RESUMO
The biocatalytic production of fuels and chemicals from plant biomass represents an attractive alternative to fossil fuel-based refineries. In this context, the mining and characterization of novel biocatalysts can promote disruptive innovation opportunities in the field of lignocellulose conversion and valorization. In the present work, we conducted the biochemical and structural characterization of two novel hydroxycinnamic acid catabolic enzymes, isolated from a lignin-degrading microbial consortium, a feruloyl-CoA synthetase, and a feruloyl-CoA hydratase-lyase, named LM-FCS2 and LM-FCHL2, respectively. Besides establishing the homology model structures for novel FCS and FCHL members with unique characteristics, the enzymes presented interesting biochemical features: LM-FCS2 showed stability in alkaline pHs and was able to convert a wide array of p-hydroxycinnamic acids to their respective CoA-thioesters, including sinapic acid; LM-FCHL2 efficiently converted feruloyl-CoA and p-coumaroyl-CoA into vanillin and 4-hydroxybenzaldehyde, respectively, and could produce vanillin directly from ferulic acid. The coupled reaction of LM-FCS2 and LM-FCHL2 produced vanillin, not only from commercial ferulic acid but also from a crude lignocellulosic hydrolysate. Collectively, this work illuminates the structure and function of two critical enzymes involved in converting ferulic acid into high-value molecules, thus providing valuable concepts applied to the development of plant biomass biorefineries. KEY POINTS: ⢠Comprehensive characterization of feruloyl-CoA synthetase from metagenomic origin. ⢠Novel low-resolution structures of hydroxycinnamate catabolic enzymes. ⢠Production of vanillin via enzymatic reaction using lignocellulosic hydrolysates.
Assuntos
Lignina , Metagenoma , Escherichia coli/genética , Hiperlipidemia Familiar Combinada , Lignina/metabolismo , SoloRESUMO
BACKGROUND: Sampson et al. developed a novel method to estimate very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) in the setting of hypertriglyceridemia. Familial Combined Hyperlipidemia (FCHL) is a common primary dyslipidemia in which lipoprotein composition interferes with LDL-C estimation. This study aimed to evaluate performance of LDL-C using this new method (LDL-S) compared with LDL-C estimated by Friedewald's and Martin eq. (LDL-F, LDL-M) in FCHL. METHODS: Data were collected from 340 subjects with confirmed FCHL. Concordance for VLDL-C measured by ultracentrifugation and LDL-C estimated using these measures compared to Sampson's, Martin's and Friedewald's equations was performed using correlation coefficients, root mean squared error (RMSE) and bias. Also, concordance of misclassified metrics according to LDL-C (< 70 and < 100 mg/dL) and Apo B (< 80 and < 65 mg/dL) thresholds were assessed. RESULTS: Sampson's equation was more accurate (RMSE 11.21 mg/dL; R2 = 0.88) compared to Martin's (RMSE 13.15 mg/dL; R2 = 0.875) and the Friedewald's equation (RMSE 13.7 mg/dL; R2 = 0.869). When assessing performance according to LDL-C, Sampson's had highest correlation and lowest RMSE compared to other equations (RMSE 19.99 mg/dL; R2 = 0.840). Comparing performance strength across triglyceride levels, Sampson's showed consistently improved correlations compared to Martin's and Friedewald's formulas for increasing triglycerides and for the FCHL phenotype of mixed dyslipidemia. Sampson's also had improved concordance with treatment goals. CONCLUSIONS: In FCHL, VLDL-C and LDL-C estimation using Sampson's formula showed higher concordance with lipid targets assessed using VLDL-C obtained by ultracentrifugation compared with Friedewald's and Martin's equations. Implementation of Sampson's formula could improve treatment monitoring in FCHL.
Assuntos
LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Hiperlipidemia Familiar Combinada/sangue , Adulto , Apolipoproteínas B/sangue , Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
Familial combined hyperlipidemia (FCHL) is the most prevalent primary dyslipidemia; however, it frequently remains undiagnosed and its precise definition is a subject of controversy. FCHL is characterized by fluctuations in serum lipid concentrations and may present as mixed hyperlipidemia, isolated hypercholesterolemia, hypertriglyceridemia, or as a normal serum lipid profile in combination with abnormally elevated levels of apolipoprotein B. FCHL is an oligogenic primary lipid disorder, which can occur due to the interaction of several contributing variants and mutations along with environmental triggers. Controversies surrounding the relevance of identifying FCHL as a cause of isolated hypertriglyceridemia and a differential diagnosis of familial hypertriglyceridemia are offset by the description of associations with USF1 and other genetic traits that are unique for FCHL and that are shared with other conditions with similar pathophysiological mechanisms. Patients with FCHL are at an increased risk of cardiovascular disease and mortality and have a high frequency of comorbidity with other metabolic conditions such as type 2 diabetes, non-alcoholic fatty liver disease, steatohepatitis, and the metabolic syndrome. Management usually requires lipid-lowering therapy directed toward reducing cholesterol and triglyceride concentrations along with cardiovascular risk protection. In recent years, the number of research studies on FCHL has been decreasing, mainly due to a lack of recognition of its impact on disease burden and comorbidity and the complexity in identifying probands for studies. This creates areas of opportunity to develop research for FCHL in epidemiology, genetics, pathophysiology, therapeutics, and cardiovascular risk management, which are discussed in depth in this review. (REV INVEST CLIN. 2018;70:224-36).
Assuntos
Doenças Cardiovasculares/prevenção & controle , Hiperlipidemia Familiar Combinada/terapia , Lipídeos/sangue , Animais , Apolipoproteínas B/sangue , Doenças Cardiovasculares/etiologia , Diagnóstico Diferencial , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/fisiopatologia , Hiperlipoproteinemia Tipo IV/diagnóstico , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: A novel method to estimate low density lipoprotein cholesterol (LDL-C) has been proposed by Martin et al. This may permit a more accurate estimation of cardiovascular risk, however, external validation is needed. Here, the performance of LDL-C using this new method (LDL-N) is compared with LDL-C estimated with Friedewald equation (LDL-F) in familial combined hyperlipidemia (FCHL), a common primary dyslipidemia in which apolipoprotein B containing particle composition is abnormal and interferes with LDL-C estimation. METHODS: A total of 410 FCHL subjects were included. LDL-C was estimated with both the Friedewald equation (LDL-F) and the novel formula (LDL-N). Apolipoprotein B levels and non- HDL-C were recorded. The correlation and concordance between LDL-F and LDL-N and both Apolipoprotein B and non-HDL-C levels were calculated. Analysis stratifying for triglyceride tertiles and FCHL lipid phenotypes was also carried out. RESULTS: The correlations between LDL-N and Apo B and non-HDL-C were ρâ¯=â¯0.777 (95%CI 0.718-0.825) and ρâ¯=â¯0.735 (95%CI 0.648-0.816), respectively. The corresponding correlations for LDL-F were ρâ¯=â¯0.551(95%CI 0.454-0.637) and ρâ¯=â¯0.394 (95%CI 0.253-0.537), respectively. In mixed dyslipidemia or isolated hypertriglyceridemia, these correlations were significantly better using LDL-N. With respect to concordance, LDL-N performed significantly better than LDL-F when considering apoB <90â¯mg/dL (κLDL-Nâ¯=â¯0.495 vs. κLDL-Fâ¯=â¯0.165) and non-HDL-C <130 (κLDL-Nâ¯=â¯0.724 vs. κLDL-Fâ¯=â¯0.253). CONCLUSIONS: In FCHL, LDL-C estimation using Martin's formula showed greater correlation and concordance with non-HDL-C and Apo B compared with the Friedewald equation.
Assuntos
LDL-Colesterol/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Modelos Biológicos , Adulto , Apolipoproteína B-100/sangue , Biomarcadores/sangue , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/genética , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Triglicerídeos/sangueRESUMO
BACKGROUND: In familial combined hyperlipidemia (FCHL) the severity of the dyslipidemia is determined by an overproduction of VLDL (very low density lipoprotein) particles and by its abnormal lipid composition. However, few are known regarding the metabolic factors that determine these abnormalities. We investigated the impact of metabolic factors on the number of atherogenic particles (apolipoprotein B level (apoB)) and the triglyceride content of very low-density lipoproteins (VLDLs-TG). METHODS: A cross-sectional study done in FCHL subjects and gender and age-matched healthy subjects. A clinical assessment, lipid profile and plasma concentrations of insulin, apolipoprotein CIII (apo CIII), apolipoprotein AII (apo AII), high sensitive C-reactive protein (HS-CRP), adiponectin and leptin were documented in 147 FCHL patients and 147 age-matched healthy subjects. Multivariate regression models were performed to investigate the independent determinants of VLDL-TG and apo B levels adjusting for confounding factors. RESULTS: The variables that determined the VLDL-triglyceride content as a surrogate of VLDL composition were apo CIII (ß=0.365, p<0.001), insulin (ß=0.281, p<0.001), Apo AII (ß=0.145, p<0.035), and adiponectin levels (ß=-0.255, p<0.001). This model explained 34% of VLDL composition (VLDL-TG) variability. However, none of these variables were independent contributors of apo B-containing particles. CONCLUSIONS: In patients with FCHL apo CIII, apo AII and adiponectin are major novel factors determining the VLDL particle composition. However, such factors do not explain apo B-containing particles.
Assuntos
Apolipoproteínas B/sangue , Biomarcadores/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Lipoproteínas VLDL/sangue , Triglicerídeos/sangue , Adulto , Idoso , Apolipoproteína C-III/sangue , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: Alterations in postprandial metabolism have been described in familial combined hyperlipidemia (FCH); however, their underlying mechanisms are not well characterized. We aimed to identify factors related to the magnitude of postprandial lipemia and apolipoprotein (apo) A-V levels in subjects with FCH. METHODS: FCH cases (n = 99) were studied using a standardized meal test. Abdominal obesity was assessed using the waist to hip ratio (WHR). A linear regression model was performed to investigate the variables associated with the triglycerides incremental area under the curve (iAUC). Independent associations between metabolic variables and apo A-V iAUC were also investigated in a randomly selected subgroup (n = 44). The study sample was classified according to the presence of fasting hypertriglyceridemia (≥150 mg/dL) and abdominal obesity (WHR ≥0.92 in men and ≥0.85 in women) to explore differences in parameters. RESULTS: The fasting apo B-48 levels (r = 0.404), and the WHR (r = 0.359) were independent factors contributing to the triglycerides iAUC (r2 = 0.29, P < 0.001). The triglycerides iAUC was independently associated with the apo A-V iAUC (r2 = 0.54, P < 0.01). Patients with both hypertriglyceridemia and abdominal obesity showed the most robust triglycerides and apo A-V postprandial responses. CONCLUSIONS: In patients with FCH the fasting apo B-48 level is the main factor associated with postprandial lipemia. Abdominal obesity also contributes to the magnitude of the postprandial response.The triglycerides postprandial increment is the principal factor associated with the apo A-V postprandial response.
Assuntos
Apolipoproteínas/sangue , Colesterol/sangue , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemias/sangue , Hipertrigliceridemia/sangue , Lipoproteínas/sangue , Obesidade Abdominal/sangue , Período Pós-Prandial , Triglicerídeos/sangue , Adulto , Estudos Transversais , Feminino , Humanos , Hiperlipidemia Familiar Combinada/epidemiologia , Hiperlipidemias/epidemiologia , Hipertrigliceridemia/epidemiologia , Masculino , México/epidemiologia , Obesidade Abdominal/complicações , Obesidade Abdominal/epidemiologiaRESUMO
Here, we discuss potential explanations for the higher prevalence of hypertriglyceridemia in populations with an Amerindian background. Although environmental factors are the triggers, the search for the ethnic related factors that explain the increased susceptibility of the Amerindians is a promising area for research. The study of the genetics of hypertriglyceridemia in Hispanic populations faces several challenges. Ethnicity could be a major confounding variable to prove genetic associations. Despite that, the study of hypertriglyceridemia in Hispanics has resulted in significant contributions. Two GWAS reports have exclusively included Mexican mestizos. Fifty percent of the associations reported in Caucasians could be generalized to the Mexicans, but in many cases the Mexican lead SNP was different than that reported in Europeans. Both reports included new associations with apo B or triglycerides concentrations. The frequency of susceptibility alleles in Mexicans is higher than that found in Europeans for several of the genes with the greatest effect on triglycerides levels. An example is the SNP rs964184 in APOA5. The same trend was observed for ANGPTL3 and TIMD4 variants. In summary, we postulate that the study of the genetic determinants of hypertriglyceridemia in Amerindian populations which have major changes in their lifestyle, may prove to be a great resource to identify new genes and pathways associated with hypertriglyceridemia.
Assuntos
Angiopoietinas/genética , Apolipoproteínas A/genética , Apolipoproteínas B/genética , Interação Gene-Ambiente , Hipertrigliceridemia/etiologia , Proteínas de Membrana/genética , Polimorfismo Genético , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina , Angiopoietinas/metabolismo , Apolipoproteína A-V , Apolipoproteínas A/metabolismo , Apolipoproteínas B/metabolismo , Suscetibilidade a Doenças , Predisposição Genética para Doença , Hispânico ou Latino , Humanos , Hiperlipidemia Familiar Combinada/etiologia , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipoproteinemia Tipo III/etiologia , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/metabolismo , Hiperlipoproteinemia Tipo IV/etiologia , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Indígenas Centro-Americanos , Indígenas Norte-Americanos , Proteínas de Membrana/metabolismo , México/etnologia , Herança Multifatorial , Estados UnidosRESUMO
C5L2, a G protein-coupled receptor, is known to be a functional receptor of acylation-stimulating protein, which is a stimulator of triglyceride synthesis and glucose transport. A novel C5L2 variant (S323I) was identified and its association with familial combined hyperlipidemia (FCH) was recently reported. We looked for this SNP in three Chinese ethnic groups, including Han, Uygur, and Kazakh controls and patients with FCH and type 2 diabetes. One hundred and eighty-two unrelated subjects (77 of Han, 57 of Uygur, and 48 of Kazakh) with FCH were genotyped by direct sequencing, and 852 subjects (342 of Han, 338 of Uygur, 172 of Kazakh) with type 2 diabetes and 200 healthy controls (67 of Han, 72 of Uygur, and 61 of Kazakh) chosen from a cardiovascular risk survey study were genotyped with PCR-RFLP analysis. All 182 subjects with FCH, 99.5% of the type 2 diabetes patients and 100% of the healthy controls were successfully genotyped. Neither the FCH subjects nor the type 2 diabetes patients were found to have the S323I variant. This variant was also not identified in the healthy controls. We found no evidence to demonstrate that the S323I polymorphism contributes to familial combined hyperlipidemia or type 2 diabetes in the Chinese population.
Assuntos
Povo Asiático , Doenças Cardiovasculares/genética , Diabetes Mellitus Tipo 2/genética , Hiperlipidemia Familiar Combinada/genética , Polimorfismo de Nucleotídeo Único , Receptores de Quimiocinas/genética , Adulto , Idoso , Alelos , Doenças Cardiovasculares/etnologia , Doenças Cardiovasculares/etiologia , Estudos de Casos e Controles , China/epidemiologia , Análise Mutacional de DNA , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/etnologia , Feminino , Frequência do Gene , Genótipo , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/etnologia , Isoleucina/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Receptor da Anafilatoxina C5a , Fatores de Risco , Serina/genéticaRESUMO
Los xantomas constituyen tumores cutáneos, y se presentan por depósitos de lipoproteínas en los macrófagos tisulares. Clínicamente se manifiestan como lesiones papulosas o nodulares de color amarillento, estando relacionada su distribución con las diferentes formas clínicas de presentación. Aunque no se observan con frecuencia, su presencia puede alertar sobre la existencia de alteraciones en los niveles lipídicos en sangre, y es por lo que se presentó este caso, donde la presencia de los xantomas fue indicador de un incremento de los niveles de colesterol y triglicéridos, lo que pudo constituir un importante factor de riesgo para que la paciente presentara alteraciones en otros sistemas...
Xanthomas are skin tumors, and they present as a cause of lipoprotein deposits in tissue macrophages. Clinically they take the form of yellow papular or nodular lesions, being related its distribution with their different forms of presentation. Though they are not very frequent, their presence can alert about the existence of alterations in the lipid levels in blood. That is why we presented this case, where the presence of xanthomas was an indicator of the cholesterol and triglycerides level increase, what probably was an important risk fact for the patient to present alterations in other systems...
Assuntos
Humanos , Feminino , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/diagnóstico , Xantomatose/classificação , Xantomatose/diagnóstico , Xantomatose/dietoterapia , Xantomatose/etiologia , Xantomatose/patologia , Xantomatose/tratamento farmacológicoRESUMO
Familial combined hyperlipidemia (FCHL) is the most frequent primary dyslipidemia. Its manifestations include hypercholesterolemia, hypertriglyceridemia or the combination of both abnormalities. In spite of its high frequency, the proper diagnosis is rarely done. For this purpose, the measurement of a lipid profile is required in at least three first-degree relatives. A critical review of the current literature in this field is presented in this paper. Prospective studies have confirmed the atherogenicity of the disease. It is possible to identify the FCHL causal genes with the current methodology because it is an oligogenic disease. Based on the use of new technologies, several loci that regulate apolipoprotein B concentrations have been identified. In addition it was demostrated that variations of the activity or the expression of various nuclear factors (USF1, TCF7L2, HNF4alfa) have a major role in the pathophysiology of FCHL. These nuclear factors regulate the expression of multiple genes involved in the metabolism of lipids or carbohydrates.