共查询到20条相似文献,搜索用时 31 毫秒
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Simon JS Karnoub MC Devlin DJ Arreaza MG Qiu P Monks SA Severino ME Deutsch P Palmisano J Sachs AB Bayne ML Plump AS Schadt EE 《Genomics》2005,86(6):648-656
Niemann-Pick C1-like 1 (NPC1L1) is an intestinal cholesterol transporter and the molecular target of ezetimibe, a cholesterol absorption inhibitor demonstrated to reduce LDL-cholesterol (LDL-C) both as monotherapy and when co-administered with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Interestingly, significant interindividual variability has been observed for rates of intestinal cholesterol absorption and LDL-C reductions at both baseline and post ezetimibe treatment. To test the hypothesis that genetic variation in NPC1L1 could influence the LDL-C response to ezetimibe, we performed extensive resequencing of the gene in 375 apparently healthy individuals and genotyped hypercholesterolemic patients from clinical trial cohorts. No association was observed between NPC1L1 single-nucleotide polymorphism and baseline cholesterol. However, significant associations to LDL-C response to treatment with ezetimibe were observed in patients treated with ezetimibe in two large clinical trials. Our data demonstrate that DNA sequence variants in NPC1L1 are associated with an improvement in response to ezetimibe pharmacotherapy and suggest that detailed analysis of genetic variability in clinical trial cohorts can lead to improved understanding of factors contributing to variable drug response. 相似文献
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Kaddurah-Daouk R Baillie RA Zhu H Zeng ZB Wiest MM Nguyen UT Wojnoonski K Watkins SM Trupp M Krauss RM 《PloS one》2011,6(10):e25482
Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy. 相似文献
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L. Jakulj M. N. Vissers A. K. Groen B. A. Hutten D. Lutjohann E. P. Veltri J. J. P. Kastelein 《Journal of lipid research》2010,51(4):755-762
Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (β = 0.020, P = 0.587 for campesterol/TC and β<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations. 相似文献
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The bile acid-activated nuclear receptor farnesoid X receptor (FXR) plays an important role in lipid and glucose metabolism, and in addition, it regulates multiple drug transporters involved in statin disposition. We examined whether a functional single nucleotide polymorphism (SNP) in FXR (-1G>T) influenced the lipid-lowering effect of rosuvastatin. In 385 Chinese patients with hyperlipidemia who had been treated with rosuvastatin 10 mg daily for at least 4 weeks, the association between the FXR -1G>T SNP and lipid response to rosuvastatin was analyzed. The FXR -1G>T SNP was not associated with baseline lipids but was significantly associated with the LDL cholesterol (LDL-C) and total cholesterol response to rosuvastatin. Carriers of the T-variant allele (GT+TT = 68+3) had 4.4% (95% CI: 1.2, 7.5%, P = 0.006) and 2.6% (95% CI: 0.3, 5.0%; P < 0.05) greater reductions in LDL-C and total cholesterol, respectively, compared with those with homozygous wild-type alleles. The association between the FXR polymorphism and the LDL-C response to rosuvastatin remained significant after adjusting for other covariants. This association of the variant allele of the FXR -1G>T polymorphism with a greater LDL-C response to rosuvastatin may suggest that this polymorphism influences the expression of the hepatic efflux transporters involved in biliary excretion of rosuvastatin. 相似文献
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ATP binding cassette transporter G5 and G8 genotypes and plasma lipoprotein levels before and after treatment with atorvastatin 总被引:2,自引:0,他引:2
Kajinami K Brousseau ME Nartsupha C Ordovas JM Schaefer EJ 《Journal of lipid research》2004,45(4):653-656
The mechanisms responsible for interindividual variation in response to statin therapy remain uncertain. It has been shown that hepatic cholesterol synthesis is associated with ATP binding cassette transporter G5 and G8 (ABCG5/8) activities. To test the hypothesis that genetic variation in ABCG5/8 might influence the plasma lipid response to statin therapy, we examined five nonsynonymous polymorphisms at the ABCG5/8 loci (Q604E, D19H, Y54C, T400K, and A632V) in 338 hypercholesterolemic patients treated with 10 mg atorvastatin. In carriers of the D19H variant, means of posttreatment values and adjusted percent reductions in LDL cholesterol (LDLC) were significantly lower (P = 0.028) and greater (P = 0.036) (112 mg/dl, 39.7%) than those of noncarriers (119 mg/dl, 36.2%), respectively, while no significant difference was observed in percent reductions in total cholesterol. Stepwise multiple regression analysis revealed significant and independent associations with absolute or percent reduction between D19H genotype and posttreatment LDL cholesterol levels. The other polymorphisms were not significantly associated with treatment effects. These results suggest that, in patients with hypercholesterolemia, the ABCG8 D19H variant is associated with greater LDLC-lowering response to atorvastatin therapy. 相似文献
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M Trupp H Zhu WR Wikoff RA Baillie ZB Zeng PD Karp O Fiehn RM Krauss R Kaddurah-Daouk 《PloS one》2012,7(7):e38386
Statins are widely prescribed for reducing LDL-cholesterol (C) and risk for cardiovascular disease (CVD), but there is considerable variation in therapeutic response. We used a gas chromatography-time-of-flight mass-spectrometry-based metabolomics platform to evaluate global effects of simvastatin on intermediary metabolism. Analyses were conducted in 148 participants in the Cholesterol and Pharmacogenetics study who were profiled pre and six weeks post treatment with 40 mg/day simvastatin: 100 randomly selected from the full range of the LDL-C response distribution and 24 each from the top and bottom 10% of this distribution ("good" and "poor" responders, respectively). The metabolic signature of drug exposure in the full range of responders included essential amino acids, lauric acid (p<0.0055, q<0.055), and alpha-tocopherol (p<0.0003, q<0.017). Using the HumanCyc database and pathway enrichment analysis, we observed that the metabolites of drug exposure were enriched for the pathway class amino acid degradation (p<0.0032). Metabolites whose change correlated with LDL-C lowering response to simvastatin in the full range responders included cystine, urea cycle intermediates, and the dibasic amino acids ornithine, citrulline and lysine. These dibasic amino acids share plasma membrane transporters with arginine, the rate-limiting substrate for nitric oxide synthase (NOS), a critical mediator of cardiovascular health. Baseline metabolic profiles of the good and poor responders were analyzed by orthogonal partial least square discriminant analysis so as to determine the metabolites that best separated the two response groups and could be predictive of LDL-C response. Among these were xanthine, 2-hydroxyvaleric acid, succinic acid, stearic acid, and fructose. Together, the findings from this study indicate that clusters of metabolites involved in multiple pathways not directly connected with cholesterol metabolism may play a role in modulating the response to simvastatin treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00451828. 相似文献
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PURPOSE OF REVIEW: Although statin therapy has been shown to reduce substantially the risk for cardiovascular disease in multiple patient subgroups, there is wide inter-individual variation in statin efficacy, in terms of both plasma lipoprotein response and clinical outcome. RECENT FINDINGS: A number of studies have reported that polymorphisms in genes affecting statin pharmacodynamics and pharmacokinetics are associated with measures of statin efficacy, but the magnitude of variation in statin response that could be explained by these associations is small. Genome-wide association studies may yield a more comprehensive set of markers for predicting statin efficacy and muscle toxicity. For the results of these analyses to have clinical value, however, there remains a need to replicate findings in multiple populations, to connect effects on LDL and other biomarkers with clinical outcomes, and to determine whether the associations apply to each individual statin. SUMMARY: Satisfying these requirements for clinical applicability will be challenging, but discovery of specific genotypes that influence statin efficacy and characterization of their functional effects in cellular or animal model systems may enhance our understanding of determinants of cardiovascular disease risk. They may also allow us to identify pathways that may be targeted to yield effective prevention and treatment. 相似文献
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Athanasios N Georgiadis Eleni C Papavasiliou Evangelia S Lourida Yannis Alamanos Christina Kostara Alexandros D Tselepis Alexandros A Drosos 《Arthritis research & therapy》2006,8(3):R82
We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis
(ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study.
These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering
from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushing's syndrome, obesity, familiar dyslipidemia and those
receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were
also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices
score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was
5.8 ± 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained
the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation
rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol
(LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower
compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly
higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C
as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes
were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by
an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may
reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients. 相似文献
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Georgiadis AN Papavasiliou EC Lourida ES Alamanos Y Kostara C Tselepis AD Drosos AA 《Arthritis research & therapy》2006,8(3):R82
We investigated lipid profiles and lipoprotein modification after immuno-intervention in patients with early rheumatoid arthritis (ERA). Fifty-eight patients with ERA who met the American College of Rheumatology (ACR) criteria were included in the study. These patients had disease durations of less than one year and had not had prior treatment for it. Smokers or patients suffering from diabetes mellitus, hypothyroidism, liver or kidney disease, Cushing's syndrome, obesity, familiar dyslipidemia and those receiving medications affecting lipid metabolism were excluded from the study. Sixty-three healthy volunteers (controls) were also included. Patients were treated with methotrexate and prednisone. Lipid profiles, disease activity for the 28 joint indices score (DAS-28) as well as ACR 50% response criteria were determined for all patients. The mean DAS-28 at disease onset was 5.8 +/- 0.9. After a year of therapy, 53 (91.3%) patients achieved the ACR 20% response criteria, while 45 (77.6%) attained the ACR 50% criteria. In addition, a significant decrease in the DAS-28, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were observed. ERA patients exhibited higher serum levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides, whereas their serum high-density lipoprotein cholesterol (HDL-C) levels were significantly lower compared to controls. As a consequence, the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was significantly higher in ERA patients compared to controls. After treatment, a significant reduction of the atherogenic ratio of TC/HDL-C as well as that of LDL-C/HDL-C was observed, a phenomenon primarily due to the increase of serum HDL-C levels. These changes were inversely correlated with laboratory changes, especially CRP and ESR. In conclusion, ERA patients are characterized by an atherogenic lipid profile, which improves after therapy. Thus, early immuno-intervention to control disease activity may reduce the risk of the atherosclerotic process and cardiovascular events in ERA patients. 相似文献
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Ostadal P Alan D Vejvoda J Cepova J Kukacka J Blasko P Martinkovicova L Vojacek J 《Molecular and cellular biochemistry》2007,306(1-2):19-23
It is widely assumed that acute benefit of statin therapy is mediated especially by non-lipid effects. The immediate influence
of statins on lipid levels in patients with acute coronary syndrome (ACS) is, however, not clear. A total of 64 consecutive
patients with ACS were randomized at admission to fluvastatin 80 mg (Group 1, N = 32) or standard therapy without statin (Group 2, N = 32). The levels of total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol
(HDL-C), and triglycerides (TG) were examined at admission and after 24 h. Baseline characteristics were comparable in both
groups. In Group 1, fluvastatin significantly decreased the levels of TC by 14.5%, LDL-C by 17.2%, and HDL-C by 10.0% (P < 0.001); TG were not influenced. In Group 2 only marginal reductions in TC (by 4.1%, P = 0.03) and HDL-C (by 7.5%, P < 0.01) were detected; the levels of LDL-C and TG were not changed. As compared with Group 2, in Group 1 the final levels
of TC (P = 0.02) and LDL-C (P = 0.01) were significantly lower. Fluvastatin therapy, when started at admission in patients with ACS, significantly reduces
TC and LDL-C already after 24 h. We suggest that the lipid-lowering effect of statins in the therapy of ACS is probably as
prompt as non-lipid effects. 相似文献
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Parsons RB Price GC Farrant JK Subramaniam D Adeagbo-Sheikh J Austen BM 《The Biochemical journal》2006,399(2):205-214
We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of Abeta (amyloid beta-peptide), the dimerization of beta-secretase and its trafficking into cholesterol-rich microdomains. As statins influence these lipid modifications in addition to their effects on cholesterol biosynthesis, we have investigated the effects of lovastatin and SIMVA (simvastatin) at a range of concentrations chosen to distinguish different cellular effects on Abeta production and beta-secretase structure and its localization in bHEK cells [HEK-293 cells (human embryonic kidney cells) transfected with the Asp-2 gene plus a polyhistidine coding tag] cells. We have compared the changes brought about by statins with those brought about by the palmitoylation inhibitor cerulenin and the farnesyltransferase inhibitor CVFM (Cys-Val-Phe-Met). The statin-mediated reduction in Abeta production correlated with an inhibition of beta-secretase dimerization into its more active form at all concentrations of statin investigated. These effects were reversed by the administration of mevalonate, showing that these effects were mediated via 3-hydroxy-3-methylglutaryl-CoA-dependent pathways. At low (1 microM) statin concentrations, reduction in Abeta production and inhibition of beta-secretase dimerization were mediated by inhibition of isoprenoid synthesis. At high (>10 microM) concentrations of statins, inhibition of beta-secretase palmitoylation occurred, which we demonstrated to be regulated by intracellular cholesterol levels. There was also a concomitant concentration-dependent change in beta-secretase subcellular trafficking. Significantly, Abeta release from cells was markedly higher at 50 microM SIMVA than at 1 microM, whereas these concentrations resulted in similar reductions in total Abeta production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer's disease. 相似文献
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Jawaid S Gertz M Corsino C Cheung J Seidle H Couch RD 《Indian journal of biochemistry & biophysics》2010,47(6):331-339
While statins, hydroxymethylglutaryl-coenzyme A reductase (HMGCR) inhibitors, are clinically proven to reduce plasma cholesterol levels, a wide variation in inter-individual response to statin therapy has been observed. Pharmacogenetic studies have identified multiple loci that potentially contribute towards the statin response, including the HMGCR gene. To examine, if a statin-resistant, catalytically-active isoform of the human HMGCR could be generated, we have rationally altered the protein to include additional residues in the flap domain, which has a role in statin binding. Comparative enzyme assays with purified wild-type and mutant isoforms reveal the alteration imposes a slight (38%) decrease in the K(app)(M) for the substrate, a near 2-fold increase in turnover number, and a 480% increase in the Ki for lovastatin. Thus, alterations in HMGCR could contribute towards the synergistic effects of multiple loci in the statin response. 相似文献
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Piperi C Kalofoutis C Lagogianni I Troupis G Kalofoutis A 《Molecular and cellular biochemistry》2004,261(1-2):71-75
The aim of this study was to evaluate the effects of the selective oestrogen receptor modulator, raloxifene, and those of statin, atorvastatin, in reducing the cardiovascular risks associated with the post-menopausal status. A detailed study of serum lipid concentrations was performed in four groups of post-menopausal women receiving either placebo, raloxifene or atorvastatin alone or their combination for the period of three months. Group A (raloxifene) showed significant decrease in total cholesterol levels (P < 0.05) and an increase in phospholipids concentration (P < 0.05), followed by a marked reduction in low-density lipoprotein cholesterol (LDL-C) levels (P < 0.01) and ApoB amounts (P < 0.001). Additionally, ApoA-I concentration was significantly increased (P < 0.01). Group B (atorvastatin) presented decreased cholesterol (P < 0.05) and triglycerides levels (P < 0.01), followed by elevated high-density lipoprotein cholesterol (HDL-C) concentration (P < 0.05) and low LDL-C amounts (P < 0.001). ApoA-I was significantly increased (P < 0.001) whereas ApoB was reduced (P < 0.001). The combined treatment in Group C (raloxifene and atorvastatin) showed significant changes in the majority of serum lipids. In particular, total cholesterol was reduced (P < 0.001), as well as triglycerides (P < 0.001) levels. Phospholipids were raised (P < 0.01) whereas LDL-C was reduced (P < 0.001) as was ApoB (P < 0.001). Furthermore, ApoA-I was elevated (P < 0.001). A further attempt to evaluate each treatment group was performed and the significance of these results is discussed. 相似文献
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目的:探讨健康体检人群血糖与血脂现况及两者之间的相关性。方法:采集我院9758例健康体检者的空腹静脉血,检测其空腹血糖(FPG)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白(HDL-C)和低密度脂蛋白(LDL-C)水平,比较不同FPG水平组间各血脂水平,分析FPG水平与血脂的相关性。结果:各年龄组FPG、TC、TG、HDL-C和LDL-C水平差异均具有统计学意义(P0.05);FPG均与TC、TG和LDL-C水平呈现正相关(r=0.127,0.189,0.141,P0.005),而与HDL-C呈现负相关(r=-0.112,P0.005);根据FPG水平由高到低分为糖尿病(DM)组,血糖调节受损(IFG)组及血糖正常组,其中对TC和LDL-C水平异常率而言,IFG组DM组血糖正常组;对TG、HDL-C水平异常率而言,DM组IFG组血糖正常组。结论:健康人群中血糖和血脂水平呈现一定的相关性,两者的水平异常会增加慢性疾病的发生风险。 相似文献
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Friday KE 《Experimental biology and medicine (Maywood, N.J.)》2003,228(7):769-778
Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events. 相似文献
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Majid Ghayour-Mobarhan David J Lamb Andrew Taylor Nandita Vaidya Callum Livingstone Timothy Wang Gordon A A Ferns 《Journal of trace elements in medicine and biology》2005,19(1):61-67
Patients previously not treated with a lipid-lowering agent (n = 20; mean age 49.15 +/- 3.28 years) were treated with either 10 mg/day of Simvastatin (n = 11), or Atorvastatin (n = 9) for 4 months. Fourteen additional patients were recruited from the same clinic at the same hospital as a control group. The medication of these latter patients was unaltered for 4 months and the same parameters were measured as for the statin groups. Serum concentrations of zinc, copper, caeruloplasmin, selenium, glutathione peroxidase (GPx) and C-reactive protein (CRP) were measured together with their lipid profiles pre- and post-treatment. In addition to reducing serum total and low-density lipoprotein (LDL) cholesterol (p < 0.0001), statin treatment was associated with a significant reduction in mean serum zinc (9%, p = 0.03), copper (9%, p < 0.01), caeruloplasmin (24%, p < 0.05), and median CRP (45%, p < 0.03). Similar changes were not observed in the control patients. No significant effects were observed for serum selenium, copper/caeruloplasmin ratio, or GPx (p > 0.05) in either statin or control groups. These changes may be related to the known anti-inflammatory properties of the statin class of drugs. 相似文献
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Mona Elbadawi-Sidhu Rebecca A. Baillie Hongjie Zhu Yii-Der Ida Chen Mark O. Goodarzi Jerome I. Rotter Ronald M. Krauss Oliver Fiehn Rima Kaddurah-Daouk 《Metabolomics : Official journal of the Metabolomic Society》2017,13(1):11