TY  - JOUR
AB  - Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a leading global cause of chronic liver disease. Our recent translational investigations have shown that the STE20-type kinases comprising the GCKIII subfamily - MST3, STK25, and MST4 - associate with hepatic lipid droplets and regulate ectopic fat storage in the liver; however, the mode of action of these proteins remains to be resolved. By comparing different combinations of the silencing of MST3, STK25, and/or MST4 in immortalized human hepatocytes, we found that their single knockdown results in a similar reduction in hepatocellular lipid content and metabolic stress, without any additive or synergistic effects observed when all three kinases are simultaneously depleted. A genome-wide yeast two-hybrid screen of the human hepatocyte library identified several interaction partners contributing to the GCKIII-mediated regulation of liver lipid homeostasis, i.e., PDCD10 that protects MST3, STK25, and MST4 from degradation, MAP4K4 that regulates their activity via phosphorylation, and HSD17B11 that controls their action via a conformational change. Finally, using in vitro kinase assays on microfluidic microarrays, we pinpointed various downstream targets that are phosphorylated by the GCKIII kinases, with known functions in lipogenesis, lipolysis, and lipid secretion, as well as glucose uptake, glycolysis, hexosamine synthesis, and ubiquitination. Together, this study demonstrates that the members of the GCKIII kinase subfamily regulate hepatocyte lipid metabolism via common pathways. The results shed new light on the role of MST3, STK25, and MST4, as well as their interactions with PDCD10, MAP4K4, and HSD17B11, in the control of liver lipid homeostasis and MASLD susceptibility.
AU  - Cansby, E.*
AU  - Caputo, M.*
AU  - Andersson, E.*
AU  - Saghaleyni, R.*
AU  - Henricsson, M.*
AU  - Xia, Y.*
AU  - Asiedu, B.*
AU  - Blüher, M.
AU  - Svensson, L.T.*
AU  - Hoy, A.J.*
AU  - Mahlapuu, M.*
C1  - 71998
C2  - 56540
TI  - GCKIII kinases control hepatocellular lipid homeostasis via shared mode of action.
JO  - J. Lipid Res.
VL  - 65
IS  - 11
PY  - 2024
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Reliability, robustness, and interlaboratory comparability of quantitative measurements is critical for clinical lipidomics studies. Lipids' different ex vivo stability in blood bears the risk of misinterpretation of data. Clear recommendations for the process of blood sample collection are required. We studied by UHPLC-high resolution mass spectrometry, as part of the "Preanalytics interest group" of the International Lipidomics Society, the stability of 417 lipid species in EDTA whole blood after exposure to either 4°C, 21°C, or 30°C at six different time points (0.5 h-24 h) to cover common daily routine conditions in clinical settings. In total, >800 samples were analyzed. 325 and 288 robust lipid species resisted 24 h exposure of EDTA whole blood to 21°C or 30°C, respectively. Most significant instabilities were detected for FA, LPE, and LPC. Based on our data, we recommend cooling whole blood at once and permanent. Plasma should be separated within 4 h, unless the focus is solely on robust lipids. Lists are provided to check the ex vivo (in)stability of distinct lipids and potential biomarkers of interest in whole blood. To conclude, our results contribute to the international efforts towards reliable and comparable clinical lipidomics data paving the way to the proper diagnostic application of distinct lipid patterns or lipid profiles in the future.
AU  - Wang, Q.*
AU  - Hoene, M.*
AU  - Hu, C.*
AU  - Fritsche, L.
AU  - Ahrends, R.*
AU  - Liebisch, G.*
AU  - Ekroos, K.*
AU  - Fritsche, A.
AU  - Birkenfeld, A.L.
AU  - Liu, X.*
AU  - Zhao, X.*
AU  - Li, Q.*
AU  - Su, B.*
AU  - Peter, A.
AU  - Xu, G.*
AU  - Lehmann, R.
C1  - 67677
C2  - 53984
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Ex vivo instability of lipids in whole blood: Preanalytical recommendations for clinical lipidomics studies.
JO  - J. Lipid Res.
VL  - 64
IS  - 6
PB  - Elsevier
PY  - 2023
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - The primary hepatic consequence of obesity is non-alcoholic fatty liver disease (NAFLD), affecting about 25% of the global adult population. Non-alcoholic steatohepatitis (NASH) is a severe form of NAFLD characterized by liver lipid accumulation, inflammation, and hepatocyte ballooning, with a different degree of hepatic fibrosis. In the light of rapidly increasing prevalence of NAFLD and NASH, there is an urgent need for improved understanding of the molecular pathogenesis of these diseases. The aim of this study was to decipher the possible role of STE20-type kinase MAP4K4 in the regulation of hepatocellular lipotoxicity and susceptibility to NAFLD. We found that MAP4K4 mRNA expression in human liver biopsies was positively correlated with key hallmarks of NAFLD (i.e., liver steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis). We also found that the silencing of MAP4K4 suppressed lipid deposition in human hepatocytes by stimulating β-oxidation and triacylglycerol secretion, while attenuating fatty acid influx and lipid synthesis. Furthermore, downregulation of MAP4K4 markedly reduced the glycolysis rate and lowered incidences of oxidative/endoplasmic reticulum stress. In parallel, we observed suppressed JNK and ERK activation and increased AKT phosphorylation in MAP4K4-deficient hepatocytes. Together, these results provide the first experimental evidence supporting the potential involvement of STE20-type kinase MAP4K4 as a component of the hepatocellular lipotoxic milieu promoting NAFLD susceptibility.
AU  - Anand, S.K.*
AU  - Caputo, M.*
AU  - Xia, Y.*
AU  - Andersson, E.A.*
AU  - Cansby, E.*
AU  - Kumari, S.*
AU  - Henricsson, M.*
AU  - Porosk, R.*
AU  - Keuenhof, K.S.*
AU  - Höög, J.L.*
AU  - Nair, S.*
AU  - Marschall, H.U.*
AU  - Blüher, M.
AU  - Mahlapuu, M.*
C1  - 65449
C2  - 52687
TI  - Inhibition of MAP4K4 signaling initiates metabolic reprogramming to protect hepatocytes from lipotoxic damage.
JO  - J. Lipid Res.
VL  - 63
IS  - 7
PY  - 2022
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Lipoprotein(a) [Lp(a)] concentrations are regulated by the LPA gene mainly via the large kringle IV-type 2 (KIV-2) copy number variation and multiple causal variants. Early studies suggested an effect of long pentanucleotide repeat (PNR) alleles (10 and 11 repeats, PNR10 and PNR11) in the LPA promoter on gene transcription and found an association with lower Lp(a). Subsequent in-vitro studies showed no effects on mRNA transcription, but the association with strongly decreased Lp(a) remained consistent. We investigated the isolated and combined effect of PNR10, PNR11 and the frequent splice site variant KIV-2 4925G>A on Lp(a) concentrations in the Cooperative Health Research in the Region of Augsburg (KORA) F4 study by multiple quantile regression in single-SNP and joint models. Data on Lp(a), apolipoprotein(a) Western blot isoforms and variant genotypes were available for n=2,858 individuals. We found a considerable linkage disequilibrium (LD) between KIV-2 4925G>A and the alleles PNR10 and PNR11. In single variant analysis adjusted for age, sex, and the shorter apo(a) isoform we determined that both PNR alleles were associated with a highly significant Lp(a) decrease (PNR10: β=-14.43 mg/dL, 95% CI: -15.84,-13.02, p=3.33e-84; PNR11: β=-17.21 mg/dL, 95% CI: -20.19,-14.23, p=4.01e-29). However, a joint model, adjusting the PNR alleles additionally for 4925G>A abolished the effect on Lp(a) (PNR10: β=+0.44 mg/dL, 95% CI: -1.73,2.60, p=0.69; PNR11: β=-1.52 mg/dL, 95% CI: -6.05,3.00, p=0.51). Collectively, we conclude that the previously reported Lp(a) decrease observed in pentanucleotide alleles PNR10 or PNR11 carriers results from an LD with the frequent splicing mutation KIV-2 4925G>A.
AU  - Grüneis, R.*
AU  - Weissensteiner, H.*
AU  - Lamina, C.*
AU  - Schönherr, S.*
AU  - Forer, L.*
AU  - Di Maio, S.*
AU  - Streiter, G.*
AU  - Peters, A.
AU  - Gieger, C.
AU  - Kronenberg, F.*
AU  - Coassin, S.*
C1  - 66624
C2  - 50527
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
SP  - 11
TI  - The kringle IV type 2 domain variant 4925G>A causes the elusive association signal of the LPA pentanucleotide repeat.
JO  - J. Lipid Res.
VL  - 63
IS  - 12
PB  - Elsevier
PY  - 2022
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs∗6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin binding site. Compared to C57BL/6N mice, LeprL536Hfs∗6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs∗6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared to C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs∗6/wt mice results in compound heterozygous LeprL536Hfs∗6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs∗6 mice. Our study suggests that the phenotype of monogenic Lepr deficient mice depends on the molecular localization of the Lepr mutation. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.
AU  - Berger, C.*
AU  - Heyne, H.O.*
AU  - Heiland, T.*
AU  - Dommel, S.*
AU  - Höfling, C.*
AU  - Guiu-Jurado, E.*
AU  - Roßner, S.*
AU  - Dannemann, M.*
AU  - Kelso, J.*
AU  - Kovacs, P.*
AU  - Blüher, M.
AU  - Klöting, N.
C1  - 62904
C2  - 51154
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Leprdb/db mice.
JO  - J. Lipid Res.
VL  - 62
PB  - Elsevier
PY  - 2021
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Non-alcoholic fatty liver disease (NAFLD) is a common metabolic dysfunction leading to hepatic steatosis. However, NAFLD's global impact on the liver lipidome is poorly understood. Using high-resolution shotgun mass spectrometry, we quantified the molar abundance of 316 species from 22 major lipid classes in liver biopsies of 365 patients, including non-steatotic patients with normal or excessive weight, patients diagnosed with NAFL (non-alcoholic fatty liver) or NASH (non-alcoholic steatohepatitis), and patients bearing common mutations of NAFLD-related protein factors. We confirmed the progressive accumulation of di- and tri- acylglycerols and cholesteryl esters in the liver of NAFL and NASH patients, while the bulk composition of glycerophospho- and sphingolipids remained unchanged. Further stratification by biclustering analysis identified sphingomyelin species comprising n24:2 fatty acid moieties as membrane lipid markers of NAFLD. Normalized relative abundance of sphingomyelins SM 43:3;2 and SM 43:1;2 containing n24:2 and n24:0 fatty acid moieties, respectively, showed opposite trends during NAFLD progression and distinguished NAFL and NASH lipidomes from the lipidome of non-steatoic livers. Together with several glycerophospholipids containing a C22:6 fatty acid moiety, these lipids serve as markers of early and advanced stages of NAFL.
AU  - Vvedenskaya, O.*
AU  - Rose, T.D.*
AU  - Knittelfelder, O.*
AU  - Palladini, A.
AU  - Wodke, J.A.H.*
AU  - Schumann, K.*
AU  - Ackerman, J.M.*
AU  - Wang, Y.*
AU  - Has, C.*
AU  - Brosch, M.*
AU  - Thangapandi, V.R.*
AU  - Buch, S.*
AU  - Züllig, T.*
AU  - Hartler, J.*
AU  - Köfeler, H.C.*
AU  - Röcken, C.*
AU  - Coskun, Ü.
AU  - Klipp, E.*
AU  - von Schoenfels, W.*
AU  - Gross, J.*
AU  - Schafmayer, C.*
AU  - Hampe, J.*
AU  - Pauling, J.K.*
AU  - Shevchenko, A.*
C1  - 62909
C2  - 51166
CY  - Radarweg 29, 1043 Nx Amsterdam, Netherlands
TI  - Non-alcoholic fatty liver disease Stratification by Liver Lipidomics.
JO  - J. Lipid Res.
VL  - 62
PB  - Elsevier
PY  - 2021
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Excessive circulating FAs have been proposed to promote insulin resistance (IR) of glucose metabolism by increasing the oxidation of FAs over glucose. Therefore, inhibition of FA oxidation (FAOX) has been suggested to ameliorate IR. However, prolonged inhibition of FAOX would presumably cause lipid accumulation and thereby promote lipotoxicity. To understand the glycemic consequences of acute and prolonged FAOX inhibition, we treated mice with the carnitine palmitoyltransferase 1 (CPT-1) inhibitor, etomoxir (eto), in combination with short-term 45% high fat diet feeding to increase FA availability. Eto acutely increased glucose oxidation and peripheral glucose disposal, and lowered circulating glucose, but this was associated with increased circulating FAs and triacylglycerol accumulation in the liver and heart within hours. Several days of FAOX inhibition by daily eto administration induced hepatic steatosis and glucose intolerance, specific to CPT-1 inhibition by eto. Lower whole-body insulin sensitivity was accompanied by reduction in brown adipose tissue (BAT) uncoupling protein 1 (UCP1) protein content, diminished BAT glucose clearance, and increased hepatic glucose production. Collectively, these data suggest that pharmacological inhibition of FAOX is not a viable strategy to treat IR, and that sufficient rates of FAOX are required for maintaining liver and BAT metabolic function.
AU  - Lundsgaard, A.M.*
AU  - Fritzen, A.M.*
AU  - Nicolaisen, T.S.*
AU  - Carl, C.S.*
AU  - Sjøberg, K.A.*
AU  - Raun, S.H.*
AU  - Klein, A.B.*
AU  - Sánchez Quant, E.S.
AU  - Langer, J.
AU  - Ørskov, C.*
AU  - Clemmensen, C.*
AU  - Tschöp, M.H.
AU  - Richter, E.A.*
AU  - Kiens, B.*
AU  - Kleinert, M.
C1  - 57773
C2  - 47881
CY  - 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
SP  - 10-19
TI  - Glucometabolic consequences of acute and prolonged inhibition of fatty acid oxidation.
JO  - J. Lipid Res.
VL  - 61
IS  - 1
PB  - Amer Soc Biochemistry Molecular Biology Inc
PY  - 2020
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - The recent characterization of functional brown adipose tissue in adult humans has opened new perspectives for regulation of energy expenditure with respect to obesity and diabetes. Furthermore, dietary recommendations have taken into account the insufficient dietary intake of ω3 PUFAs and the concomitant excessive intake of ω6 PUFA associated with the occurrence of overweight/obesity. We aimed to study whether ω3 PUFAs could play a role in the recruitment and function of energy-dissipating brown/brite adipocytes. We show that ω3 PUFA supplementation has a beneficial effect on the thermogenic function of adipocytes. In vivo, a low dietary ω6:ω3 ratio improved the thermogenic response of brown and white adipose tissues to β3-adrenergic stimulation. This effect was recapitulated in vitro by PUFA treatment of hMADS adipocytes. We pinpointed the ω6- derived eicosanoid prostaglandin (PG)F2α as the molecular origin because the effects were mimicked with a specific PGF2α receptor agonist. PGF2α level in hMADS adipocytes was reduced in response to ω3 PUFA supplementation. The recruitment of thermogenic adipocytes is influenced by the local quantity of individual oxylipins, which is controlled by the ω6:ω3 ratio of available lipids. In human nutrition, energy homeostasis may thus benefit from the implementation of a more balanced dietary ω6:ω3 ratio.
AU  - Ghandour, R.A.*
AU  - Colson, C.*
AU  - Giroud, M.
AU  - Maurer, S.*
AU  - Rekima, S.*
AU  - Ailhaud, G.*
AU  - Klingenspor, M.*
AU  - Amri, E.Z.*
AU  - Pisani, D.F.*
C1  - 53230
C2  - 44791
SP  - 452-461
TI  - Impact of dietary ω3 polyunsaturated fatty acid supplementation on brown and brite adipocyte function.
JO  - J. Lipid Res.
VL  - 59
IS  - 3
PY  - 2018
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Meta-inflammation of hypothalamic areas governing energy homeostasis has recently emerged as a process of potential pathophysiological relevance for the development of obesity and its metabolic sequelae. The current model suggests that diet-induced neuronal injury triggers microgliosis and astrocytosis, conditions which ultimately may induce functional impairment of hypothalamic circuits governing feeding behavior, systemic metabolism, and body weight. Epidemiological data indicate that low circulating HDL levels, besides conveying cardiovascular risk, also correlate strongly with obesity. We simulated that condition by using a genetic loss of function mouse model (apoA-I/) with markedly reduced HDL levels to investigate whether HDL may directly modulate hypothalamic inflammation. Astrogliosis was significantly enhanced in the hypothalami of apoA-I/ compared with apoA-I+/+mice and was associated with compromised mitochondrial function. apoA-I/ mice exhibited key components of metabolic disease, like increased fat mass, fasting glucose levels, hepatic triglyceride content, and hepatic glucose output compared with apoA-I+/+controls. Administration of reconstituted HDL (CSL-111) normalized hypothalamic inflammation and mitochondrial function markers in apoA-I/ mice. Treatment of primary astrocytes with apoA-I resulted in enhanced mitochondrial activity, implying that circulating HDL levels are likely important for astrocyte function. HDL-based therapies may consequently avert reactive gliosis in hypothalamic astrocytes by improving mitochondrial bioenergetics and thereby offering potential treatment and prevention for obesity and metabolic disease.
AU  - Götz, A.
AU  - Lehti, M.*
AU  - Donelan, E.*
AU  - Striese, C.
AU  - Cucuruz, S.
AU  - Sachs, S.
AU  - Yi, C.X.*
AU  - Woods, S.C.*
AU  - Wright, S.D.*
AU  - Tschöp, M.H.
AU  - Gao, Y.*
AU  - Hofmann, S.M.
C1  - 53922
C2  - 45092
CY  - 9650 Rockville Pike, Bethesda, Md 20814-3996 Usa
SP  - 1649-1659
TI  - Circulating HDL levels control hypothalamic astrogliosis via apoA-I.
JO  - J. Lipid Res.
VL  - 59
IS  - 9
PB  - Amer Soc Biochemistry Molecular Biology Inc
PY  - 2018
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10−30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10−10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population’s mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10−4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.
AU  - Mack, S.*
AU  - Coassin, S.*
AU  - Rueedi, R.*
AU  - Yousri, N.A.*
AU  - Seppälä, I.*
AU  - Gieger, C.
AU  - Schoenherr, S.*
AU  - Forer, L.*
AU  - Erhart, G.*
AU  - Marques-Vidal, P.*
AU  - Ried, J.S.
AU  - Waeber, G.*
AU  - Bergmann, S.*
AU  - Daehnhardt, D.*
AU  - Stoeckl, A.*
AU  - Raitakari, O.T.*
AU  - Khahonen, M.*
AU  - Peters, A.
AU  - Meitinger, T.
AU  - Strauch, K.
AU  - Kedenko, L.*
AU  - Paulweber, B.*
AU  - Lehtimäki, T.J.*
AU  - Hunt, S.C.*
AU  - Vollenweider, P.*
AU  - Lamina, C.*
AU  - Kronenberg, F.*
C1  - 51862
C2  - 43536
CY  - Bethesda
SP  - 1834-1844
TI  - A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.
JO  - J. Lipid Res.
VL  - 58
IS  - 9
PB  - Amer Soc Biochemistry Molecular Biology Inc
PY  - 2017
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Fatty acid desaturases play an important role in the formation of omega-6 and omega-3 highly unsaturated fatty acids (HUFAs). The composition of HUFAs in the human metabolome is important for membrane fluidity and for the modulation of essential physiological functions such as inflammation processes and brain development. Several recent studies reported significant associations of single nucleotide polymorphisms (SNPs) in the human FADS gene cluster with HUFA levels and composition. The presence of the minor allele correlated with a decrease of desaturase reaction products and an accumulation of substrates. We performed functional studies with two of the associated polymorphisms (rs3834458 and rs968567) and showed an influence of polymorphism rs968567 on FADS2 promoter activity by luciferase reporter gene assays. Electrophoretic mobility shift assays proved allele-dependent DNA-binding ability of at least two protein complexes to the region containing SNP rs968567. One of the proteins binding to this region in an allele-specific manner was shown to be the transcription factor ELK1. These results indicate that rs968567 influences FADS2 transcription and offer first insights into the modulation of complex regulation mechanisms of FADS2 gene transcription by SNPs.
AU  - Lattka, E.
AU  - Eggers, S.
AU  - Möller, G.
AU  - Heim, K.
AU  - Weber, M.
AU  - Mehta, D.
AU  - Prokisch, H.
AU  - Illig, T.
AU  - Adamski, J.
C1  - 883
C2  - 26580
SP  - 182-191
TI  - A common FADS2 promoter polymorphism increases promoter activity and facilitates binding of transcription factor ELK1.
JO  - J. Lipid Res.
VL  - 51
IS  - 1
PB  - American Society Biochemistry Molecular Biology Inc.
PY  - 2010
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Apolipoprotein A5 (APOA5) gene variants were reported to be associated with two components of metabolic syndrome (MetS): higher TG levels and lower HDL levels. Moreover, a recent Japanese case-control study found variant -1131T>C associated with MetS itself. Thus, our study systematically analyzed the APOA5 gene for association with lipid parameters, any other features of MetS, including waist circumference, glucose-related parameters, blood pressure, uric acid, and MetS itself in Caucasians. Ten polymorphisms were analyzed in a large fasting sample of the population-based Cooperative Health Research in the Region of Augsburg (KORA) survey S4 (n = 1,354; southern Germany) and in a second fasting sample, the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) study (n = 1,770; Austria). Minor alleles of variants -1131T>C, -3A>G, c.56C>G, 476G>A, and 1259T>C were significantly associated with higher TG levels in single polymorphism (P < 0.001) and haplotype (P G was associated with higher risk for MetS [odds ratio (95% confidence interval) = 1.43 (1.04, 1.99), P = 0.03 for KORA and 1.48 (1.10, 1.99), P = 0.009 for SAPHIR). Our study confirms the association of the APOA5 locus with TG and HDL levels in humans. Furthermore, the data suggest a different mechanism of APOA5 impact on MetS in Caucasians, as variant c.56C>G (not analyzed in the Japanese study) and not -1131T>C, as in the Japanese subjects, was associated with MetS.
AU  - Grallert, H.
AU  - Sedlmeier, E.-M.
AU  - Huth, C.
AU  - Kolz, M.
AU  - Heid, I.M.
AU  - Meisinger, C.
AU  - Herder, C.*
AU  - Strassburger, K.*
AU  - Gehringer, A.*
AU  - Haak, M.*
AU  - Giani, G.*
AU  - Kronenberg, F.*
AU  - Wichmann, H.-E.
AU  - Adamski, J.
AU  - Paulweber, B.*
AU  - Illig, T.
AU  - Rathmann, W.*
C1  - 4887
C2  - 25006
SP  - 2614-2621
TI  - APOA5 variants and metabolic syndrome in Caucasians.
JO  - J. Lipid Res.
VL  - 48
IS  - 12
PY  - 2007
SN  - 0022-2275
ER  - 

TY  - JOUR
AU  - Lingenhel, A.*
AU  - Lhotta, K.*
AU  - Neyer, U.*
AU  - Heid, I.M.
AU  - Rantner, B.*
AU  - Kronenberg, M.F.*
AU  - König, P.*
AU  - von Eckardstein, A.*
AU  - Schober, M.*
AU  - Dieplinger, H.*
AU  - Kronenberg, F.*
C1  - 5803
C2  - 24284
SP  - 2071-2079
TI  - Role of the kidney in the metabolism of apolipoprotein A-IV: Influence of the type of proteinuria.
JO  - J. Lipid Res.
VL  - 47
PY  - 2006
SN  - 0022-2275
ER  - 

TY  - JOUR
AB  - Experimental data support a protective function of apolipoprotein E (apoE) against restenosis, the main factor limiting the long-term benefit of percutaneous coronary interventions. We investigated the possibility that the single nucleotide polymorphisms (SNPs) -219G/T, 113G/C, 334T/C, and 472C/T of the gene encoding apoE (APOE) are associated with the incidence of death and myocardial infarction or restenosis after stenting in coronary arteries. In addition, we asked whether the apoE isotype-related epsilon2/epsilon3/epsilon4 polymmorphism, defined by specific allele combinations (haplotypes) of the 334T/C and 472C/T polymorphism, and other APOE haplotypes, derived from all four SNPs investigated, are associated with adverse clinical and angiographic outcomes after stenting. Our study included 1,850 consecutive patients with symptomatic coronary artery disease (CAD) who underwent stent implantation. Follow-up angiography was performed in 1,556 patients (84.1%) at 6 months after the intervention. We found that none of the APOE SNPs is associated with death and myocardial infarction or restenosis after stenting. In addition, we observed no relationship between APOE haplotypes and adverse outcomes. In conclusion, the APOE -219G/T, 113G/C, 334T/C, and 472C/T polymorphisms, either alone or in combination, do not represent genetic markers of the risk of thrombotic and restenotic complications in patients with CAD treated with coronary stenting. Koch, W.J. Mehilli, A. Pfeufer, A. Schomig, and A. Kastrati. Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting.
AU  - Koch, W.*
AU  - Mehilli, J.*
AU  - Pfeufer, A.
AU  - Schömig, A.*
AU  - Kastrati, A.*
C1  - 23555
C2  - 31365
SP  - 2221-2226
TI  - Apolipoprotein E gene polymorphisms and thrombosis and restenosis after coronary artery stenting.
JO  - J. Lipid Res.
VL  - 45
IS  - 12
PB  - AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
PY  - 2004
SN  - 0022-2275
ER  - 

TY  - JOUR
AU  - Mohr, M.*
AU  - Klempt, M.*
AU  - Rathkolb, B.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, M.*
AU  - Aigner, B.*
C1  - 2695
C2  - 22198
SP  - 2132-2137
TI  - Hypercholesterolemia in ENU-induced mouse mutants.
JO  - J. Lipid Res.
VL  - 45
PY  - 2004
SN  - 0022-2275
ER  -