Showing papers in "Journal of Lipids in 2012"
TL;DR: Recent advances in the understanding of bile acid signaling in regulation of glucose and lipid metabolism are summarized, and the potentials of developing novel therapeutic strategies that target bile Acid metabolism for the treatment of metabolic disorders are summarized.
Abstract: Obesity, diabetes, and metabolic syndromes are increasingly recognized as health concerns worldwide. Overnutrition and insulin resistance are the major causes of diabetic hyperglycemia and hyperlipidemia in humans. Studies in the past decade provide evidence that bile acids are not just biological detergents facilitating gut nutrient absorption, but also important metabolic regulators of glucose and lipid homeostasis. Pharmacological alteration of bile acid metabolism or bile acid signaling pathways such as using bile acid receptor agonists or bile acid binding resins may be a promising therapeutic strategy for the treatment of obesity and diabetes. On the other hand, bile acid signaling is complex, and the molecular mechanisms mediating the bile acid effects are still not completely understood. This paper will summarize recent advances in our understanding of bile acid signaling in regulation of glucose and lipid metabolism, and the potentials of developing novel therapeutic strategies that target bile acid metabolism for the treatment of metabolic disorders.
146 citations
TL;DR: The body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects are discussed, which may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways.
Abstract: Non-alcoholic fatty liver disease (NAFLD) is currently evolving as the most common liver disease worldwide. It may progress to liver cirrhosis and liver cancer and is poised to represent the most common indication for liver transplantation in the near future. The pathogenesis of NAFLD is multifactorial and not fully understood, but it represents an insulin resistance state characterized by a cluster of cardiovascular risk factors including obesity, dyslipidemia, hyperglycemia, and hypertension. Importantly, NAFLD also has evolved as independent risk factor for cardiovascular disease. Unfortunately thus far no established treatment does exist for NAFLD. The bile acid-activated nuclear farnesoid X receptor (FXR) has been shown to play a role not only in bile acid but also in lipid and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. This review discusses the body's complex response to the activation of FXR with its beneficial actions but also potential undesirable side effects.
100 citations
TL;DR: The NLFA 16:1ω5 appears to be a feasible indicator for AM fungi of the Glomales group in the complex field soils, whereas the use of PLFA 16:"ω5 for hyphae is unsuitable and should be restricted to controlled laboratory studies.
Abstract: Biomass estimation of arbuscular mycorrhiza (AM) fungi, widespread plant root symbionts, commonly employs lipid biomarkers, predominantly the fatty acid 16:1ω5. We briefly reviewed the application of this signature fatty acid, followed by a case study comparing biochemical markers with microscopic techniques in an arable soil following a change to AM non-host plants after 27 years of continuous host crops, that is, two successive cropping seasons with wheat followed by amaranth. After switching to the non-host amaranth, spore biomass estimated by the neutral lipid fatty acid (NLFA) 16:1ω5 decreased to almost nil, whereas microscopic spore counts decreased by about 50% only. In contrast, AM hyphal biomass assessed by the phospholipid (PLFA) 16:1ω5 was greater under amaranth than wheat. The application of PLFA 16:1ω5 as biomarker was hampered by background level derived from bacteria, and further enhanced by its incorporation from degrading spores used as microbial resource. Meanwhile, biochemical and morphological assessments showed negative correlation for spores and none for hyphal biomass. In conclusion, the NLFA 16:1ω5 appears to be a feasible indicator for AM fungi of the Glomales group in the complex field soils, whereas the use of PLFA 16:1ω5 for hyphae is unsuitable and should be restricted to controlled laboratory studies.
87 citations
TL;DR: Novel findings revealed that both PON2 and PON3 locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress, and this could be used in putative future therapies to target atherosclerosis and cancer.
Abstract: Cancer and atherosclerosis are major causes of death in western societies. Deregulated cell death is common to both diseases, with significant contribution of inflammatory processes and oxidative stress. These two form a vicious cycle and regulate cell death pathways in either direction. This raises interest in antioxidative systems. The human enzymes paraoxonase-2 (PON2) and PON3 are intracellular enzymes with established antioxidative effects and protective functions against atherosclerosis. Underlying molecular mechanisms, however, remained elusive until recently. Novel findings revealed that both enzymes locate to mitochondrial membranes where they interact with coenzyme Q10 and diminish oxidative stress. As a result, ROS-triggered mitochondrial apoptosis and cell death are reduced. From a cardiovascular standpoint, this is beneficial given that enhanced loss of vascular cells and macrophage death forms the basis for atherosclerotic plaque development. However, the same function has now been shown to raise chemotherapeutic resistance in several cancer cells. Intriguingly, PON2 as well as PON3 are frequently found upregulated in tumor samples. Here we review studies reporting PON2/PON3 deregulations in cancer, summarize most recent findings on their anti-oxidative and antiapoptotic mechanisms, and discuss how this could be used in putative future therapies to target atherosclerosis and cancer.
72 citations
TL;DR: The relative concentrations of sphingolipids including S1P in the plasma subfraction containing lipoproteins compared to those in the remaining plasma proteins were determined and it was found that different plasma pools of S1p may have different contributions to S 1P signaling in health and disease.
Abstract: The physiological significance of sphingosine 1-phosphate (S1P) transport in blood has been debated. We have recently reported a comprehensive sphingolipid profile in human plasma and lipoprotein particles (VLDL, LDL, and HDL) using HPLC-MS/MS (Hammad et al., 2010). We now determined the relative concentrations of sphingolipids including S1P in the plasma subfraction containing lipoproteins compared to those in the remaining plasma proteins. Sphingomyelin and ceramide were predominantly recovered in the lipoprotein-containing fraction. Total plasma S1P concentration was positively correlated with S1P concentration in the protein-containing fraction, but not with S1P concentration in the lipoprotein-containing fraction. The percentage of S1P transported in plasma lipoproteins was positively correlated with HDL cholesterol (HDL-C) concentration; however, S1P transport in lipoproteins was not limited by the concentration of HDL-C in the individual subject. Thus, different plasma pools of S1P may have different contributions to S1P signaling in health and disease.
58 citations
TL;DR: PON1 activity recovery after dialysis suggests that uremic toxins may play a mechanistic role in PON1 inactivation, and future research should focus on mechanistic studies on causes for low Pon1 activity and mass.
Abstract: In this review we summarize the findings from the literature and our own laboratory on the decreased PON1 activity in renal failure, the mechanisms proposed and the effect of interventions. In addition to profound alterations in lipoproteins, reduced serum PON1 activity has been clearly established in the past decade and could contribute to accelerated development of atherosclerosis in ESRD and in HD. PON1 lactonase activity is lower in ESRD patients. Hemodialysis partially restores PON1 lactonase and the other activities. PON1 activity recovery after dialysis suggests that uremic toxins may play a mechanistic role in PON1 inactivation. Lower PON1 activity in CRF patients is associated with low thiol concentration, high CRP, and is beneficially enhanced with vitamin C and flavonoids. Changes in HDL subclasses, namely lower HDL3 in these patients may also play a role in PON1 lower activity. Future research should focus on: (1) mechanistic studies on causes for low PON1 activity and mass; (2) prospective studies focusing on whether there is an added predictive value in measuring PON1 activity (and PON1 activity in HDL3) in this patient population; (3) intervention studies attempting to increase PON1 activity.
53 citations
TL;DR: Understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD.
Abstract: The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. Unexpectedly, ezetimibe treatment also induces a complete resistance to cholesterol gallstone formation and nonalcoholic fatty liver disease (NAFLD) in addition to preventing hypercholesterolemia in mice on a Western diet. Because chylomicrons are the vehicles with which the enterocytes transport cholesterol and fatty acids into the body, ezetimibe could prevent these two most prevalent hepatobiliary diseases possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver. It is highly likely that there is an intestinal and hepatic cross-talk through the chylomicron pathway. Therefore, understanding the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine could offer an efficacious novel approach to the prevention and the treatment of cholesterol gallstones and NAFLD.
44 citations
TL;DR: Recent progress in understanding the regulation of PON1 expression in hepatocytes is summarized, which shows that pharmacological modulation of Pon1 activity or P ON1 gene expression could constitute a useful approach for preventing atherosclerosis.
Abstract: Serum paraoxonase-1 (PON1) is a member of the paraoxonases family (PON1, PON2, and PON3). PON1 is synthesized and secreted by the liver, and in circulation it is associated with HDL. PON1 has antioxidative properties, which are associated with the enzyme's capability to decrease oxidative stress in atherosclerotic lesions and to attenuate atherosclerosis development. Epidemiological evidence demonstrates that low PON1 activity is associated with increased risk of cardiovascular events and cardiovascular disease and is an independent risk factor for coronary artery disease. Therefore, pharmacological modulation of PON1 activity or PON1 gene expression could constitute a useful approach for preventing atherosclerosis. A primary determinant of serum PON1 levels is the availability of the enzyme for release by the liver, the principal site of PON1 production. Together with the enzyme secretion rate, enzymatic turnover, and protein stability, the level of PON1 gene expression is a major determinant of PON1 status. This paper summarizes recent progress in understanding the regulation of PON1 expression in hepatocytes.
38 citations
TL;DR: Understanding the mechanisms underlying the involvement of nuclear receptors in the pathogenesis of nonalcoholic fatty liver disease may offer targets for the development of new treatments for this liver disease.
Abstract: Nuclear receptors comprise a superfamily of ligand-activated transcription factors that are involved in important aspects of hepatic physiology and pathophysiology. There are about 48 nuclear receptors in the human. These nuclear receptors are regulators of many hepatic processes including hepatic lipid and glucose metabolism, bile acid homeostasis, drug detoxification, inflammation, regeneration, fibrosis, and tumor formation. Some of these receptors are sensitive to the levels of molecules that control lipid metabolism including fatty acids, oxysterols, and lipophilic molecules. These receptors direct such molecules to the transcriptional networks and may play roles in the pathogenesis and treatment of nonalcoholic fatty liver disease. Understanding the mechanisms underlying the involvement of nuclear receptors in the pathogenesis of nonalcoholic fatty liver disease may offer targets for the development of new treatments for this liver disease.
37 citations
TL;DR: Current understanding about the pleiotropic role of SHP is examined, and principal metabolic aspects connected with SHP function will be also discussed.
Abstract: Nuclear receptors (NRs) comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. Small heterodimer partner (SHP; NR0B2) is a unique orphan NR lacking a DNA-binding domain but contains a putative ligand-binding domain. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. About half of all mammalian NRs and several transcriptional coregulators can interact with SHP. The SHP-mediated repression of target transcription factors includes at least three mechanisms including direct interference with the C-terminal activation function 2 (AF2) coactivator domains of NRs, recruitment of corepressors, or direct interaction with the surface of NR/transcription factors. Future research must focus on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities. Current understanding about the pleiotropic role of SHP is examined in this paper, and principal metabolic aspects connected with SHP function will be also discussed.
37 citations
TL;DR: This study identifies new genetic variants that predict additional PON1 arylesterase (AREase) activity and determines if these variants predict carotid artery disease (CAAD).
Abstract: Background. Paraoxonase 1 (PON1) enzymatic activity has been consistently predictive of cardiovascular disease, while the genotypes at the four functional polymorphisms at PON1 have not. The goal of this study was to identify additional variation at the PON gene cluster that improved prediction of PON1 activity and determine if these variants predict carotid artery disease (CAAD). Methods. We considered 1,328 males in a CAAD cohort. 51 tagging single-nucleotide polymorphisms (tag SNPs) across the PON cluster were evaluated to determine their effects on PON1 activity and CAAD status. Results. Six SNPs (four in PON1 and one each in PON2/3) predicted PON1 arylesterase (AREase) activity, in addition to the four previously known functional SNPs. In total, the 10 SNPs explained 30.1% of AREase activity, 5% of which was attributable to the six identified predictive SNPs. We replicate rs854567 prediction of 2.3% of AREase variance, the effects of rs3917510, and a PON3 haplotype that includes rs2375005. While AREase activity strongly predicted CAAD, none of the 10 SNPs predicting AREase predicted CAAD. Conclusions. This study identifies new genetic variants that predict additional PON1 AREase activity. Identification of SNPs associated with PON1 activity is required when evaluating the many phenotypes associated with genetic variation near PON1.
TL;DR: It is suggested that analyses and comparisons of mycoplasma polar lipids may serve as a novel and useful tool for classification, and the finding that a terminal phosphocholine containing glycolipids of M. fermentans with host cells is markedly stimulated by lyso-ether lipids are important steps toward understanding the molecular mechanisms of M.'s fermentans pathogenicity.
Abstract: The de novo synthesized polar lipids of Mycoplasma species are rather simple, comprising primarily of the acidic glycerophospholipids PG and CL. In addition, when grown in a medium containing serum, significant amounts of PC and SPM are incorporated into the mycoplasma cell membrane although these lipids are very uncommon in wall-covered bacteria. The exogenous lipids are either incorporated unchanged or the PC incorporated is modified by a deacylation-acylation enzymatic cycle to form disaturated PC. Although their small genome, in some Mycoplasma species, other genes involved in lipid biosynthesis were detected, resulting in the synthesis of a variety of glycolipis, phosphoglycolipids and ether lipids. We suggest that analyses and comparisons of mycoplasma polar lipids may serve as a novel and useful tool for classification. Nonetheless, to evaluate the importance of polar lipids in mycoplasma, further systematic and extensive studies on more Mycoplasma species are needed. While studies are needed to elucidate the role of lipids in the mechanisms governing the interaction of mycoplasmas with host eukaryotic cells, the finding that a terminal phosphocholine containing glycolipids of M. fermentans serves both as a major immune determinants and as a trigger of the inflammatory responses, and the findings that the fusogenicity of M. fermentans with host cells is markedly stimulated by lyso-ether lipids, are important steps toward understanding the molecular mechanisms of M. fermentans pathogenicity.
TL;DR: The fatty acids profiles of Tunisian Opuntia ficus indica seeds (spiny and thornless form) were investigated and results of supercritical carbon dioxide (SC-CO2) and soxhlet n-hexane extract were compared.
Abstract: The fatty acids profiles of Tunisian Opuntia ficus indica seeds (spiny and thornless form) were investigated. Results of supercritical carbon dioxide (SC-CO2) and soxhlet n-hexane extract were compared. Quantitatively, the better yield was obtained through soxhlet n-hexane: 10.32% (spiny) and 8.91% (thornless) against 3.4% (spiny) and 1.94% (thornless) by SC-CO2 extract (T = 40°C, 𝑃=180 bar, time = 135 mn, CO2 flow rate = 15 mL·s−1). Qualitatively, the main fatty acids components were the same for the two types of extraction. Linoleic acid was the major compound, SC-CO2: 57.60% (spiny), 59.98% (thornless), soxhlet n-hexane: 57.54% (spiny), 60.66% (thornless), followed by oleic acid, SC-CO2: 22.31% (spiny), 22.40% (thornless), soxhlet n-hexane: 25.28% (spiny), 20.58% (thornless) and palmitic acid, SC-CO2: 14.3% (spiny), 12.92% (thornless), soxhlet n-hexane: 11.33% (spiny), 13.08% (thornless). The SC-CO2 profiles fatty acids showed a richness with other minority compounds such as C20:1, C20:2, and C22.The seeds oil was highly unsaturated (US = 4.44–5.25), and the rising temperatures donot affect the selectivity of fatty acids extract by SC-CO2: US = 4.44 (T = 40°C) and 4.13 (T = 70°C).
TL;DR: Human AGP binding characteristics of the LPS from a number of pathogenic Gram-negative bacteria are characterized, consistent with the role of AGP in the binding and transport of LPS in plasma during acute-phase inflammatory responses to invading Gram- negative bacteria.
Abstract: The ability of AGP to bind circulating lipopolysaccharide (LPS) in plasma is believed to help reduce the proinflammatory effect of bacterial lipid A molecules Here, for the first time we have characterized human AGP binding characteristics of the LPS from a number of pathogenic Gram-negative bacteria: Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia, Pseudomonas aeruginosa, and Serratia marcescens The binding affinity and structure activity relationships (SAR) of the AGP-LPS interactions were characterized by surface plasma resonance (SPR) In order to dissect the contribution of the lipid A, core oligosaccharide and O-antigen polysaccharide components of LPS, the AGP binding affinity of LPS from smooth strains, were compared to lipid A, Kdo2-lipid A, R(a), R(d), and R(e) rough LPS mutants The SAR analysis enabled by the binding data suggested that, in addition to the important role played by the lipid A and core components of LPS, it is predominately the unique species- and strain-specific carbohydrate structure of the O-antigen polysaccharide that largely determines the binding affinity for AGP Together, these data are consistent with the role of AGP in the binding and transport of LPS in plasma during acute-phase inflammatory responses to invading Gram-negative bacteria
TL;DR: The results suggest that the anti-oxidative and anti-inflammatory functions of PON2 and PON3 are an important part of the innate defense system against P. aeruginosa infections.
Abstract: The pathogen Pseudomonas aeruginosa causes serious damage in immunocompromised patients by secretion of various virulence factors, among them the quorum sensing N-(3-oxododecanoyl)-L-homoserine lactone (3OC12) and the redox-active pyocyanin (PCN). Paraoxonase-2 (PON2) may protect against P. aeruginosa infections, as it efficiently inactivates 3OC12 and diminishes PCN-induced oxidative stress. This defense could be circumvented because 3OC12 mediates intracellular Ca2+-rise in host cells, which causes rapid inactivation and degradation of PON2. Importantly, we recently found that the PON2 paralogue PON3 prevents mitochondrial radical formation. Here we investigated its role as additional potential defense mechanism against P. aeruginosa infections. Our studies demonstrate that PON3 diminished PCN-induced oxidative stress. Moreover, it showed clear anti-inflammatory potential by protecting against NF-κB activation and IL-8 release. The latter similarly applied to PON2. Furthermore, we observed a Ca2+-mediated inactivation and degradation of PON3, again in accordance with previous findings for PON2. Our results suggest that the anti-oxidative and anti-inflammatory functions of PON2 and PON3 are an important part of our innate defense system against P. aeruginosa infections. Furthermore, we conclude that P. aeruginosa circumvents PON3 protection by the same pathway as for PON2. This may help identifying underlying mechanisms in order to sustain the protection afforded by these enzymes.
TL;DR: It is shown here that these bioactive compounds are major constituents of several aerial parts of olive tree, a crop exploited so far almost exclusively for its fruit and oil.
Abstract: Plant triterpenoids represent a large and structurally diverse class of natural products. A growing interest has been focused on triterpenoids over the past decade due to their beneficial effects on human health. We show here that these bioactive compounds are major constituents of several aerial parts (floral bud, leaf bud, stem, and leaf) of olive tree, a crop exploited so far almost exclusively for its fruit and oil. O. europaea callus cultures were analyzed as well. Twenty sterols and twenty-nine nonsteroidal tetra- and pentacyclic triterpenoids belonging to seven types of carbon skeletons (oleanane, ursane, lupane, taraxerane, taraxastane, euphane, and lanostane) were identified and quantified by GC and GC-MS as free and esterified compounds. The oleanane-type compounds, oleanolic acid and maslinic acid, were largely predominant in all the organs tested, whereas they are practically absent in olive oil. In floral buds, they represented as much as 2.7% of dry matter. In callus cultures, lanostane-type compounds were the most abundant triterpenoids. In all the tissues analyzed, free and esterified triterpene alcohols exhibited different distribution patterns of their carbon skeletons. Taken together, these data provide new insights into largely unknown triterpene secondary metabolism of Olea europaea.
TL;DR: It is proposed that alterations of mitochondrial bioenergetics in the heart result in decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol, resulting in lipotoxicity and increasing the cardiovascular risk in the menopausal women.
Abstract: Menopause is a consequence of the normal aging process in women. This fact implies that the physiological and biochemical alterations resulting from menopause often blur with those from the aging process. It is thought that menopause in women presents a higher risk for cardiovascular disease although the precise mechanism is still under discussion. The postmenopause lipid profile is clearly altered, which can present a risk factor for cardiovascular disease. Due to the role of mitochondria in fatty acid oxidation, alterations of the lipid profile in the menopausal women will also influence mitochondrial fatty acid oxidation fluxes in several organs. In this paper, we propose that alterations of mitochondrial bioenergetics in the heart, consequence from normal aging and/or from the menopausal process, result in decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol, resulting in lipotoxicity and increasing the cardiovascular risk in the menopausal women.
TL;DR: Results suggested that a chronic low dose of dietary CLA increases liver mass and lipid accumulation due to activation of lipogenesis and insufficient induction of LCFA oxidation and VLDL assembly/secretion.
Abstract: Dietary trans-10, cis-12-conjugated linoleic acid (trans-10, cis-12-CLA) fed to obese and nonobese rodents reduces body fat but leads to greater liver mass due to steatosis. The molecular mechanisms accompanying such responses remain largely unknown. Our study investigated the effects of chronic low trans-10, cis-12-CLA supplementation on hepatic expression of 39 genes related to metabolism, inflammation, and stress in growing mice. Feeding a diet supplemented with 0.3% trans-10, cis-12-CLA (wt/wt basis) for 6 weeks increased liver mass and concentration of long-chain fatty acids (LCFAs) in liver, while adipose tissue mass decreased markedly. These changes were accompanied by greater expression of genes involved in LCFA uptake (Cd36), lipogenesis, and triacylglycerol synthesis (Acaca, Gpam, Scd, Pck1, Plin2). Expression of these genes was in line with upregulation of the lipogenic transcription factor Srebf1. Unlike previous studies where higher >0.50% of the diet) doses of trans-10, cis-12-CLA were fed, we found greater expression of genes associated with VLDL assembly/secretion (Mttp, Cideb), ketogenesis (Hmgcs2, Bdh1), and LCFA oxidation (Acox1, Pdk4) in response to trans-10, cis-12-CLA. Dietary CLA, however, did not affect inflammation- and stress-related genes. Results suggested that a chronic low dose of dietary CLA increases liver mass and lipid accumulation due to activation of lipogenesis and insufficient induction of LCFA oxidation and VLDL assembly/secretion.
TL;DR: In hyperlipidemic adults who were treated with lipid-lowering drugs, the consumption of additional 3 eggs per day to their regular diet will increase the level of HDL-ch cholesterol and decrease the ratio of LDL-cholesterol to HDL- cholesterol.
Abstract: Background. Limiting egg consumption to avoid high cholesterolemia is recommended to reduce risk of cardiovascular disease. However, recent evidences suggest that cholesterol from diet has limited influence on serum cholesterol. Objective. To assess the effect of egg consumption on lipid profiles in hyperlipidemic adults treated with lipid-lowering drugs. Material and Method. Sixty hyperlipidemic subjects, mean age of 61 years, who had been treated with lipid-lowering drugs. Every subject was assigned to consume additional 3 eggs per day with their regular diet for 12 weeks. Measurements for lipid profiles and body compositions were performed. Results. An additional consumption of 3 eggs per day for 12 weeks increased HDL-cholesterol by 2.46±6.81 mg/dL (P<0.01) and decreased LDL-cholesterol to HDL-cholesterol ratio by 0.13±0.46 (P<0.05). No significant changes were found in other lipid profiles. Body weight and body mass index were significantly increased at 12th week by 0.52±1.83 kg and 0.31±0.99 kg/m2, respectively (P<0.05). Conclusion. In hyperlipidemic adults who were treated with lipid-lowering drugs, the consumption of additional 3 eggs per day to their regular diet will increase the level of HDL-cholesterol and decrease the ratio of LDL-cholesterol to HDL-cholesterol.
TL;DR: The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet, and showed a lower PON 1 activity in serum of both groups of celiac patients with respect to control subjects.
Abstract: Paraoxonase-1 (PON1) plays an antioxidant and anti-inflammatory role. Aim of the study was to investigate the alteration of paraoxonase-1 activity in celiac disease (CD), an intestinal disorder characterized by toxic injury exerted by gluten peptides. Activities of PON1, levels of biochemical markers of lipid peroxidation and total antioxidant capacity were evaluated in serum obtained from 27 celiac patients (11 at diagnosis, 16 treated with gluten free diet) and 25 healthy subjects. Moreover, the serum susceptibility of Cu2+-induced lipid peroxidation was investigated in controls and patients. The results showed a lower PON1 activity in serum of both groups of celiac patients with respect to control subjects. PON1 activity in CD was related with markers of disease severity and was negatively correlated with the levels of lipid hydroperoxide and with the susceptibility of serum to lipid peroxidation induced in vitro by metal ions. The alteration of PON1 activity and markers of lipid peroxidation realized at lower extent in patients who were on a gluten-free diet.
TL;DR: LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic Atherogenic HbA1c, which suggests a role for serum HDL and Pon1 in LA- 13OOH accumulation.
Abstract: Human carotid plaque components interact directly with circulating blood elements and thus they might affect each other. We determined plaque paraoxonase1 (PON1) hydrolytic-catalytic activity and compared plaque and blood levels of lipids, HDL, PON1, and HbA1c, as well as plaque-oxidized lipids in symptomatic and asymptomatic patients. Human carotid plaques were obtained from symptomatic and asymptomatic patients undergoing routine endarterectomy, and the lesions were ground and extracted for PON activity and lipid content determinations. Plaque PONs preserved paraoxonase, arylesterase, and lactonase activities. The PON1-specific inhibitor 2-hydroxyquinoline almost completely inhibited paraoxonase and lactonase activities, while only moderately inhibiting arylesterase activity. Oxysterol and triglyceride levels in plaques from symptomatic and asymptomatic patients did not differ significantly, but plaques from symptomatic patients had significantly higher (135%) linoleic acid hydroperoxide (LA-13OOH) levels. Their serum PON1 activity, cholesterol and triglyceride levels did not differ significantly, but symptomatic patients had significantly lower (28%) serum HDL levels and higher (18%) HbA1c levels. Thus LA-13OOH, a major atherogenic plaque element, showed significant negative correlations with serum PON1 activity and HDL levels, and a positive correlation with the prodiabetic atherogenic HbA1c. Plaque PON1 retains its activity and may decrease plaque atherogenicity by reducing specific oxidized lipids (e.g., LA-13OOH). The inverse correlation between plaque LA-13OOH level and serum HDL level and PON1 activity suggests a role for serum HDL and PON1 in LA-13OOH accumulation.
TL;DR: Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation, and emerging data suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease.
Abstract: Cholesterol gallstone disease is highly prevalent in western countries, particularly in women and some specific ethnic groups. The formation of water-insoluble cholesterol crystals is due to a misbalance between the three major lipids present in the bile: cholesterol, bile salts, and phospholipids. Many proteins implicated in biliary lipid secretion in the liver are regulated by several transcription factors, including nuclear receptors LXR and FXR. Human and murine genetic, physiological, pathophysiological, and pharmacological evidence is consistent with the relevance of these nuclear receptors in gallstone formation. In addition, there is emerging data that also suggests a role for estrogen receptor ESR1 in abnormal cholesterol metabolism leading to gallstone disease. A better comprehension of the role of nuclear receptor function in gallstone formation may help to design new and more effective therapeutic strategies for this highly prevalent disease condition.
TL;DR: Based on the G2E6 polar mutations, an engineered variant of PON1 with high activity against cyclosarin (GF) is “humanized” and found that it was still very active against GF with much greater similarity to the human sequence.
Abstract: Paraoxonase-1 (PON1) is a serum protein, the activity of which is related to susceptibility to cardiovascular disease and intoxication by organophosphorus (OP) compounds. It may also be involved in innate immunity, and it is a possible lead molecule in the development of a catalytic bioscavenger of OP pesticides and nerve agents. Human PON1 expressed in E. coli is mostly found in the insoluble fraction, which motivated the engineering of soluble variants, such as G2E6, with more than 50 mutations from huPON1. We examined the effect on the solubility, activity, and stability of three sets of mutations designed to solubilize huPON1 with fewer overall changes: deletion of the N-terminal leader, polar mutations in the putative HDL binding site, and selection of the subset of residues that became more polar in going from huPON1 to G2E6. All three sets of mutations increase the solubility of huPON1; the HDL-binding mutant has the largest effect on solubility, but it also decreases the activity and stability the most. Based on the G2E6 polar mutations, we "humanized" an engineered variant of PON1 with high activity against cyclosarin (GF) and found that it was still very active against GF with much greater similarity to the human sequence.
TL;DR: The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL and five novel loci merit further investigation.
Abstract: The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.
TL;DR: In this paper, the effects of dietary oil and feed withdrawal treatments on fatty acid composition of phospholipids of triacylglycerol in pars costalis diaphragmatis muscle and subcutaneous fat from the brisket were determined.
Abstract: This study was designed to determine the effects of dietary oil and feed withdrawal treatments on fatty acid composition of phospholipids of triacylglycerol in pars costalis diaphragmatis muscle and subcutaneous fat from the brisket. A 2 × 3 factorial experiment was conducted with crossbred steers with an initial body weight of 280.5 ± 5.8 kg. Steers were fed either a control or an oil containing diet where 5% of the control diet was replaced with an equal mixture sunflower and flax oil while undergoing one of three feed withdrawal treatments: no withdrawal, a single 48 h withdrawal before initiation of fattening at one year of age, or 48 h withdrawal at 8 wk intervals from weaning to initiation of fattening. At time of processing samples of muscle and fat were obtained and analyzed to determine fatty acid composition. Disproportionate distribution of the fatty acids was observed by diet, feed withdrawal regimen and whether the sample was from muscle or fat. Differences are discussed in detail, and our data suggests a special function for the fatty acids that accumulate in specific positions of the triacylglycerol due to treatment.
TL;DR: The objectives of this special issue on paraoxonases (PONs) are to bring the latest aspects of para oxonases research on the genetics, biochemistry, cell biology, and structural biology of PONs to the public.
Abstract: The objectives of this special issue on paraoxonases (PONs) are to bring the latest aspects of paraoxonases (PON 1, 2, 3) research on the genetics, biochemistry, cell biology, and structural biology of PONs. The issue also addresses the role of PONs in human diseases (cardiovascular, cancer, renal failure, and gastrointestinal disorders). Inflammatory and oxidative stress-related diseases, such as diabetes or rheumatoid arthritis are also favorably affected by PON. PONs also provide microbial protection by hydrolyzing bacterial quorum lactone. The pivotal role of the PON family in a variety of inflammatory diseases, and in preventing the toxicity of organophosphorus insecticides and nerve agents, has made PONs an interesting target for both clinicians and scientists alike. Research into the paraoxonase family of enzymes has increased dramatically, especially following the initiation of the paraoxonase conferences. Five international conferences on paraoxonases were organized between 2004 and 2012, where the PON scientific community gathered to discuss PONs research achievements and future scientific directions. Columbus (OH). According to PubMed, only few PON papers were published before 1980. From 1980 till these days, about 3000 papers were published. The PONs gene cluster contains three adjacent gene members, and all of the three PON genes share high sequence, indentify a similar β propeller protein structure, and hydrolyze esterase/lactonase activities. PONs play a clear protective role against cardiovascular diseases. Major cardioprotective PON characteristics include, beside their potent antioxidant properties, the following: for PON 1, favorable effects on macrophage cholesterol metabolism, for PON 2, attenuation of macrophage triglyc-eride accumulation, and for PON 3, improvement in bile acids metabolism. Human serum HDL-associated paraoxonase (PON1) is an esterase that possesses cardiovascular protective properties which result in the following antiatherogenic functions: (1) attenuated oxidative stress in serum, in lipopro-teins, in macrophages, and in atherosclerotic lesions; (2) decreased oxidized LDL uptake by macrophages; (3) inhibited macrophage cholesterol biosynthesis rate; (4) stimulated HDL-mediated cholesterol efflux from macrophages. Major PON1 inactivators (and reversal of their action) include (1) oxidative stress (and reversal effect by antioxi-dants such as the pomegranate polyphenolic tannin puni-calagin); (2) high cholesterol (and reversal effect by statins); (3) high triglycerides (and reversal effect by fibrates); (4) high glucose (and reversal effect by insulin). Macrophage PON2 regulation (as related to atheroge-nesis) differs from that of serum PON 1 in the following characteristics: (1) stimulation (not inhibition as shown for PON1) by oxidative stress and also by anti oxidants (like PON1); (2) stimulation by high …
TL;DR: It is found that individuals carrying PON1 55 LL genotype are significantly more represented among AMI patients affected by NSTEMI; moreover, the patients carrying LL genotypes showed significantly higher levels of myoglobin in comparison to LM + MM carriers patients.
Abstract: It is well known that serum paraoxonase (PON1) plays an important role in the protection of LDL from oxidation. PON1 55 polymorphism is currently investigated for its possible involvement in cardiovascular diseases. The objective of our study is to verify if PON1 55 polymorphism is associated with risk of acute coronary syndrome (ACS) and with biochemical myocardial ischemia markers, such as troponin I, creatine kinase (CK)-MB, myoglobin, and C-reactive protein. We analysed PON1 55 polymorphism in a total of 440 elderly patients who underwent an ACS episode: 98 patients affected by unstable angina (UA), 207 AMI (acute myocardial infarction) patients affected by STEMI (ST elevation), and 135 AMI patients affected by NSTEMI (no ST elevation). We found that individuals carrying PON1 55 LL genotype are significantly more represented among AMI patients affected by NSTEMI; moreover, the patients carrying LL genotype showed significantly higher levels of myoglobin in comparison to LM + MM carriers patients. Our study suggests that PON1 55 polymorphism could play a role in the pathogenesis of cardiac ischemic damage. In particular, the significant association between PON1 55 LL genotype and the occurrence of a NSTEMI may contribute to improve the stratification of the cardiovascular risk within a population.
TL;DR: The identification of bile acid-activated nuclear receptor farnesoid X receptor (FXR) and cell surface G-protein-coupled receptor TGR5 has significantly advanced the authors' understanding on how bile Acid signaling regulates cellular metabolism in health and disease.
Abstract: In this special issue of Journal of Lipids, we acknowledge the contributions by several experts offering timely perspectives on the complex interactions between bile acids and nuclear receptors (NRs) on lipid metabolism and liver diseases at different levels and contexts in the body.
NRs are found within the interior of cells and are defined as ligand-activated transcriptional regulators of several key aspects of body physiology and pathophysiology. NRs regulate gene transcription through interaction with cellular coactivators and corepressors. In the liver, NRs play a key role in a large variety of metabolic processes such as cholesterol, bile acid, fatty acid, and glucose homeostasis, as well as drug disposition. Also, additional critical processes involving the pathophysiology of liver diseases—inflammation and fibrosis, regeneration, cell differentiation, and tumor formation—are modulated by NRs. Of note, NRs are or might soon become drug targets. Despite the huge accumulation of knowledge in the field, the true comprehension of interactions between bile acids and NRs on lipid metabolism and hepatobiliary diseases has remained elusive. Thus continuous efforts are being made to understand the molecular functions of NRs, the significance of bile acid-controlled signaling pathways, and interactions of NRs on a number of metabolic and hepatic diseases.
The paper of T. Li and Y. L. Chiang is focused on the role of bile acid signaling in the regulation of glucose and lipid metabolism. Besides their detergent properties and key physiological functions, bile acids are also acting as potent metabolic regulators of glucose and lipid homeostasis. The identification of bile acid-activated nuclear receptor farnesoid X receptor (FXR) and cell surface G-protein-coupled receptor TGR5 has significantly advanced our understanding on how bile acid signaling regulates cellular metabolism in health and disease. Thus, novel therapeutic strategies can be envisioned which target bile acid metabolism for the treatment of metabolic disorders such as obesity, insulin resistance, and the metabolic syndrome.
NRs comprise one of the most abundant classes of transcriptional regulators of metabolic diseases and have emerged as promising pharmaceutical targets. The paper by G. Garruti et al. deals with the myriad roles of small heterodimer partner (SHP), a unique orphan nuclear receptor lacking a DNA-binding domain, but containing a putative ligand-binding domain. About half of mammalian NRs and several transcriptional coregulators can interact with SHP. SHP is a transcriptional regulator affecting multiple key biological functions and metabolic processes including cholesterol, bile acid, and fatty acid metabolism, as well as reproductive biology and glucose-energy homeostasis. In humans, studies are emerging on the association of SHP genetic variation with birth weight, high body mass index, obesity, insulin resistance, and diabetes. Future research must be focused on synthetic ligands acting on SHP as a potential therapeutic target in a series of metabolic abnormalities.
One important issue in lipidology is the understanding of the molecular mechanisms whereby cholesterol and fatty acids are absorbed from the intestine and are transported to the liver. The cholesterol absorption inhibitor ezetimibe can significantly reduce plasma total and LDL cholesterol concentrations by inhibiting the Niemann-Pick C1-like 1 protein (NPC1L1), an intestinal sterol influx transporter that can actively facilitate the uptake of cholesterol for intestinal absorption. The paper by O. de Bari et al. emphasizes the novel concept that, ezetimibe treatment also induces a complete resistance to two frequent metabolic abnormalities, namely, cholesterol gallstones and nonalcoholic fatty liver disease (NAFLD). Furthermore, it prevented hypercholesterolemia in mice on a Western diet. This model has high translational value and points to a key role for chylomicrons, the natural lipid carriers used by enterocytes to transport cholesterol and fatty acids into the body. The hypothesis that ezetimibe could prevent two prevalent hepatobiliary diseases (i.e., cholesterol cholelithiasis and liver steatosis) possibly through the regulation of chylomicron-derived cholesterol and fatty acid metabolism in the liver is discussed here.
Because several proteins are implicated in determining biliary lipid secretion in the liver and are regulated by several transcription factors, including nuclear receptors liver X receptor (LXR) and FXR, the paper by M. C. Vazquez et al. is focused on molecular mechanisms underlying the link between nuclear receptor function and the formation of cholesterol gallstones. A potent role for estrogen receptors in the pathogenesis of cholesterol gallstone disease, involving both genomic and nongenomic activation of signaling pathways, is discussed. Evidence in this respect is heavily supported by human and murine genetic, physiological, pathophysiological, and pharmacological studies. Indeed, expanding the knowledge about the role of NRs in gallstone formation will certainly lead to the discovery of novel and more effective therapeutic strategies in a typical example of a metabolic “mass disease,” that is, cholesterol cholelithiasis.
In the wide field of lipopathy, NAFLD is currently evolving as the most common liver disease worldwide, with potential costly and severe sequelae, including liver cirrhosis and hepatocellular carcinoma. In his paper, M. Fuchs underscored the concept that NAFLD not only represents an insulin resistance state characterized by a cluster of dysmetabolic cardiovascular risk factors, but also represents an independent risk factor for cardiovascular diseases. Of note, the bile acid-activated nuclear receptor FXR has been shown to play a role not only in bile acid but also in lipid (cholesterol and triglyceride) metabolism and glucose homeostasis. Specific targeting of FXR may be an elegant and very effective way to readjust dysregulated nuclear receptor-mediated metabolic pathways. Activation of FXR may result in not only beneficial actions but also potential undesirable side effects. One example is the (still unpredictable) balance between pro- and anti-atherogenic effects of FXR activation.
J. A. Lopez-Velazquez et al. described the important role of several NRs in the liver as regulators of several critical metabolic steps involved in the pathogenesis of NAFLD. Such crucial steps include fat storage, export, uptake, oxidation, and lipolysis. A whole family of NRs is targeted by many ligands controlling lipid metabolism including fatty acids, oxysterols, and lipophilic molecules. Understanding the molecular mechanisms underlying the involvement of NRs in the pathogenesis of NAFLD may, therefore, offer targets for the development of new treatments of one of the most frequent chronic liver diseases worldwide.
In their paper, R. Mullenbach et al. provided an update on genetic variants of NRs involved in regulating important aspects of liver metabolism. One such aspect is the application of NRs in genetic diagnosis of monogenic (Mendelian) liver diseases and their uses in clinical diagnosis. Moreover, a role of NR polymorphisms in common diseases can be anticipated, linking regulatory networks to complex and variable phenotypes. Technical advances contribute to the restless expansion of knowledge and include transgenic animal models, expression quantitative trait loci (eQTL) mapping, and genomewide association studies (GWASs). Thus, it is highly likely that personal genome information might eventually be able to predict a variety of risks associated with an individual's lifestyle such as high fat diet and alcohol as well as susceptibility to infectious liver diseases such as hepatitis B or C.
Menopause is a consequence of the normal aging process in women and it is thought that menopause is associated with a higher risk for cardiovascular diseases. Indeed, the post-menopause lipid profile is often altered, which represents a risk factor for cardiovascular diseases. The paper by P. J. Oliveira et al. reports on the mechanisms linking alterations of mitochondrial bioenergetics in the heart, as a consequence from normal aging and/or from the menopausal process, to decreased fatty acid oxidation and accumulation of fatty acid intermediates in the cardiomyocyte cytosol. Such lipotoxic consequences might represent the important link to increased cardiovascular risk in the menopausal women.
In conclusion, the field of lipidology has become even more complex and exciting when considering that the discovery of NRs and their pleiotropic functions have opened the way to multidimensional, multidisciplinary and translational studies. Since NRs are involved in virtually all physiological functions, understanding how NRs work is therefore essential to explain the complex pathophysiological mechanisms underlying liver and extrahepatic diseases. A new era in which NRs will represent valid therapeutic targets for several disorders is hopefully approaching.
Lastly, we hope that this contribution will also help both young and experienced investigators in their daily difficult task to expand their research in the field of experimental and clinical lipidology in health and disease.
David Q.-H. Wang
Brent A. Neuschwander-Tetri
Piero Portincasa
William M. Pandak
TL;DR: This assay, developed similarly but independently from the approach by Don and Rosen (2008), is a fluorescence-based ceramide kinase assay, using N-[7-(4-nitrobenz-2-oxa-1,3-diazole)]-6-aminohexanoyl-sphingenine (NBD-C6-ceramide) as substrate, suitable for high-throughput screening to search for CERK modulators.
Abstract: Ceramide kinase (CERK) has been implicated in important cellular processes such as inflammation and apoptosis. Its activity is usually measured using radiolabeled ceramide or [γ-32P]-ATP, followed by extraction, thin-layer chromatography, and detection of the formed labeled ceramide-1-phosphate. To eliminate the use of radioactivity, we developed similarly but independently from the approach by Don and Rosen (2008), a fluorescence-based ceramide kinase assay, using N-[7-(4-nitrobenz-2-oxa-1,3-diazole)]-6-aminohexanoyl-sphingenine (NBD-C6-ceramide) as substrate. Its Km value (4 μM) was comparable to that of N-hexanoyl-sphingenine (C6-ceramide). The produced fluorescent NBD-C6-ceramide-1-phosphate was captured by means of solid-phase extraction on an aminopropyl phase, resulting in a fast and sensitive CERK measurement. By performing this assay in a 96-well format, it is also suitable for high-throughput screening (HTS) to search for CERK modulators. A limited screen revealed that some protein kinase inhibitors (e.g., U-0126; IC50 4 μM) and ceramide analogues (e.g., fenretinide, AMG-9810; IC50 1.1 μM) affect CERK in vitro.
TL;DR: This review recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic (“Mendelian”) liver disease and their use in clinical diagnosis and offers perspectives and cautionary advice for their use as handles towards diagnosis and treatment.
Abstract: This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic (“Mendelian”) liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment.