RESUMEN
BACKGROUND: The notion that hepatic expression of genes involved in lipid metabolism is altered in obese patients is relatively new and its relationship with hepatic steatosis and cardiometabolic alterations remains unclear. OBJECTIVE: We assessed the impact of Roux-en-Y gastric bypass surgery (RYGB) on the expression profile of genes related to metabolic syndrome in liver biopsies from morbidly obese individuals using a custom-made, focused cDNA microarray, and assessed the relationship between the expression profile and hepatic steatosis regression. MATERIALS AND METHODS: Plasma and liver samples were obtained from patients at baseline and 12 months after surgery. Samples were assayed for chemical and gene expression analyses, as appropriate. Gene expression profiles were assessed using custom-made, focused TaqMan low-density array cards. RESULTS: RYGB-induced weight loss produced a favorable reduction in fat deposits, insulin resistance (estimated by homeostasis model assessment of insulin resistance (HOMA-IR)), and plasma and hepatic lipid levels. Compared with the baseline values, the gene expression levels of key targets of lipid metabolism were significantly altered: CD36 was significantly downregulated (-40%; P=0.001), whereas APOB (+27%; P=0.032) and SCARB1 (+37%; P=0.040) were upregulated in response to surgery-induced weight reduction. We also observed a favorable reduction in the expression of the PAI1 gene (-80%; P=0.007) and a significant increase in the expression of the PPARA (+60%; P=0.014) and PPARGC1 genes (+36%; P=0.015). Notably, the relative fold decrease in the expression of the CD36 gene was directly associated with a concomitant reduction in the cholesterol (Spearman's r=0.92; P=0.001) and phospholipid (Spearman's r=0.76; P=0.04) contents in this tissue. CONCLUSIONS: For the first time, RYGB-induced weight loss was shown to promote a favorable downregulation of CD36 expression, which was proportional to a favorable reduction in the hepatic cholesterol and phospholipid contents in our morbidly obese subjects following surgery.
Asunto(s)
Antígenos CD36/metabolismo , Hígado Graso/prevención & control , Derivación Gástrica , Hígado/metabolismo , Síndrome Metabólico/prevención & control , Obesidad Mórbida/cirugía , Pérdida de Peso/fisiología , Regulación hacia Abajo , Hígado Graso/metabolismo , Humanos , Resistencia a la Insulina/fisiología , Metabolismo de los Lípidos/fisiología , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Análisis por Micromatrices , Obesidad Mórbida/complicaciones , Obesidad Mórbida/metabolismo , Fosfolípidos/metabolismoRESUMEN
BACKGROUND: Although bariatric surgery is currently the most common practice for inducing weight loss in morbidly obese patients (BMI>40 kg/m2), its effect on the lipid content of adipose tissue and its lipases (lipoprotein lipase [LPL] and hormone-sensitive lipase [HSL]) are controversial. METHODS: We analyzed LPL and HSL activities and lipid content from plasma as well as subcutaneous (SAT) and visceral (VAT) adipose tissue of 34 morbidly obese patients (MO) before and after (6 and 12 months) Roux-en-Y gastric bypass surgery and compare the values with those of normal weight (control) patients. RESULTS: LPL activity was significantly higher in MO (SAT=32.9+/-1.0 vs VAT=36.4+/-3.3 mU/g tissue; p<0.001) than in control subjects (SAT=8.2+/-1.4 vs VAT=6.8+/-1.0 mU/g tissue) in both adipose depots. HSL activity had similar values in both types of tissue (SAT=32.8+/-1.6 and VAT=32.9+/-1.6 mU/g) of MO. In the control group, we found similar results but with lower values (SAT=11.9+/-1.4 vs VAT=12.1+/-1.4 mU/g tissue). Twelve months after surgery, SAT LPL activity diminished (9.8+/-1.4 mU/g tissue, p<0.001 vs morbidly obese), while HSL (46.6+/-3.7 mU/g tissue) remained high. All lipids in tissue and plasma diminished after bariatric surgery except plasma nonesterified fatty acids, which maintained higher levels than controls (16+/-3 vs 9+/-0 mg/dL; p<0.001, respectively). CONCLUSIONS: When obese patients lose weight, they lose not only part of the lipid content of the cells but also the capacity to store triacylglycerides in SAT depots.
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Derivación Gástrica , Lipoproteína Lipasa/sangre , Obesidad Mórbida/cirugía , Esterol Esterasa/sangre , Pérdida de Peso , Adulto , Estudios de Casos y Controles , Femenino , Estudios de Seguimiento , Humanos , Grasa Intraabdominal/metabolismo , Grasa Intraabdominal/patología , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/fisiopatología , Grasa Subcutánea/metabolismo , Grasa Subcutánea/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Although bariatric surgery is the most common procedure used to induce weight loss in morbidly obese patients, its effect on plasma satiety factors (leptin, ghrelin, and apolipoprotein (apo)-AIV) is controversial. The aim of this work was to analyze these parameters before and at different times after surgery. METHODS: Plasma was obtained from 34 patients before undergoing Roux-en-Y gastric bypass and during weight loss in the 12 months following surgery. RESULTS: Morbidly obese patients had significantly higher values (147%) of leptin than normal-weight (NW) persons, while their ghrelin levels were 46% less than NW. Apo-AIV levels had approximately the same value in both groups (obese and NW). During weight loss, leptin decreased by 75% and ghrelin increased by 78%. Both parameters reached values less than or near NW, respectively, at 1 year after surgery. During the first month after surgery, apo-AIV plasma levels decreased (47%) but later increased and finally returned to preoperative values. Apo-AIV levels were correlated negatively with leptin and positively with ghrelin. High-density lipoprotein (HDL) levels were positively correlated with those of ghrelin and apo-AIV. CONCLUSIONS: During weight loss, plasma leptin and ghrelin could be good markers of total fat decrease. Ghrelin could also indicate gastric mucous improvement, whereas apo-AIV could indicate the recovery of intestinal function. Changes produced in the HDL levels of morbidly obese patients during weight loss suggest a decreased risk of coronary disease.
Asunto(s)
Apolipoproteínas A/sangre , Ghrelina/sangre , Leptina/sangre , Obesidad Mórbida/sangre , Pérdida de Peso/fisiología , Tejido Adiposo/metabolismo , Adulto , Biomarcadores/sangre , Femenino , Derivación Gástrica , Humanos , Insulina/sangre , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Obesidad Mórbida/cirugía , Saciedad/fisiología , Delgadez/sangre , Factores de TiempoRESUMEN
OBJECTIVE: To study the effect of oral oleoyl-estrone on the plasma lipoprotein profile and tissue lipase activities in order to determine the handling of circulating lipids by adipose tissue, liver and muscle of obese female rats. DESIGN: Lean (Fa/?) and obese (fa/fa) female Zucker rats treated for 10 days with a daily gavage of 0.2 ml sunflower oil containing 0 (controls) or 10 micromol/kg of oleoyl-estrone. After sacrifice, samples of tissues and plasma were taken. MEASUREMENTS: Plasma lipoprotein classes and composition; lipoprotein lipase and hepatic lipase activities in plasma, liver, skeletal muscle and periovaric and mesenteric white adipose tissue (WAT). RESULTS: Oleoyl-estrone decreased plasma cholesterol (mainly in HDLs: 76%) of lean rats, but dramatically decreased all lipid classes in obese rats, in which chylomicra and VLDL lost most of their triacylglycerols (95 and 81%, respectively). Hepatic lipase activity decreased markedly with oleoyl-estrone in all groups, both in plasma (79% lean, 100% obese) and liver (62% in both groups). Lipoprotein lipase activity was largely unchanged by oleoyl-estrone in lean rats, but in the obese it decreased in WAT (82% in periovaric, and 49% in mesenteric), and increased in plasma (x4) and in skeletal muscle (x5); liver levels showed no change. CONCLUSIONS: The shift observed in obese rats from a decrease in liver and WAT lipoprotein lipase and hepatic lipase activities to an increase in muscle lipoprotein lipase is coincident with the hypolipemic effect of oleoyl-estrone, especially in obese rats, and indicates that muscle is a key site for the disposal of endogenous fat mobilized due to oleoyl-estrone treatment.
Asunto(s)
Fármacos Antiobesidad/farmacología , Estrona/análogos & derivados , Estrona/farmacología , Lipasa/metabolismo , Lipoproteínas/sangre , Obesidad/sangre , Obesidad/enzimología , Ácidos Oléicos/farmacología , Tejido Adiposo/enzimología , Animales , Fármacos Antiobesidad/administración & dosificación , Colesterol/sangre , HDL-Colesterol/sangre , Estrona/administración & dosificación , Femenino , Lipasa/sangre , Lipoproteína Lipasa/sangre , Lipoproteína Lipasa/metabolismo , Hígado/enzimología , Músculo Esquelético/enzimología , Ácidos Oléicos/administración & dosificación , Ratas , Ratas ZuckerRESUMEN
INTRODUCTION: Tumor necrosis factor (TNFalpha) has been invoked as an adipostat. Accordingly, the adipose tissue expression of TNFalpha has been shown to be proportional to the degree of adiposity. The regulatory role of TNFalpha in obesity may be controlled by several mechanisms. These include the inhibitory effect on LPL activity, the mediation on glucose homeostasis or the effect on leptin. To assess the role of TNFalpha in obesity we measured adipocyte TNFalpha expression in 96 females with a wide range of adiposity and with or without type 2 diabetes. We analysed the relationship between TNFalpha expression, adipocyte LPL activity, insulin resistance and leptin in this population. RESULTS: The TNFalpha and leptin expression of the adipose tissue in obese and morbid obese patients were significantly higher than in controls. Obese and morbid obese patients had slightly higher levels of LPL activity, but these differences were not significant. We observed a significant relationship between adipose TNFalpha expression and body mass index (r=0.35, P<0.001). TNFalpha expression was negatively related to LPL activity (r=-0.28, P<0.05) and positively related to leptin expression (r=0.35, P<0.001). CONCLUSION: Our results indicate that obese women, even those with morbid obesity, over-express TNFalpha in subcutaneous adipose tissue in proportion to the magnitude of the fat depot and independently of the presence of type 2 diabetes. The TNFalpha system may be a homeostatic mechanism that prevents further fat deposition by regulating LPL activity and leptin production.
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Tejido Adiposo/metabolismo , Expresión Génica , Leptina/biosíntesis , Lipoproteína Lipasa/metabolismo , Obesidad/metabolismo , Factor de Necrosis Tumoral alfa/genética , Adipocitos/enzimología , Adipocitos/metabolismo , Adolescente , Adulto , Anciano , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Diabetes Mellitus/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Humanos , Insulina/sangre , Resistencia a la Insulina , Leptina/genética , Persona de Mediana Edad , Obesidad Mórbida/metabolismo , ARN Mensajero/análisis , Triglicéridos/sangreRESUMEN
Adult female lean and obese Zucker rats maintained under standard conditions were used for the estimation of plasma, liver and white adipose tissue (WAT) activity of lipoprotein lipase, plasma and liver hepatic lipase and plasma lecithin-cholesterol acyltransferase. No differences in plasma or tissue levels of lipoprotein lipase between lean and obese rats were detected, but the larger WAT size of the obese rats resulted in higher lipase activity per unit of rat weight. Hepatic lipase levels in plasma were higher in the obese, but in liver, the higher activity was found in lean rats. No significant differences were found for lecithin-cholesterol acyltransferase activity, except when the levels in the HDL fraction were expressed per unit of protein weight, showing lower activity in the obese rats. In conclusion, the essentially maintained enzyme activities in obese rat tissues suggest that they cannot explain the deficient lipoproteins processing of obese rats, and, consequently their dislipidaemia.
Asunto(s)
Tejido Adiposo/metabolismo , Lipoproteína Lipasa/metabolismo , Hígado/metabolismo , Obesidad/metabolismo , Esterol O-Aciltransferasa/metabolismo , Animales , Femenino , Hiperlipidemias/complicaciones , Hiperlipidemias/metabolismo , Lipasa/metabolismo , Lipoproteína Lipasa/sangre , Lipoproteínas HDL/metabolismo , Obesidad/complicaciones , Ratas , Ratas Zucker , Esterol O-Aciltransferasa/sangre , Delgadez/metabolismoRESUMEN
AIMS: Obesity is characterized by dislipoproteinaemia with increased cholesterol and triacylglycerol levels and lower chylomicra disposal rates. We studied here whether these alterations were related to lipoprotein number and/or size and composition. METHODS: Plasma from lean and obese Zucker rats was fractionated into lipoprotein classes (chylomicra, very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)) by differential centrifugation. The apoprotein and lipid composition of each fraction were measured. Lipoprotein particle size was estimated by dynamic light scattering and used to tabulate the mean diameter and volume of lipoprotein micelles. Particle mass was calculated from the density and volume. The mass of lipids and protein in each fraction/ml of plasma allowed the estimation of mean particle concentration and then the number of molecules of lipid and protein/unit of lipoprotein micelle. RESULTS: A large part of hyperlipidaemia of obese rats is due to the accumulation of chylomicra: 1.3 +/- 0.2 mg/ml in lean rats [LR] (34% of all lipoproteins) and 8.2 +/- 0.9 mg/ml in the obese rats [OR] (66% of all lipoproteins). Lipid percentage composition of lipoproteins was similar in both groups. The particle size of LDL and HDL was much higher in OR than in LR: LDLs weighed 31.1 +/- 7.5 ag (LR) vs. 273 +/- 81 ag (OR), and HDLs weighed 31.7 +/- 12.6 ag (LR) and 375 +/- 103 ag (OR). In chylomicra and VLDL there was a relative scarcity of apoproteins in OR compared with LR. The whole architecture of LDLs is altered in OR, with a predominance of surface lipids: phospholipid and free cholesterol, and lower amounts of core lipids: triacylglycerols and cholesterol esters, with surface/core lipids ratios of 0.74 (LR) and 1.89 (OR). The consequences of anomalous LDL and HDL composition, size and overall structure may result in magnified lipoprotein metabolism alterations that hamper their ability to transfer apolipoproteins to larger chylomicra and VLDL, and to alter cholesterol transfer and binding of their apoproteins to cell surface receptors. The smaller number of LDL and HDL particles may further compound these difficulties and thus change the free to esterified cholesterol ratios observed in OR. CONCLUSIONS: The main conclusions of this study are the key importance of chylomicron analysis for a better understanding of the transfer of lipids, and the altered lipoprotein size and apoprotein distribution in obese rats, which seriously hamper cholesterol interchange, resulting in hypercholesterolaemia, and thus triggering even more far-reaching consequences for the well-being of the obese.
Asunto(s)
Apolipoproteínas/sangre , Lipoproteínas/sangre , Obesidad/sangre , Análisis de Varianza , Animales , Colesterol/sangre , Quilomicrones/sangre , Electroforesis en Gel de Poliacrilamida , Femenino , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Micelas , Obesidad/genética , Fosfolípidos/sangre , Ratas , Ratas Zucker , Valores de Referencia , Triglicéridos/sangreRESUMEN
Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both normal and diabetic rodents. Administration of a rexinoid such as LG100268 (LG268) to normal or diabetic rats results in a rapid increase in serum triglyceride levels. LG268 has no effect on hepatic triglyceride production but suppresses post-heparin plasma lipoprotein lipase (LPL) activity suggesting that the hypertriglyceridemia results from diminished peripheral processing of plasma very low density lipoproteins particles. Treatment of diabetic rats with rexinoids suppresses skeletal and cardiac muscle but not adipose tissue LPL activity. This effect is independent of changes in LPL mRNA. In C2C12 myocytes, LG268 suppresses the level of cell surface (i.e., heparin-releasable) LPL activity without altering LPL mRNA. This effect is very rapid (t(1/2) = 2 h) and is blocked by the transcriptional inhibitor actinomycin D. These studies demonstrate that RXR ligands can have dramatic effects on the post-translational processing of LPL and suggest that skeletal muscle may be an important target of rexinoid action. In addition, these data underscore that the metabolic consequences of RXR activation are distinct from either retinoic acid receptor or peroxisome proliferator-activated receptor activation.
Asunto(s)
Lipoproteína Lipasa/metabolismo , Ácidos Nicotínicos/farmacología , Receptores de Ácido Retinoico/metabolismo , Tetrahidronaftalenos/farmacología , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , Corazón/efectos de los fármacos , Hipertrigliceridemia/sangre , Hipertrigliceridemia/inducido químicamente , Lipoproteína Lipasa/efectos de los fármacos , Lipoproteínas VLDL/efectos de los fármacos , Lipoproteínas VLDL/metabolismo , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/enzimología , Miocardio/enzimología , Miocardio/metabolismo , Ácidos Nicotínicos/efectos adversos , Ratas , Ratas Sprague-Dawley , Ratas Zucker , Receptores de Ácido Retinoico/efectos de los fármacos , Receptores X Retinoide , Retinoides , Tetrahidronaftalenos/efectos adversos , Factores de Transcripción/efectos de los fármacos , Triglicéridos/sangreRESUMEN
BACKGROUND: Food deprivation induces the mobilization of fat reserves and, consequently, the transport of lipids in plasma. Zucker obese rats are grossly hyperlipidemic and do not use lipids as an efficient energy substrate. They also have lower circulating levels of acyl-estrone than expected because of their large fat stores. AIM OF THE STUDY: To measure the effect of 24 h food deprivation on hyperlipidemia and acyl-estrone distribution in plasma in Zucker obese rats. METHODS: The plasma lipoprotein distribution and composition of Zucker lean (Fa/?) and obese (fa/fa) rats was determined after 24 hours of food deprivation. Lipid classes: phospholipid, free and esterified cholesterol and triacylglycerols, and protein and total (mainly acyl-) estrone were also measured in total plasma and lipoprotein fractions. RESULTS: Food-deprived rats showed lower triacylglycerol levels than fed rats, but obese rats maintained high lipid levels, mainly in the VLDL fraction. The ratio of total plasma free-to-esterified cholesterol was lower in fed lean rats (0.29) than in the obese (0.61); the situation improved slightly after 24-h starvation, since the corresponding ratios were 0.30 and 0.41. Acyl estrone levels changed little with 24-h food deprivation. The chylomicra + VLDL total estrone compartment was essentially unchanged in lean and obese fed and starved groups, but the HDL pool decreased with food deprivation in the obese. CONCLUSION: Short-term starvation helped to enhance the differences between lean and obese Zucker rats in the handling of lipoprotein lipids, the latter showing a marked impairment in their ability to dispose of circulating lipids. The different pace of plasma lipid utilization may compound the problems of cholesterol transfer, partly explaining the dyslipemia that characterizes this animal model of obesity. The differences in acyl-estrone distribution also indicate that fat mass is preserved more effectively in obese rats even after food deprivation.
Asunto(s)
Estrona/análogos & derivados , Estrona/sangre , Privación de Alimentos/fisiología , Hiperlipidemias/sangre , Lipoproteínas/química , Obesidad/sangre , Ácidos Oléicos/sangre , Tejido Adiposo/metabolismo , Animales , Proteínas Sanguíneas/análisis , Quilomicrones/sangre , Femenino , Hiperlipidemias/metabolismo , Lípidos/sangre , Lipoproteínas/sangre , Obesidad/metabolismo , Ratas , Ratas ZuckerRESUMEN
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which heterodimerize with the retinoid X receptor and bind to peroxisome proliferator response elements in the promoters of regulated genes. Despite the wealth of information available on the function of PPARalpha and PPARgamma, relatively little is known about the most widely expressed PPAR subtype, PPARdelta. Here we show that treatment of insulin resistant db/db mice with the PPARdelta agonist L-165041, at doses that had no effect on either glucose or triglycerides, raised total plasma cholesterol concentrations. The increased cholesterol was primarily associated with high density lipoprotein (HDL) particles, as shown by fast protein liquid chromatography analysis. These data were corroborated by the chemical analysis of the lipoproteins isolated by ultracentrifugation, demonstrating that treatment with L-165041 produced an increase in circulating HDL without major changes in very low or low density lipoproteins. White adipose tissue lipoprotein lipase activity was reduced following treatment with the PPARdelta ligand, but was increased by a PPARgamma agonist. These data suggest both that PPARdelta is involved in the regulation of cholesterol metabolism in db/db mice and that PPARdelta ligands could potentially have therapeutic value.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Lípidos/sangre , Receptores Citoplasmáticos y Nucleares/metabolismo , Factores de Transcripción/metabolismo , Acetatos/farmacología , Tejido Adiposo/metabolismo , Animales , Glucemia/metabolismo , Colesterol/química , Colesterol/metabolismo , Cromatografía Liquida , Proteínas de Unión al ADN/química , Ligandos , Lipoproteína Lipasa/metabolismo , Lipoproteínas/química , Lipoproteínas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Mutantes , Fenoles/farmacología , Fenoxiacetatos , Receptores Citoplasmáticos y Nucleares/química , Factores de Transcripción/química , Triglicéridos/sangre , UltracentrifugaciónRESUMEN
The effect of fasting on hepatic lipase was studied during postnatal development in the rat. It was found that fasting produced a significant decrease in hepatic lipase only in neonatal (1-day-old) and adult (60-day-old) rats. We studied the effect of fasting on the distribution of hepatic lipase between extracellular (heparin-releasable) and intracellular (liver-retained or residual) compartments in perfused livers, and on the secretion of hepatic lipase by isolated hepatocytes. Fasting had similar effects in neonates and adults: it decreased both the heparin-releasing and the residual activities in perfused livers, and also decreased the rate of hepatic lipase secretion by isolated hepatocytes. Finally, the effect of fasting on hepatic lipase mRNA relative abundance in developing rat livers was determined. No difference was observed among the groups studied. It is concluded that the mechanisms involved in the effect of fasting on hepatic lipase appear to be similar in neonates and adult animals and may involve the post-translational processing of the enzyme.
Asunto(s)
Ayuno/fisiología , Lipasa/metabolismo , Hígado/enzimología , Hígado/crecimiento & desarrollo , Envejecimiento , Animales , Animales Recién Nacidos , Femenino , Heparina/metabolismo , Lipasa/genética , Masculino , Procesamiento Proteico-Postraduccional , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
3-Thia fatty acids are modified fatty acids that promote hepatic peroxisome proliferation and decrease serum triacylglycerol, cholesterol and free fatty acid levels in rats. In vivo administration of tetradecylthioacetic acid (TTA) to rats led to a significant decrease in liver apolipoproteins apoA-I, A-II, A-IV, and C-III mRNA levels, and to an increase of liver acyl-CoA oxidase (ACO), carnitine palmitoyltransferase-II, and 3-hydroxy-3-methylglutaryl coenzyme A synthase (HMG-CoA synthase) mRNA levels and activities. By contrast, no significant changes of lipoprotein lipase (LPL) mRNA levels were detected in rat epididymal adipose tissue. Liver carnitine palmitoyltransferase-I, apoB, apoE, and LDL receptor mRNA levels were not significantly affected. When tested in vitro, TTA increased rat ACO and carnitine palmitoyltransferase-I mRNA levels in primary rat hepatocytes and also LPL mRNA levels in 3T3-L1 preadipocytes. TTA also enhanced the transcriptional activity of chimeras containing the DNA binding domain of the yeast transcription factor Gal4 fused to the ligand binding domain of either human PPARalpha or human PPARgamma. The effect depended on the concentration tested and the cell type. In conclusion, our data suggest that in vitro, TTA activates both PPARalpha and PPARgamma, but the latter with much lower affinity. TTA affects serum lipid levels in vivo in rats by acting mainly on the liver via PPARalpha where it decreases the liver expression of genes involved in vascular lipid transport and increases the expression of genes involved in intracellular fatty acid metabolism. -Raspé, E., L. Madsen, A-M. Lefebvre, I. Leitersdorf, L. Gelman, J. Peinado-Onsurbe, J. Dallongeville, J-C. Fruchart, R. Berge, and B. Staels. Modulation of rat liver apolipoprotein gene expression and serum lipid levels by tetradecylthioacetic acid (TTA) via PPARalpha activation.
Asunto(s)
Apolipoproteínas/genética , Regulación de la Expresión Génica/efectos de los fármacos , Lípidos/sangre , Hígado/metabolismo , Receptores Citoplasmáticos y Nucleares/fisiología , Sulfuros/farmacología , Factores de Transcripción/fisiología , Células 3T3 , Tejido Adiposo/química , Tejido Adiposo/metabolismo , Animales , Células Cultivadas , Ácidos Grasos , Humanos , Hígado/química , Hígado/citología , Masculino , Ratones , Isoformas de Proteínas/efectos de los fármacos , Ratas , Ratas Wistar , Células Tumorales CultivadasRESUMEN
Pooled adult normal rat plasma was used for the separation of lipoprotein fractions: VLDL, LDL and HDL, from which a total lipids extract was obtained. The presence of fragments with the MW of estrone and oleoyl-estrone in the lipoprotein fractions was analyzed by HPLC-MS. The results show that oleoyl-estrone is the major estrone component in lipoproteins; this molecular species was present in all three lipoprotein lipid extracts. The lipoprotein fractions were used for the analysis of protein and lipid classes: triacylglycerols, total and esterified cholesterol and phospholipids as well as acyl-estrone. About half of the total acyl-estrone was in the HDL fraction and only about 10% in the VLDL fraction. HDLs contained about one molecule in 50 particles, LDLs one molecule per particle and VLDLs 15 molecules per particle, i.e. given their size, the larger lipoproteins contained more oleoyl-estrone than the HDLs. The distribution of this hormone suggests that oleoyl-estrone is lost with other lipids as the lipoproteins shrink. The results presented show that oleoyl-estrone is a molecule found naturally in rat lipoproteins in low concentrations - the lowest in HDLs - that are consistent with its postulated role in the control of body weight.
Asunto(s)
Estrona/análogos & derivados , Lipoproteínas/sangre , Ácidos Oléicos/sangre , Animales , Ésteres del Colesterol/análisis , Ésteres del Colesterol/sangre , HDL-Colesterol/análisis , HDL-Colesterol/sangre , LDL-Colesterol/análisis , LDL-Colesterol/sangre , VLDL-Colesterol/análisis , VLDL-Colesterol/sangre , Cromatografía Líquida de Alta Presión , Estrona/análisis , Estrona/sangre , Lipoproteínas/análisis , Masculino , Espectrometría de Masas , Ácidos Oléicos/análisis , Ratas , Ratas ZuckerRESUMEN
Type I hyperlipoproteinemia (type I HLP) is a rare disorder of lipid metabolism characterized by fasting chylomicronemia and reduced postheparin plasma lipoprotein lipase (LPL) activity. Most cases of type I HLP are due to genetic defects in the LPL gene or in its activator, the apolipoprotein CII gene. Several cases of acquired type I HLP have also been described in the course of autoimmune diseases due to the presence of circulating inhibitors of LPL. Here we report a case of type I HLP due to a transient defect of LPL activity during puberty associated with chronic idiopathic urticaria (CIU). The absence of any circulating LPL inhibitor in plasma during the disease was demonstrated. The LPL genotype showed that the patient was heterozygous for the D9N variant. This mutation, previously described, can explain only minor defects in the LPL activity. The presence of HLP just after the onset of CIU, and the elevation of the LPL activity with remission of the HLP when the patient recovered from CIU, indicate that type I HLP was caused by CIU. In summary, we report a new etiology for type I HLP - a transient decrease in LPL activity associated with CIU and with absence of circulating inhibitors. This is the first description of this association, which suggests a new mechanism for type I HLP.
Asunto(s)
Hiperlipoproteinemia Tipo I/etiología , Urticaria/complicaciones , Adolescente , Apolipoproteína A-I/sangre , Apolipoproteínas B/sangre , Apolipoproteínas E/genética , Colesterol/sangre , HDL-Colesterol/sangre , Quilomicrones/sangre , Femenino , Genotipo , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Hiperlipoproteinemia Tipo I/sangre , Hiperlipoproteinemia Tipo I/tratamiento farmacológico , Lipasa/sangre , Lipoproteína Lipasa/sangre , Lipoproteína Lipasa/genética , Triglicéridos/sangre , Urticaria/sangre , Urticaria/tratamiento farmacológicoRESUMEN
The expression of lipoprotein lipase (LPL) and actin genes was examined in heart, muscle and white adipose tissue (WAT) and the expression of albumin and actin genes was examined in regenerating liver after 2/3 hepatectomy. Both surgical stress and partial hepatectomy (PH) affected LPL and actin mRNA levels in muscle and WAT, but not in heart. The changes in LPL mRNA suggest transcriptional regulation of the enzyme during hepatic regeneration. Our results show for the first time that the LPL gene expression in the different tissues studied is altered not only by the surgical stress, but also by PH per se. Actin expression is also affected in some tissues. In liver, PH and surgical stress altered the expression of albumin and total mRNA. The total mRNA of the other tissues studied did not change. The changes observed in LPL in different tissues, especially in WAT and muscle, may be responsible for some of the changes in lipidic metabolism, thus allowing for some plasma lipoproteins to be used as substrates by the LPL activity that arises in the liver during hepatic regeneration. The fatty acids derived from these lipoproteins would constitute not only an energy source but also the building material needed in the process of restoration of the lost hepatic mass. It is suggested that hormonal changes taking place after surgery are responsible for the variation in the levels of the different mRNAs studied.
Asunto(s)
Actinas/metabolismo , Lipoproteína Lipasa/metabolismo , Hígado/enzimología , Estrés Fisiológico/enzimología , Actinas/genética , Tejido Adiposo/metabolismo , Animales , Hepatectomía , Lipoproteína Lipasa/genética , Regeneración Hepática , Masculino , Músculo Esquelético/metabolismo , Miocardio/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Statins are hypolipidemic drugs which not only improve cholesterol but also triglyceride levels. Whereas their cholesterol-reducing effect involves inhibition of de novo biosynthesis of cellular cholesterol through competitive inhibition of its rate-limiting enzyme 3-hydroxy-3-methylglutaryl CoA reductase, the mechanism by which they lower triglycerides remains unknown and forms the subject of the current study. Treatment of normal rats for 4 days with simvastatin decreased serum triglycerides significantly, whereas it increased high density lipoprotein cholesterol moderately. The decrease in triglyceride concentrations after simvastatin was caused by a reduction in the amount of very low density lipoprotein particles which were of an unchanged lipid composition. Simvastatin administration increased the lipoprotein lipase mRNA and activity in adipose tissue and heart. This effect on lipoprotein lipase was accompanied by decreased mRNA as well as plasma levels of the lipoprotein lipase inhibitor apolipoprotein C-III. These results suggest that the triglyceride-lowering effect of statins involves a stimulation of lipoprotein lipase-mediated clearance of triglyceride-rich lipoproteins.
Asunto(s)
Apolipoproteínas C/sangre , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Lipoproteína Lipasa/sangre , Simvastatina/farmacología , Triglicéridos/sangre , Animales , Apolipoproteína A-I/sangre , Apolipoproteína A-II/sangre , Apolipoproteína C-III , Apolipoproteínas C/efectos de los fármacos , Colesterol/sangre , HDL-Colesterol/sangre , Lipoproteína Lipasa/efectos de los fármacos , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
Thiazolidinediones are antidiabetic agents, which not only improve glucose metabolism but also reduce blood triglyceride concentrations. These compounds are synthetic ligands for PPAR gamma, a transcription factor belonging to the nuclear receptor subfamily of PPARs, which are important transcriptional regulators of lipid and lipoprotein metabolism. The goal of this study was to evaluate the influence of a potent thiazolidinedione, BRL49653, on serum lipoproteins and to determine whether its lipid-lowering effects are mediated by changes in the expression of key genes implicated in lipoprotein metabolism. Treatment of normal rats for 7 days with BRL49653 decreased serum triglycerides in a dose-dependent fashion without affecting serum total and HDL cholesterol and apolipoprotein (apo) A-I and apo A-II concentrations. The decrease in triglyceride concentrations after BRL49653 was mainly due to a reduction of the amount of VLDL particles of unchanged lipid and apo composition. BRL49653 treatment did not change triglyceride production in vivo as analyzed by injection of Triton WR-1339, indicating a primary action on triglyceride catabolism. Analysis of the influence of BRL49653 on the expression of LPL and apo C-III, two key players in triglyceride catabolism, showed a dose-dependent increase in mRNA levels and activity of LPL in epididymal adipose tissue, whereas liver apo C-III mRNA levels remained constant. Furthermore, addition of BRL49653 to primary cultures of differentiated adipocytes increased LPL mRNA levels, indicating a direct action of the drug on the adipocyte. Simultaneous administration of BRL49653 and fenofibrate, a hypolipidemic drug that acts primarily on liver through activation of PPAR alpha both decreased liver apo C-III and increased adipose tissue LPL mRNA levels, resulting in a more pronounced lowering of serum triglycerides than each drug alone. In conclusion, both fibrates and thiazolidinediones exert a hypotriglyceridemic effect. While fibrates act primarily on the liver by decreasing apo C-III production, BRL49653 acts primarily on adipose tissue by increasing lipolysis through the induction of LPL expression. Drugs combining both PPAR alpha and gamma activation potential should therefore display a more efficient hypotriglyceridemic activity than either compound alone and may provide a rationale for improved therapy for elevated triglycerides.
Asunto(s)
Fenofibrato/farmacología , Hipolipemiantes/farmacología , Lipoproteínas/metabolismo , Tiazoles/farmacología , Tiazolidinedionas , Tejido Adiposo/metabolismo , Animales , Apolipoproteínas/genética , Combinación de Medicamentos , Expresión Génica , Lipoproteína Lipasa/genética , Lipoproteína Lipasa/metabolismo , Lipoproteínas/sangre , Lipoproteínas VLDL/sangre , Lipoproteínas VLDL/química , Hígado/fisiología , Masculino , Concentración Osmolar , Ratas , Ratas Sprague-Dawley , Rosiglitazona , Triglicéridos/sangreRESUMEN
Increased activity of lipoprotein lipase (LPL) may explain the hypotriglyceridemic effects of fibrates, thiazolidinediones and fatty acids, which are known activators (and/or ligands) of the various peroxisome proliferator-activated receptors (PPARs). Treatment with compounds which activate preferentially PPARalpha, such as fenofibrate, induced LPL expression exclusively in rat liver. In contrast, the antidiabetic thiazolidinedione BRL 49653, a high affinity ligand for PPARgamma, had no effect on liver, but induced LPL expression in rat adipose tissue. In the hepatocyte cell line AML-12, fenofibric acid, but not BRL 49653, induced LPL mRNA, whereas in 3T3-L1 preadipocytes, the PPARgamma ligand induced LPL mRNA levels much quicker and to a higher extent than fenofibric acid. In both the in vivo and in vitro studies, inducibility by either PPARalpha or gamma activators, correlated with the tissue distribution of the respective PPARs: an adipocyte-restricted expression of PPARgamma, whereas PPARalpha was expressed predominantly in liver. A sequence element was identified in the human LPL promoter that mediates the functional responsiveness to fibrates and thiazolidinediones. Methylation interference and gel retardation assays demonstrated that a PPARalpha or gamma and the 9-cis retinoic acid receptor (RXR) heterodimers bind to this sequence -169 TGCCCTTTCCCCC -157. These data provide evidence that transcriptional activation of the LPL gene by fibrates and thiazolidinediones is mediated by PPAR-RXR heterodimers and contributes significantly to their hypotriglyceridemic effects in vivo. Whereas thiazolidinediones predominantly affect adipocyte LPL production through activation of PPARgamma, fibrates exert their effects mainly in the liver via activation of PPARalpha.
Asunto(s)
Lipoproteína Lipasa/genética , Regiones Promotoras Genéticas/genética , Receptores Citoplasmáticos y Nucleares/genética , Tiazolidinedionas , Factores de Transcripción/genética , Activación Transcripcional/efectos de los fármacos , Células 3T3 , Adipocitos/química , Tejido Adiposo/química , Animales , Línea Celular , ADN/metabolismo , Dimerización , Fenofibrato/análogos & derivados , Fenofibrato/farmacología , Humanos , Hipoglucemiantes/farmacología , Hipolipemiantes/farmacología , Hígado/química , Hígado/citología , Ratones , Ratones Endogámicos C57BL , Miocardio/química , Especificidad de Órganos , ARN Mensajero/análisis , Ratas , Ratas Sprague-Dawley , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de Ácido Retinoico/metabolismo , Receptores X Retinoide , Rosiglitazona , Tiazoles , Factores de Transcripción/metabolismoRESUMEN
We examined the expression of lipoprotein lipase (LPL) gene and LPL activity following a two-thirds hepatectomy and during liver regeneration. In most of the tissues studied, LPL activity increased a few hours after partial hepatectomy, but soon returned to normal levels. The greatest increase was found in the adrenal glands, plasma and liver. This increase in LPL activity in the liver could be partially due to an increase in the influx of the enzyme from extrahepatic tissues. There is, however, also a re-expression of LPL mRNA in the liver after partial hepatectomy (during the first hours). It is well known that LPL is expressed in the liver of neonatal animals, but progressively decreases during post-natal development, to reach adult levels around the time of weaning. Our results show by the first time that the remaining liver re-expresses LPL gene during the regeneration process and that the hepatocytes de-differentiate and acquire some of the neonatal characteristics. The increase in LPL mRNA will contribute to the rise in LPL activity after hepatectomy. This presence of LPL could enable the liver to take up fatty acids from the circulating triacylglycerols, which are needed as energetic and plastic substrates during the process of hepatic regeneration.
Asunto(s)
Lipoproteína Lipasa/biosíntesis , Regeneración Hepática , Hígado/enzimología , Transcripción Genética , Tejido Adiposo/enzimología , Tejido Adiposo Pardo/enzimología , Glándulas Suprarrenales/enzimología , Animales , Peso Corporal , Inducción Enzimática , Hepatectomía , Lipoproteína Lipasa/sangre , Masculino , Músculo Esquelético/enzimología , Miocardio/enzimología , Tamaño de los Órganos , Especificidad de Órganos , ARN Mensajero/biosíntesis , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Variations in hepatic lipase (HL) activity were studied for the first time in liver, plasma and adrenal glands of partially hepatectomized (70%), sham-operated and intact rats. Activity profiles performed during 7 days in liver, plasma and adrenal glands of sham-operated rats were similar to those obtained in intact animals. However, HL activity in intact animals appeared to be slightly higher during the first 24 hours. Following surgery, hepatectomized animals showed a reduction of about 300 U in liver HL activity which persisted for 7 days. Plasma HL activity of hepatectomized rats was undetectable at 6 hours post-surgery but in increased afterwards. A high correlation between liver and adrenal gland HL activity was found in hepatectomized but not in sham-operated animals. HL mRNA levels in hepatectomized rats showed a 40% decrease during the first 24 hours after surgery, but they returned to the normal range later. On the other hand, HL mRNA values increased in sham-operated rats but no increase in HL activity was detected in these animals. To conclude, our results show that HL activity decreases dramatically during hepatic regeneration due to a concomitant decrement in the expression of the gene that encodes the enzyme and to other undetermined factors.