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1.
Int J Mol Sci ; 22(21)2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34768942

RESUMO

Recent studies suggest that treatment with SGLT-2 inhibitors can reduce hepatic lipid storage and ameliorate non-alcoholic fatty liver disease (NAFLD) development beyond their glycemic benefits. However, the exact mechanism involved is still unclear. We investigated the hepatic metabolic effect of empagliflozin (10 mg/kg/day for eight weeks) on the development of NAFLD and its complications using HHTg rats as a non-obese prediabetic rat model. Empagliflozin treatment reduced neutral triacylglycerols and lipotoxic diacylglycerols in the liver and was accompanied by significant changes in relative mRNA expression of lipogenic enzymes (Scd-1, Fas) and transcription factors (Srebp1, Pparγ). In addition, alterations in the gene expression of cytochrome P450 proteins, particularly Cyp2e1 and Cyp4a, together with increased Nrf2, contributed to the improvement of hepatic lipid metabolism after empagliflozin administration. Decreased circulating levels of fetuin-A improved lipid metabolism and attenuated insulin resistance in the liver and in peripheral tissues. Our results highlight the beneficial effect of empagliflozin on hepatic lipid metabolism and lipid accumulation independent of obesity, with the mechanisms understood to involve decreased lipogenesis, alterations in cytochrome P450 proteins, and decreased fetuin-A. These changes help to alleviate NAFLD symptoms in the early phase of the disease and before the onset of diabetes.


Assuntos
Compostos Benzidrílicos/farmacologia , Glucosídeos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Animais , Sistema Enzimático do Citocromo P-450/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Hiperglicemia/tratamento farmacológico , Hiperglicemia/etiologia , Hiperglicemia/metabolismo , Hiperlipoproteinemia Tipo IV/complicações , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Hiperlipoproteinemia Tipo IV/metabolismo , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Masculino , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Estado Pré-Diabético/complicações , Ratos , Ratos Mutantes , Ratos Wistar
2.
Int J Mol Sci ; 22(14)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34299301

RESUMO

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids-triglycerides, cholesteryl esters and the lipotoxic intermediates-diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.


Assuntos
Ácido Araquidônico/metabolismo , Metformina/farmacologia , Miocárdio/metabolismo , Estado Pré-Diabético/tratamento farmacológico , Estado Pré-Diabético/metabolismo , Animais , Metabolismo Basal/efeitos dos fármacos , Biomarcadores/sangue , Cardiotônicos/farmacologia , Modelos Animais de Doenças , Ácidos Graxos Dessaturases/metabolismo , Coração/efeitos dos fármacos , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Hiperlipoproteinemia Tipo IV/metabolismo , Hipoglicemiantes/farmacologia , Mediadores da Inflamação/sangue , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Ratos , Ratos Wistar , Fatores de Risco
3.
Lipids Health Dis ; 20(1): 14, 2021 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-33588820

RESUMO

BACKGROUND: Familial hypertriglyceridemia (FHTG) is a partially characterized primary dyslipidemia which is frequently confused with other forms hypertriglyceridemia. The aim of this work is to search for specific features that can help physicians recognize this disease. METHODS: This study included 84 FHTG cases, 728 subjects with common mild-to-moderate hypertriglyceridemia (CHTG) and 609 normotriglyceridemic controls. All subjects underwent genetic, clinical and biochemical assessments. A set of 53 single nucleotide polymorphisms (SNPs) previously associated with triglycerides levels, as well as 37 rare variants within the five main genes associated with hypertriglyceridemia (i.e. LPL, APOC2, APOA5, LMF1 and GPIHBP1) were analyzed. A panel of endocrine regulatory proteins associated with triglycerides homeostasis were compared between the FHTG and CHTG groups. RESULTS: Apolipoprotein B, fibroblast growth factor 21(FGF-21), angiopoietin-like proteins 3 (ANGPTL3) and apolipoprotein A-II concentrations, were independent components of a model to detect FHTG compared with CHTG (AUC 0.948, 95%CI 0.901-0.970, 98.5% sensitivity, 92.2% specificity, P < 0.001). The polygenic set of SNPs, accounted for 1.78% of the variance in triglyceride levels in FHTG and 6.73% in CHTG. CONCLUSIONS: The clinical and genetic differences observed between FHTG and CHTG supports the notion that FHTG is a unique entity, distinguishable from other causes of hypertriglyceridemia by the higher concentrations of insulin, FGF-21, ANGPTL3, apo A-II and lower levels of apo B. We propose the inclusion of these parameters as useful markers for differentiating FHTG from other causes of hypertriglyceridemia.


Assuntos
Proteínas Semelhantes a Angiopoietina/genética , Apolipoproteína A-II/genética , Fatores de Crescimento de Fibroblastos/genética , Hiperlipoproteinemia Tipo IV/diagnóstico , Hipertrigliceridemia/diagnóstico , Adulto , Proteína 3 Semelhante a Angiopoietina , Apolipoproteína A-V/genética , Apolipoproteína C-II/genética , Apolipoproteínas B/genética , Diagnóstico Diferencial , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hiperlipoproteinemia Tipo IV/patologia , Hipertrigliceridemia/genética , Hipertrigliceridemia/metabolismo , Hipertrigliceridemia/patologia , Insulina/genética , Lipase Lipoproteica/genética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Receptores de Lipoproteínas/genética , Triglicerídeos/genética
4.
Metabolism ; 63(7): 887-94, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24768220

RESUMO

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 Unidos
5.
Mol Cell Biochem ; 366(1-2): 41-8, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22438203

RESUMO

The study was focused to the influence of higher intake of cholesterol on properties of the renal Na,K-ATPase, a key system in maintaining the homeostasis of sodium in the organism. Feeding for 4 weeks with cholesterol-enriched food for rats afflicted with hereditary hypertriglyceridemia by itself enhanced the activity of Na,K-ATPase, probably as a consequence of higher number of active enzyme molecules as suggested by 32 % increase of V (max) value. This may be hypothesized as a reason for the increased retention of sodium. Three-week-lasting treatment of animals kept on high cholesterol diet with antioxidant SMe1EC2 in a dose of 10 mg kg(-1) day(-1) normalized the function of renal Na,K-ATPase to the level comparable in hypertriglyceridemic rats fed with the standard diet. Therefore, our results suggest that the antioxidant SMe1EC2 in the applied dose seems to be effective in the attenuation of cholesterol-induced retention of sodium. Treatment for 3 weeks with Fenofibrate in a dose of 100 mg kg(-1) day(-1) reversed the function of renal Na,K-ATPase only slightly.


Assuntos
Antioxidantes/farmacologia , Colesterol na Dieta/efeitos adversos , Homeostase/efeitos dos fármacos , Hiperlipoproteinemia Tipo IV/metabolismo , Indóis/farmacologia , Piridinas/farmacologia , Sódio/metabolismo , Animais , Antioxidantes/uso terapêutico , Peso Corporal , Colesterol/sangue , Taxa de Filtração Glomerular/efeitos dos fármacos , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Hiperlipoproteinemia Tipo IV/fisiopatologia , Indóis/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/fisiopatologia , Cinética , Masculino , Tamanho do Órgão , Estresse Oxidativo , Proteínas/metabolismo , Piridinas/uso terapêutico , Ratos , ATPase Trocadora de Sódio-Potássio , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Triglicerídeos/sangue
6.
Neuro Endocrinol Lett ; 33 Suppl 3: 48-52, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23353843

RESUMO

OBJECTIVES: The aim of this study was to investigate whether rosuvastatin affects expression and activity of rat CYP2C6. This cytochrome P450 is considered to be a counterpart of human CYP2C9, which metabolizes many drugs, including diclofenac, ibuprofen or warfarin. DESIGN: Male hereditary hypertriglyceridemic (HHTg) rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD: STD + 1% of cholesterol w/w + 10% of lard fat w/w) for 21 days. A third group of rats were fed high a cholesterol diet with rosuvastatin added (0.03% w/w). Expression of CYP2C6 was measured in liver samples using real-time PCR (mRNA level) and Western blotting (protein level). Formation of diclofenac metabolites (typical enzyme activity of CYP2C6) was analyzed using HPLC with UV detection. RESULTS: Administration of rosuvastatin to HHTg rats resulted in significantly increased mRNA expression and enzyme activity in HCD-fed animals; changes of CYP2C6 protein were non-significant. These results suggest that CYP2C6 expression and activity are positively affected by rosuvastatin in hereditary hypertriglyceridemic rats after intake of HCD. CONCLUSION: The results presented open the possibility that in humans, rosuvastatin may affect the metabolism of many drugs by influencing expression and activity of CYP2C6 (counterpart of human CYP2C9). Further studies are needed to elucidate the effects of this statin on CYP2C9 in humans.


Assuntos
Fluorbenzenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Pirimidinas/farmacologia , Esteroide 21-Hidroxilase/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Hidrocarboneto de Aril Hidroxilases/metabolismo , Colesterol na Dieta/farmacologia , Citocromo P-450 CYP2C9 , Família 2 do Citocromo P450 , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Masculino , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , RNA Mensageiro/metabolismo , Ratos , Ratos Mutantes , Ratos Wistar , Rosuvastatina Cálcica , Esteroide 21-Hidroxilase/genética , Esteroide 21-Hidroxilase/metabolismo , Transcrição Gênica/efeitos dos fármacos
7.
Curr Opin Lipidol ; 22(4): 247-53, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21519249

RESUMO

PURPOSE OF REVIEW: Hypertriglyceridemia (HTG) is a common diagnosis. Although secondary factors are important for clinical expression, susceptibility to HTG has a strong genetic component, which we review here. RECENT FINDINGS: Severe HTG in a few families follows Mendelian - typically autosomal recessive - inheritance of rare loss-of-function mutations in genes such as LPL, APOC2, APOA5, LMF1, and GPIHBP1. In contrast, common complex HTG results from the cumulative influence of small-effect variants (single nucleotide polymorphisms) in genes such as APOA5, GCKR, LPL, and APOB. Intensive resequencing of these four genes has also shown accumulated heterozygous rare variants in HTG patients. Together, more than 20% of the susceptibility to HTG is now accounted for by common and rare variants. Further, classical Fredrickson HTG phenotypes, which were once considered to be distinct based on biochemical features, have a shared genetic architecture. SUMMARY: Compared to other complex traits, genetic variants account for a high proportion of HTG diagnoses. By tallying the number of HTG risk alleles, it is possible to discriminate between individuals with HTG and normolipidemia, particularly in those with extreme scores. Future directions include finding the missing genetic component and determining whether genetic profiling can help with diagnosis or personalized treatment advice.


Assuntos
Hiperlipoproteinemia Tipo IV/genética , Fenótipo , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Apolipoproteínas A/genética , Proteínas de Transporte/genética , Estudo de Associação Genômica Ampla , Humanos , Hiperlipoproteinemia Tipo IV/metabolismo , Lipase Lipoproteica/deficiência , Lipase Lipoproteica/genética , Proteínas de Membrana/genética , Mutação , Receptores de LDL/genética , Receptores de Lipoproteínas
8.
Food Chem Toxicol ; 47(10): 2624-30, 2009 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-19635522

RESUMO

UNLABELLED: Differences in expression of mRNA of genes regulating lipid and drug metabolism between hereditary hypertriglyceridemic rats (HHTg, accepted model of metabolic syndrome) and healthy Wistar-Kyoto (WKY) rats were studied. Also, differences in expression due to intake of high cholesterol diet (1% w/w) were determined to investigate possible differences in response of the WKY and HHTg rats to increased intake of dietary cholesterol. Levels of ATP-binding cassette transporters (ABCG5, ABCG8), fatty acid synthase (FAS) and cytochrome P450 (CYP2C11) mRNA were significantly lower in HHTg rats on standard laboratory diet; in contrary, CYP7A1, CYP2C6 and CYP2B2 gene expression was significantly higher. The WKY rats responded to high cholesterol diet by an increase in expression of mRNAs for sterol regulatory element binding protein (SREBP1c), CYP2B2 and CYP7A1; lower expression was found in the FAS, ABCG5, ABCG8, CYP4A1, CYP4A2 and acyl-CoA oxidase. HHTg rats responded to cholesterol intake in a similar manner, however, differences were found in expression of the FAS and CYP4A1 mRNA (decrease was not observed), CYP2B2 (decrease instead of an increase). CONCLUSIONS: (i) dietary cholesterol significantly influences expression of genes involved in lipid homeostasis and drug metabolism, and (ii) the HHTg rats responded to dietary cholesterol in a different way.


Assuntos
Colesterol na Dieta/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Hiperlipoproteinemia Tipo IV/genética , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Homeostase , Hiperlipoproteinemia Tipo IV/metabolismo , Lipogênese/genética , Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos WKY , Organismos Livres de Patógenos Específicos
9.
Atherosclerosis ; 198(1): 49-56, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-17980882

RESUMO

Hypertriglyceridemia being an independent cardiovascular risk factor, we have compared the potential of sera from asymptomatic hypertriglyceridemic (HTG) type IIb, type IV or normolipidemic (NLP) subjects to promote both fractional cholesterol efflux and cellular cholesterol mass changes using macrophage foam cells. The J774 cells loaded with cholesterol by incubation with acetylated LDL were incubated in the absence or presence of cAMP to upregulate ABCA1 (ATP binding cassette transporter A1) and then incubated for 24h with 1% serum. Compared with NLP, type IV sera exhibited a major increase in ABCA1-dependent efflux while type IIb sera exhibited a moderate but not significant increased ABCA1-mediated efflux. Moreover, positive correlations were established between ABCA1-dependent efflux and the serum prebeta-HDL or TG concentrations. The major finding was that the sera from type IV induced higher total cholesterol and cholesteryl ester mass depletions from ABCA1-expressing cells compared with other groups. Moreover, negative correlations were obtained between total cholesterol or cholesteryl ester mass changes and serum prebeta-HDL levels. In conclusion, we demonstrated for the first time that the serum prebeta-HDL present in high proportions in type IV HTG subjects are not only responsible for higher cholesterol efflux potential but also for increased abilities to promote net removal of cholesterol from macrophage foam cells.


Assuntos
Células Espumosas/metabolismo , Hiperlipoproteinemia Tipo IV/imunologia , Hiperlipoproteinemia Tipo IV/metabolismo , Lipoproteínas LDL/farmacocinética , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Animais , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Células Cultivadas , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Células Espumosas/citologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Receptores Depuradores Classe B/metabolismo , Triglicerídeos/sangue , Trítio
10.
Mol Genet Metab ; 93(3): 282-94, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18023224

RESUMO

Monogenic disorders that cause abnormal levels of plasma cholesterol and triglycerides have received much attention due to their role in metabolic dysfunction and cardiovascular disease. While these disorders often present clinically during adulthood, some present most commonly in the pediatric population and can have serious consequences if misdiagnosed or untreated. This review provides an overview of monogenic lipid disorders that present with unusually high or low levels of plasma cholesterol and/or triglycerides during infancy, childhood and adolescence. Biochemical and genetic findings, clinical presentation and treatment options are discussed with an emphasis upon recent advances in our understanding and management of these monogenic disorders.


Assuntos
Dislipidemias , Serina Endopeptidases/genética , Adolescente , Ácidos e Sais Biliares/metabolismo , Criança , Dislipidemias/classificação , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/terapia , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hiperlipoproteinemia Tipo IV/terapia , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Hipolipoproteinemias/terapia , Mutação , Pró-Proteína Convertase 9 , Pró-Proteína Convertases
11.
J Basic Clin Physiol Pharmacol ; 18(1): 21-35, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17569244

RESUMO

OBJECTIVES: Most of the lipids of the skin surface come from sebaceous glands secretions, called sebum. Some of the sebum lipids are synthesized by sebaceous cells while some are reportedly derived from the plasma. Role of blood lipoproteins in sebum secretion rate and composition is unclear. To this end, excretion rate and composition of skin surface lipids of normo- and type IV hyperlipoproteinemic subjects were compared. DESIGN AND METHODS: Quantitative analysis of skin surface lipids was performed by three successive sampling on left, middle, and right zones of the forehead with a sebumeter. Skin surface lipid samples for the compositional analysis were collected from the forehead, extracted into n-hexane, and analyzed by high performance thin layer chromatography (HPTLC). HPTLC plates were scanned with a densitometer for the quantification of the lipids. RESULTS: Skin surface lipids from type IV hyperlipoproteinemic subjects contained higher proportion of wax ester + cholesterol ester compared with that from normolipoproteinemic subjects. However, skin surface lipid excretion rates of normo- and hyperlipoproteinemic subjects were found to be similar. CONCLUSIONS: Plasma lipid/lipoprotein concentration may be a determinant factor in sebum lipid composition.


Assuntos
Testa , Hiperlipoproteinemia Tipo IV/metabolismo , Lipídeos/química , Sebo/química , Pele , Adulto , Colesterol/química , Cromatografia Líquida de Alta Pressão , Humanos , Concentração de Íons de Hidrogênio , Metabolismo dos Lipídeos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Sebo/metabolismo , Esqualeno/química , Triglicerídeos/química , Água , Ceras/química
12.
Plant Foods Hum Nutr ; 62(2): 59-63, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17333395

RESUMO

This work focused on the effect of Maca on lipid, anti-oxidative, and glucose parameters in hereditary hypertriglyceridemic (HHTg) rat. Maca (1%) was administred to rats as a part of a high-sucrose diet (HSD) for 2 weeks. Rosiglitazone (0.02%) was used as a positive control. Maca significantly decreased the levels of VLDL (very low density lipoproteins), LDL (low density lipoproteins), and total cholesterol, and also the level of TAG (triacylglycerols) in the plasma, VLDL, and liver. Maca, as well as rosiglitazone, significantly improved glucose tolerance, as the decrease of AUC (area under the curve) of glucose showed, and lowered levels of glucose in blood. The activity of SOD (superoxide dismutase) in the liver, the GPX (glutathione peroxidase) in the blood, and the level of GSH (glutathione) in liver increased in all cases significantly. Results demonstrate that maca seems to be promising for a positive influence on chronic human diseases (characterized by atherogenous lipoprotein profile, aggravated antioxidative status, and impaired glucose tolerance), and their prevention.


Assuntos
Antioxidantes/farmacologia , Metabolismo dos Carboidratos/efeitos dos fármacos , Colesterol/sangue , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Lepidium/química , Metabolismo dos Lipídeos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Área Sob a Curva , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Glucose/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hiperlipoproteinemia Tipo IV/metabolismo , Fígado/enzimologia , Fígado/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/análise , Triglicerídeos/sangue
13.
Lik Sprava ; (5-6): 22-5, 2003.
Artigo em Russo | MEDLINE | ID: mdl-14618795

RESUMO

In patients with atherosclerosis of coronary vessels, particular features of antioxidative homeostasis which reflect dynamic balance between reactions of peroxide oxidation of lipids and those of the antioxidant system were studied. Different mechanisms have been revealed of maintenance of antioxidative homeostasis in patients with atherosclerosis of coronary vessels depending on the type of lipid abnormalities. In calculating the coefficient of significance (Kj) formulas have been deduced of significant parameters of antioxidative homeostasis in those atherosclerotic patients revealing normolipidemia, dyslypoproteidemia, type II and IV, that can be used as additional diagnostic and prognostic criteria for the course of the atherosclerotic process.


Assuntos
Antioxidantes/metabolismo , Arteriosclerose/metabolismo , Vasos Coronários/metabolismo , Homeostase , Metabolismo dos Lipídeos , Adulto , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo IV/metabolismo , Peroxidação de Lipídeos , Masculino
14.
Circ Res ; 93(8): 717-25, 2003 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-14512442

RESUMO

Oxysterols are key regulators of lipid metabolism and regulate gene expression by activating the liver X receptor (LXR). LXR plays a vital role in macrophage foam cell formation, a central event in atherosclerosis. It is known that addition of exogenous oxysterols to cultured macrophages activates LXR, leading to increased expression of ABCA1 and cholesterol efflux. In this study, we tested the novel hypothesis that stimulation of endogenous oxysterol synthesis would block foam cell formation induced by atherogenic lipoproteins. Macrophage synthesis of 24(S),25-epoxycholesterol, a potent LXR ligand, increased 60-fold by partial inhibition of 2,3-oxidosqualene:lanosterol cyclase (OSC), a microsomal enzyme in both the cholesterol biosynthetic pathway and the alternative oxysterol synthetic pathway. When macrophages were challenged with human hypertriglyceridemic VLDL (HTG-VLDL), cellular cholesteryl ester accumulation increased 12-fold. This was reduced dramatically, by 65%, after preincubation with an OSC inhibitor (OSCi). The HTG-VLDL-induced accumulation of macrophage TG (70-fold) was unaffected by the OSCi or exogenous 24(S),25-epoxycholesterol, an effect associated with suppression of SREBP-1 processing. By contrast, TO901317, a synthetic LXR agonist, increased cellular TG significantly and markedly increased SREBP-1 processing. OSC inhibition decreased HTG-VLDL uptake through downregulation of LDL-receptor expression, despite substantial inhibition of cholesterol synthesis. Furthermore, OSC inhibition significantly upregulated ABCA1 and ABCG1 expression, which led to enhanced macrophage cholesterol efflux, an effect mediated through LXR activation. Therefore, increased macrophage synthesis of endogenous oxysterols represents a new mechanism for the dual regulation of LXR- and SREBP-responsive genes, an approach that inhibits foam cell formation without detrimental effect on TG synthesis.


Assuntos
Colesterol/análogos & derivados , Colesterol/biossíntese , Células Espumosas/metabolismo , Transferases Intramoleculares/antagonistas & inibidores , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Linhagem Celular , Células Cultivadas , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hiperlipoproteinemia Tipo IV/metabolismo , Metabolismo dos Lipídeos , Lipase Lipoproteica/metabolismo , Lipoproteínas VLDL/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/enzimologia , Camundongos , RNA Mensageiro/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Triglicerídeos/biossíntese , Triglicerídeos/metabolismo
15.
J Inherit Metab Dis ; 26(2-3): 267-87, 2003.
Artigo em Inglês | MEDLINE | ID: mdl-12889666

RESUMO

Disorders of lipoproteins often lead to disease in humans. Most often the sequelae of long-term dyslipoproteinaemia lead to atherosclerotic vascular disease in all arterial beds. Plasma elevation of low-density lipoprotein cholesterol (LDL-C), very low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of high-density lipoproteins (HDL-C) are risk factors for coronary artery disease. Severe elevations of plasma triglycerides may lead to acute pancreatitis. In Western societies and in emerging economies, lifestyle contributes to the expression of lipoprotein disorders. Many dyslipoproteinaemias have a genetic aetiology. This review will examine the contribution of genetic lipoprotein disorders in human disease. Emphasis will be placed on monogenic disorders that are associated with coronary artery disease and novel causes of disorders of high-density lipoproteins. The consideration of screening and treatment of affected individuals, especially children, must take into account the severity of the phenotype, the long-term risk of developing vascular disease and available evidence of clinical benefit in a group of diseases that are mostly asymptomatic until manifestations of organ ischaemia in the heart, limbs or brain.


Assuntos
Doenças Cardiovasculares/etiologia , Lipoproteínas/metabolismo , Transporte Biológico , Humanos , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo III/metabolismo , Hiperlipoproteinemia Tipo IV/metabolismo , Lipoproteínas/química , Lipoproteínas HDL/metabolismo , Risco
16.
Clin Ther ; 24(7): 1105-16, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12182255

RESUMO

BACKGROUND: Newer fibrates such as micronized fenofibrate lower triglyceride (TG) levels, raise high-density lipoprotein cholesterol (HDL-C) levels, and lower fibrinogen levels, in addition to markedly lowering levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). A new microcoated "suprabioavailable" formulation of fenofibrate has demonstrated a superior pharmacokinetic profile compared with micronized fenofibrate 200 mg/d and may effectively reduce cardiovascular risk factors at the lower dose of 160 mg/d. OBJECTIVE: The goal of this study was to assess the efficacy and tolerability of the suprabioavailable" formulation of fenofibrate in patients with type IIa, type IIb, or type IV dyslipidemia. METHODS: This was a pooled analysis of data from 2 unpublished multicenter, open-label trials with a common protocol. After a 4-week washout period, patients with dyslipidemias not corrected by diet alone were assigned to receive microcoated fenofibrate 160 mg/d for 12 weeks. Changes in lipid profiles and safety variables (vital signs, body weight, and laboratory measures) were monitored throughout the study, and adverse events occurring between visits 1 and 5 were recorded by the study investigators. RESULTS: The 2 trials included 375 men and women (mean age, 55.2 years) with type IIa (n = 158), type IIb (n = 195), type IV (n = 21), or other (n = 1) dyslipidemias. At end point. HDL-C levels in patients with type IIa, IIb, or IV dyslipidemia were increased by a respective 10.9% (P < 0.001), 16.1% (P < 0.001), and 12.1% (P < 0.05), whereas TG levels were decreased by a respective 27.7% (P < 0.001), 46.4% (P < 0.001), and 40.2% (P < 0.05). In patients with type IIa or IIb dyslipidemia, TC decreased (-14.3% in each group), LDL-C decreased (-20.6% and -13.2%, respectively), and the LDL-C/HDL-C ratio decreased (-26.7% and -22.0%) (all, P < 0.001). Overall, 121 of 375 (32.3%) patients experienced > or = adverse event (AE) (202 nonserious, 8 serious). Of these, 10.1% were judged to be possibly drug related. The most common nonserious AEs were those affecting the body as a whole (2.7% of patients) and the digestive system (5.3% of patients). No serious AE was considered drug related. CONCLUSIONS: The new "suprabioavailable" microcoated, micronized formulation of fenofibrate appears to maintain the good efficacy and safety profile of micronized fenofibrate. In the study population with moderate dyslipidemia (types IIa and IIb), it promoted beneficial changes in major lipid risk factors for cardiovascular disease.


Assuntos
Fenofibrato/uso terapêutico , Hiperlipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adolescente , Adulto , Idoso , Disponibilidade Biológica , HDL-Colesterol/sangue , HDL-Colesterol/metabolismo , Ensaios Clínicos como Assunto , Feminino , Fenofibrato/efeitos adversos , Humanos , Hiperlipidemias/metabolismo , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Hiperlipoproteinemia Tipo IV/metabolismo , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Resultado do Tratamento , Triglicerídeos/sangue , Triglicerídeos/metabolismo
17.
Arterioscler Thromb Vasc Biol ; 21(12): 2039-45, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11742882

RESUMO

Familial hypertriglyceridemia (FHTG), a disease characterized by elevated plasma very low density lipoprotein triglyceride levels, has been associated with impaired intestinal absorption of bile acids. The aim of this study was to test the hypothesis that defects in the active ileal absorption of bile acids are a primary cause of FHTG. Single-stranded conformation polymorphism analysis was used to screen the ileal Na(+)/bile acid cotransporter gene (SLC10A2) for FHTG-associated mutations. Analysis of 20 hypertriglyceridemic patients with abnormal bile acid metabolism revealed 3 missense mutations (V98I, V159I, and A171S), a frame-shift mutation (646insG) at codon 216, and 4 polymorphisms in the 5' flanking sequence of SLC10A2. The SLC10A2 missense mutations and 5' flanking sequence polymorphisms were not correlated with bile acid production or turnover in the hypertriglyceridemic patients and were equally prevalent in the unaffected control subjects. In transfected COS cells, the V98I, V159I, and A171S isoforms all transported bile acids similar to the wild-type SLC10A2. The 646insG frame-shift mutation abolished bile acid transport activity in transfected COS cells but was found in only a single FHTG patient. These findings indicate that the decreased intestinal bile acid absorption in FHTG patients is not commonly associated with inherited defects in SLC10A2.


Assuntos
Ácidos e Sais Biliares/metabolismo , Proteínas de Transporte/análise , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Ílio/fisiopatologia , Transportadores de Ânions Orgânicos Dependentes de Sódio , Simportadores , Adulto , Feminino , Mutação da Fase de Leitura , Frequência do Gene , Humanos , Absorção Intestinal , Masculino , Pessoa de Meia-Idade
19.
Atherosclerosis ; 146(1): 19-23, 1999 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10487482

RESUMO

The role of plasma triglycerides as a risk factor for cardiovascular disease is still under scrutiny. While recent studies have shown that postprandial triglyceridemia is an independent risk factor, normalization of fasting plasma triglycerides through modification of nutritional habits remains the primary approach in the treatment of hypertriglyceridemia. To address the issue of whether a satisfactory dietary regimen results in the control of postprandial lipemia, 53 type IV hypertriglyceridemic patients underwent an hypolipidemic diet for 3 months. All patients had a reduction of fasting lipid parameters (average TG: from 516+/-208 to 229+/-99 mg/dl; total cholesterol (Chol): from 261+/-42 to 213+/-40 mg/dl and HDL Chol: from 33+/-9 to 38+/-8 mg/dl). Taking plasma TG < or =200 mg/dl as the target for dietary intervention 26 patients were classified as 'responders' while the remaining 27 were 'non responders'. Even if fasting total TG, total Chol, HDL and LDL Chol were normal, both responders and non responders (P<0.0001) showed an exaggerated postprandial response to an oral fat load as compared to controls (20 normolipidemic subjects). Also when 10 responders and 10 controls, all male, were matched for plasma TG (129+/-43 versus 121+/-41 mg/dl) and other lipid parameters, a statistically significant difference between the two groups was observed at the time of each of the postprandial tests (P<0.0001) and for the area under the curve. The fact that the post prandial response is poorly modified by a dietary regimen, that effectively reduces plasma fasting TG, suggests that commonly used dietary regimens fail to restore a normal postprandial metabolism. Whether the cardiovascular risk for these patients is reduced after diet remains, therefore, to be addressed.


Assuntos
Hiperlipoproteinemia Tipo IV/dietoterapia , Triglicerídeos/sangue , Adulto , Análise de Variância , Dieta Aterogênica , Feminino , Humanos , Hiperlipoproteinemia Tipo IV/diagnóstico , Hiperlipoproteinemia Tipo IV/metabolismo , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Falha de Tratamento , Triglicerídeos/metabolismo
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