of fasting in both muscle and liver. The activities of LPL and HSL presented a trend that increased firstly, decreased subsequently, and then raised again with the prolonged fasting experiment (P < 0.05). However, activities and mRNA levels of FAS decreased significantly after 1 day of fasting in both muscle and liver. Moreover, activities and mRNA levels of FAS showed a moderate correlation in muscle. These results suggested that FAS had a sooner response to fasting than LPL and HSL in both muscle and liver tissues. LPL and HSL played important roles in lipolysis mainly by increasing enzyme activities in the early stage of fasting and mRNA levels in the later stage of fasting in both muscle and liver. Our results also provided useful information on regulating muscle fat content by fasting. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Lipids are a potent stimulus for the secretion of glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic peptide (GIP). Traditionally, this effect was thought to involve the sensing of lipid digestion products by free fatty acid receptor 1 (FFA1) and G-protein coupled receptor 119 (GPR119) on the apical surface of enteroendocrine cells. However, recent evidence suggests that lipids may in fact be sensed basolaterally, and that fatty acid absorption and chylomicron synthesis may be a prerequisite for their stimulatory effect on gut peptide release. Therefore, we investigated the effect of chylomicrons on GLP-1 and GIP secretion in vitro. Methods: The effect of chylomicrons on incretin secretion was investigated using GLUTag cells and duodenal cultures of both murine and human origin. The role of lipoprotein lipase (LPL) and FFA1 in GLUTag cells was assessed by pharmacological inhibition and small (short) interfering RNA (siRNA)-mediated knockdown. The effect of chylomicrons on intracellular calcium concentration ([Ca]) was determined by imaging GLUTag cells loaded with Fura-2. In the primary setting, the contributions of FFA1 and GPR119 were investigated using L cell-specific Gpr119 knockout cultures treated with the FFA1 antagonist GW1100. Results: Chylomicrons stimulated GLP-1 release from GLUTag cells, and both GLP-1 and GIP secretion from human and murine duodenal cultures. Chylomicron-triggered GLP-1 secretion from GLUTag cells was largely abolished following lipase inhibition with orlistat or siRNA-mediated knockdown of Lpl. In GLUTag cells, both GW1100 and siRNA-mediated Ffar1 knockdown reduced GLP-1 secretion in response to chylomicrons, and, consistent with FFA1 G-coupling, chylomicrons triggered an increase in [Ca]. However, LPL and FFA1 inhibition had no significant effect on chylomicron-mediated incretin secretion in murine cultures. Furthermore, the loss of GPR119 had no impact on GLP-1 secretion in response to chylomicrons, even in the presence of GW1100. Conclusions/interpretation: Chylomicrons stimulate incretin hormone secretion from GLUTag cells as well as from human and murine duodenal cultures. In GLUTag cells, the molecular pathway was found to involve LPL-mediated lipolysis, leading to the release of lipid species that activated FFA1 and elevated intracellular calcium. [ABSTRACT FROM AUTHOR]

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Aims/hypothesis: Regulation of energy balance involves the participation of many factors, including nutrients, among which are circulating lipids, acting as peripheral signals informing the central nervous system of the energy status of the organism. It has been shown that neuronal lipoprotein lipase (LPL) participates in the control of energy balance by hydrolysing lipid particles enriched in triacylglycerols. Here, we tested the hypothesis that LPL in the mediobasal hypothalamus (MBH), a well-known nucleus implicated in the regulation of metabolic homeostasis, could also contribute to the regulation of body weight and glucose homeostasis. Methods: We injected an adeno-associated virus (AAV) expressing Cre-green fluorescent protein into the MBH of Lpl-floxed mice (and wild-type mice) to specifically decrease LPL activity in the MBH. In parallel, we injected an AAV overexpressing Lpl into the MBH of wild-type mice. We then studied energy homeostasis and hypothalamic ceramide content. Results: The partial deletion of Lpl in the MBH in mice led to an increase in body weight compared with controls (37.72 ± 0.7 g vs 28.46 ± 0.12, p < 0.001) associated with a decrease in locomotor activity. These mice developed hyperinsulinaemia and glucose intolerance. This phenotype also displayed reduced expression of Cers1 in the hypothalamus as well as decreased concentration of several C18 species of ceramides and a 3-fold decrease in total ceramide intensity. Conversely, overexpression of Lpl specifically in the MBH induced a decrease in body weight. Conclusions/interpretation: Our study shows that LPL in the MBH is an important regulator of body weight and glucose homeostasis. [ABSTRACT FROM AUTHOR]

The lipA gene, encoding a solvent-tolerant extracellular lipase from Proteus sp. SW1, was displayed on the cell surface of Escherichia coli by fusing it to an antigen 43 anchoring motif. The display of LipA on the Escherichia coli cell surface was directly confirmed by immunofluorescence microscopy and flow cytometry. After 6 days of incubation in media containing 1 % used cooking oil, an Escherichia coli strain expressing surface displayed lipase was able to degrade 27 % of the oil. The biosurfactant, pseudopyronine B, was purified from culture supernatants of Pseudomonas sp. SL31. Its critical micelle concentration was determined to be 1400 mg/l, and the surfactant was stable within a temperature range from 0 to 120 °C and a pH range of 3-11. Pseudopyronine B-containing crude media extracts efficiently removed up to 51 % of the cadmium from contaminated water. We demonstrated the oil degradation ability of the mixed culture of four bacterial strains, namely the recombinant Escherichia coli expressing cell surface displayed lipase (pKKJlipA), His-tagged lipase (pETlipA), extracellular lipase-producing Proteus sp. SW1, and pseudopyronine B-producing Pseudomonas sp. SL31 by culturing in LB media containing 1 % oil. The consortium degraded 29 % of oil in one day and reached 84 % after 7 days. [ABSTRACT FROM AUTHOR]

Specific features of indicators of the thyroid status and blood serum lipoprotein level were revealed in girls and women of the Buryat ethnos and Europeoid race. Buryat versus Europeoid females develop adaptive responses of the pituitary-thyroid part of the neuroendocrine regulatory system (increased free T3 levels in girls and decreased TTH levels in women). Changes in lipid metabolism indicators consist in lower levels of atherogenic cholesterol fractions in Buryat girls and higher levels of cholesterol-containing blood components in Europeoid adolescents. At the older ages, an inverse tendency is observed, characterized by a higher activity of lipid metabolism in females of the indigenous nationality. [ABSTRACT FROM AUTHOR]

We studied the relationship between lipoprotein lipase (LPL) gene HindIII polymorphism and the development of acute pancreatitis in the Russian population. Whole blood samples were collected from 145 patients with acute non-biliary pancreatitis and 191 healthy individuals. Genotyping of LPL gene HindIII ( rs320) polymorphism was performed by PCR with TaqMan assay. It was found that allele H+ (OR=0.63, 95%CI 0.41-0.96, p=0.03) and genotype H+/ H+ (OR=1.79, 95%CI 1.06-3.04, p=0.03) were associated with the risk of acute non-biliary pancreatitis only in males. In this study, the relationship between HindIII polymorphism of LPL gene with the risk of acute non-biliary pancreatitis was revealed. [ABSTRACT FROM AUTHOR]

Musa sapientum Linn. (English 'Banana' family Musaceae), is a plant with nutritive, as well as medicinal value. Antihypercholesterolemic and antioxidant effect of methanolic extract of stem of this plant was investigated in hypercholesterolemic rats. Rats were made hypercholesterolemic by feeding cholesterol (100 mg/kg/day) suspended in soya oil. Treatment groups received extract at a dose of 10, 20 and 40 mg/kg/day in addition to cholesterol orally once daily. Fasting blood samples were collected before and after 6 weeks treatment. Animals were sacrificed and liver stored at -80 °C. Total cholesterol, HDL-cholesterol and triacylglycerol were estimated in blood. Malondialdehyde, reduced glutathione, superoxide dismutase and catalase were measured in blood and liver. Total lipids, HMG CoA redutase and lipoprotein lipase were investigated in liver. Most effective dose was found to be 20 mg/kg/day. Rise in total cholesterol, LDL + VLDL-cholesterol and triacylglycerol in animals receiving only cholesterol was 179 %, 417 % and 74 % respectively, while in animals receiving 20 mg/kg dose rise in these parameters was restricted to 40 %, 106 % and 24 %. HDL-cholesterol decreased by 12 % in extract treated group, while it decreased to 36 % in untreated hypercholesterolemic rats. Malonaldialdehyde, marker of lipid peroxidation decreased while reduced glutathione and enzymes superoxide dismutase and catalase increased significantly in blood and liver ( p < 0.01). Total lipids in liver decreased and enzymes of lipid metabolism viz. HMG CoA redutase and lipoprotein lipase were restored to near normal. Gas chromatography mass spectroscopy indicated high content of sterols in extract. Study demonstrated that methanol extract of stem of Musa sapientum has significant antihypercholesterolemic and antioxidant effects. [ABSTRACT FROM AUTHOR]

The impact of juvenile idiopathic arthritis (JIA) in periodontal diseases is controversial probably due to gender and age heterogeneity. We therefore evaluated a homogeneous female post-pubertal JIA population for these conditions. Thirty-five JIA patients and 35 gender/age comparable healthy controls were evaluated according to demographic data, complete periodontal evaluation, fasting lipoproteins, and anti-lipoprotein lipase antibodies. JIA scores, laboratorial tests, X-rays, and treatment were also assessed. Current age was similar in JIA patients and controls (11.90 ± 2.0 vs. 12.50 ± 3.0 years, p = 0.289). Complete periodontal assessments revealed that gingival index, dental plaque, gingival bleeding, and clinical dental attachment indices were alike in JIA patients and controls ( p > 0.05), except for gingival enlargement in former group ( p < 0.0001). Further analysis of patients with and without gingivitis revealed that cyclosporine use was more often observed in JIA patients with gingivitis (37 vs. 0 %, p = 0.01), whereas no differences were evidenced in demographic, JIA scores, inflammatory markers, and lipid profile in both groups. Of note, two parameters of periodontal assessment were correlated with JIA scores [gingival index (GI) and Childhood Health Assessment Questionnaire (CHAQ) ( r = +0.402, p = 0.020)] and plaque index (PI) and visual analog scale (VAS) physician ( r = +0.430, p = 0.013). In addition, evaluation of dental assessment demonstrated that JIA activity scores had positive correlation with decayed, missing, and filled teeth (DMF-T) and junvenile athritis disease activity score (JADAS) ( r = +0.364, p = 0.037), VAS physician ( r = +0.401, p = 0.021) and VAS patient ( r = +0.364, p = 0.037). We demonstrated, using rigorous criteria, that periodontal and dental condition in JIA is similar to controls. In spite of that, the finding of a correlation with disease parameters provides additional evidence that increased activity and reduced functional ability underlies the deleterious effect of JIA in oral health. [ABSTRACT FROM AUTHOR]

The parameters of lipid metabolism in the spectrum of blood serum are the most commonly used indicators in clinical practice. Their disturbances (dyslipidemia) can be manifested as elevated levels of total cholesterol and triglycerides or as changes in other indices resulting from aberrations in the lipoprotein synthesis, transport or cleavage. The clinical importance of a range of metabolic disorders, defined overall as dyslipidemia, is associated primarily with a high risk of cardiovascular disease, diabetes mellitus type 2, and obesity. Here, we examined the association of certain SNPs ( G2548A in the promoter region of leptin gene LEP; A223G, in the exon 4 of leptin receptor gene LEPR; T495G, in the intron 8 in lipoprotein lipase gene LPL; and C34G, in exon 8 of the peroxisome proliferator-activated nuclear receptor γ PPARG) with disruptions in lipid metabolism; and we demonstrated their cumulative contribution towards the development of dyslipidemia. [ABSTRACT FROM AUTHOR]

Background: Bariatric surgery has proven results for diabetes remission in obese diabetics. Despite this, a lot of ambiguity exists around patient selection. The objectives of this study are the following: (1) evaluation of results of laparoscopic Roux-en-y gastric bypass (LRYGB) in obese type 2 diabetic (T2DM) Indian patients at 5 years and (2) to define predictors of success after surgery. Methods: This is a prospective observational study. One hundred six Indian patients underwent LRYGB from January 2004 to July 2009. Patients were evaluated for percent excess weight loss (%EWL) and remission of T2DM. Mean age 50.34 ± 9.08 years, mean waist circumference 129.8 ± 20.8 cm, mean weight 119.2 ± 23.6 kg, mean BMI 45.01 ± 7.9 kg/m, and mean duration of diabetes 8.2 ± 6.2 years. Results: At 5 years, mean EWL% was 61.4 ± 20.3, mean weight regain of 8.6 ± 6.2 kg was seen in 63.6 %, mean glycosylated hemoglobin dropped from 8.7 ± 2.1 to 6.2 ± 01.3 %, mean triglycerides declined by 31 %, and serum high density lipoprotein rose by 18.4 %. Mean low-density lipoprotein levels declined by 6.8 %. Age, BMI, fasting C-peptide levels, duration of T2DM, and pre-op use of insulin emerged as significant predictors of success after surgery. One hundred percent remission was seen in patients with T2DM <5 years. Conclusions: LRYGB is safe and efficacious for long-term remission of T2DM (BMI ≥ 35 kg/m). In a country with the second largest population of type 2 diabetics in the world, predictors of success after surgery can help in prioritizing patients who have a greater chance to benefit from metabolic surgery. [ABSTRACT FROM AUTHOR]

Background: Paralleling the growth of bariatric surgery, the demand for post-bariatric body-contouring surgery is increasing and placing additional burdens on already strained health care systems. In Austria, medically necessary body contouring is covered by public health care. In a sample of 622 women, we assessed the proportion of patients that underwent post-bariatric surgery at least 2 years after gastric bypass. Methods: Former bariatric patients were asked whether they had undergone post-bariatric surgery or were planning to do so by structured telephone interviews. For patients who had undergone body contouring, the degree of satisfaction with the results was inquired. Costs for bariatric and post-bariatric procedures were assessed. Results: Of 622 patients, 93 (14.9 %) had undergone body contouring and 68 (10.9 %) considered a procedure, while 454 (73 %) definitely stated that they did not want plastic surgery. Cost coverage was declined in 7 patients (1.1 %). Plastic procedures ( n = 101) included 65 abdominoplasties, 25 lower body lifts without thigh lifts, 7 brachioplasties, and 4 minor procedures. Forty-nine patients were very satisfied with the results, 28 were fairly satisfied, and 16 were not satisfied. Body contouring added about 6 % to the costs of surgical treatment for morbid obesity. Conclusions: Fewer patients than in other studies expressed a desire for post-bariatric surgery, 15 % actually proceeded to this step. The low demand was neither due to denied coverage nor to unfavourable results of plastic surgery. Additional costs for body contouring were less than expected. [ABSTRACT FROM AUTHOR]

Familial hypercholesterolaemia (FH) is an autosomal dominant inherited disease characterised by increased low-density lipoprotein cholesterol (LDL-C) levels. The functionality of four novel variants within the LDLR 5′UTR and promoter located at c.-13A>G, c.-101T>C, c.-121T>C and c.-215A>G was investigated using in silico and in vitro assays, and a systemic bioinformatics analysis of all 36 reported promoter variants are presented. Bioinformatic tools predicted that all four variants occurred in sites likely to bind transcription factors and that binding was altered by the variant allele. Luciferase assay was performed for all the variants. Compared with wild type, the c.-101T>C and c.-121T>C variants showed significantly lower mean (±SD) luciferase activity (64±8 and 72±8%, all P<0.001), suggesting that these variants are causal of the FH phenotype. No significant effect on gene expression was seen for the c.-13A>G or c.-215A>G variants (96±15 and 100±12%), suggesting these variants are not FH causing. Similar results were seen for the c.-101T>C and c.-121T>C variants in lipid-depleted serum. However, a significant reduction in luciferase activity was seen in the c.-215A>G variant in lipid-depleted serum. Electrophoretic-mobility shift assays identified allele-specific binding of liver (hepatoma) nuclear proteins to c.-121T>C and suggestive differential binding to c.-101T>C but no binding to c.-215A>G. These data highlight the importance of in vitro testing of reported LDLR promoter variants to establish their role in FH. The functional assays performed suggest that the c.-101T>C and c.-121T>C variants are pathogenic, whereas c.-13A>G variant is benign, and the status of c.-215A>G remains unclear. [ABSTRACT FROM AUTHOR]