RESUMEN
PURPOSE OF REVIEW: Lipoprotein-X (Lp-X) is an abnormal lipoprotein containing abundant free cholesterol and phospholipids, as well as some apolipoprotein E (apoE). Serum Lp-X increases in patients with cholestasis and lecithin-cholesterol acyltransferase deficiency, as well as in those receiving intravenous lipid emulsion. Lp-X is often associated with skin xanthomas in cholestatic patients. However, earlier studies showed that Lp-X is not taken up by murine macrophages, but exerts antiatherogenic actions. In this review, we discuss the heterogeneity of Lp-X and its potential atherogenicity. RECENT FINDINGS: Mass spectrometry revealed that Lp-X of cholestatic patients is similar in lipid composition to low-density lipoprotein (LDL) and high-density lipoprotein, but not to bile acids, suggesting that Lp-X is synthesized in the liver. Palmar xanthomas appear in patients with cholestasis, but regress over months after improvement of hypercholesterolemia. Lp-X isolated from cholestatic patients is rich in apoE, and causes more lipid accumulation than oxidized LDL and acetyl LDL in human monocyte-derived macrophages. SUMMARY: Lp-X is heterogeneous in apoE content. Lp-X is taken up in cholestatic patients by apoE-recognizing lipoprotein receptors. Further research is warranted to fully understand the atherogenicity of Lp-X and the clinical significance of elevated Lp-X concentrations, particularly in cholestatic patients.
Asunto(s)
Aterosclerosis/etiología , Lipoproteína X/toxicidad , Aterosclerosis/metabolismo , Colestasis/metabolismo , Humanos , Lipoproteína X/metabolismo , Macrófagos/metabolismoRESUMEN
Familial LCAT deficiency (FLD) is due to mutations in lecithin:cholesterol acyltransferase (LCAT), a plasma enzyme that esterifies cholesterol on lipoproteins. FLD is associated with markedly reduced levels of plasma high-density lipoprotein and cholesteryl ester and the formation of a nephrotoxic lipoprotein called LpX. We used a mouse model in which the LCAT gene is deleted and a truncated version of the SREBP1a gene is expressed in the liver under the control of a protein-rich/carbohydrate-low (PRCL) diet-regulated PEPCK promoter. This mouse was found to form abundant amounts of LpX in the plasma and was used to determine whether treatment with recombinant human LCAT (rhLCAT) could prevent LpX formation and renal injury. After 9 days on the PRCL diet, plasma total and free cholesterol, as well as phospholipids, increased 6.1 ± 0.6-, 9.6 ± 0.9-, and 6.7 ± 0.7-fold, respectively, and liver cholesterol and triglyceride concentrations increased 1.7 ± 0.4- and 2.8 ±0.9-fold, respectively, compared with chow-fed animals. Transmission electron microscopy revealed robust accumulation of lipid droplets in hepatocytes and the appearance of multilamellar LpX particles in liver sinusoids and bile canaliculi. In the kidney, LpX was found in glomerular endothelial cells, podocytes, the glomerular basement membrane, and the mesangium. The urine albumin/creatinine ratio increased 30-fold on the PRCL diet compared with chow-fed controls. Treatment of these mice with intravenous rhLCAT restored the normal lipoprotein profile, eliminated LpX in plasma and kidneys, and markedly decreased proteinuria. The combined results suggest that rhLCAT infusion could be an effective therapy for the prevention of renal disease in patients with FLD.
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Modelos Animales de Enfermedad , Riñón/metabolismo , Deficiencia de la Lecitina Colesterol Aciltransferasa/tratamiento farmacológico , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lipoproteína X/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/administración & dosificación , Animales , Dieta Baja en Carbohidratos/efectos adversos , Proteínas en la Dieta/efectos adversos , Femenino , Riñón/efectos de los fármacos , Riñón/patología , Deficiencia de la Lecitina Colesterol Aciltransferasa/patología , Lipoproteína X/antagonistas & inhibidores , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones TransgénicosRESUMEN
BACKGROUND: Lipoprotein-X (Lp-X) is an abnormal phospholipid-rich lipoprotein found in patients with cholestatic liver disease. Some patients exhibit skin xanthomas and severe hyperlipidemia. OBJECTIVE: We investigated whether Lp-X induces foam cell formation in human-derived macrophages. METHODS: To compare the atherogenic properties of Lp-X and modified LDL, we isolated Lp-X from 2 patients who had drug-induced cholestasis and xanthoma striata in the interphalangeal folds. We prepared oxidized LDL and acetylated LDL from healthy volunteers for the positive control experiments. RESULTS: When human monocyte-derived macrophages were incubated with these lipoproteins, the isolated Lp-X induced more prominent lipid accumulation than oxidized LDL or acetylated LDL. One case underwent liver biopsy, with the bile ducts showing marked damage, fulfilling the criteria for vanishing bile duct syndrome. The other case was clinically diagnosed as drug-induced hypersensitivity syndrome. In both cases, Lp-X levels decreased markedly and the xanthomas disappeared completely after the improvement of cholestasis. CONCLUSION: This study indicates that Lp-X induces foam cell formation in human-derived macrophages. Our findings strongly suggest that persistently elevated Lp-X may cause xanthomas.
Asunto(s)
Colestasis/inmunología , Colestasis/metabolismo , Células Espumosas/citología , Lipoproteína X/metabolismo , Xantomatosis/complicaciones , Adulto , Colestasis/complicaciones , Femenino , Humanos , Persona de Mediana Edad , Monocitos/citología , Adulto JovenRESUMEN
Severe cholestatic disease and hyperlipidemia are both commonly encountered by medical professionals. This article reviews the current pathophysiological model of lipoprotein-X syndrome related to 3 cases from 2 academic medical centers in the United States.
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Enfermedades Autoinmunes/complicaciones , Colestasis/complicaciones , Colestasis/metabolismo , Lipoproteína X/metabolismo , Hepatopatías/complicaciones , Adulto , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Lipoprotein X (Lp-X) is an abnormal lipoprotein that may typically be formed in intra- and extrahepatic cholestasis and potentially interfere with lipid analysis in the routine lab. To gain insight into lipid class and species composition, Lp-X, LDL and HDL from cholestatic and control serum samples were subjected to mass spectrometric analysis including phospholipids (PL), sphingolipids, free cholesterol (FC), cholesteryl esters (CE) and bile acids. Our analysis of Lp-X revealed a content of 46% FC, 49% PL with 34% phosphatidylcholine (PC) as main PL component. The lipid species pattern of Lp-X showed remarkable high fractions of mono-unsaturated species including PC 32:1 and PC 34:1 and phosphatidylethanolamine (PE) 32:1 and 34:1. LDL and HDL lipid composition in the same specimens strongly reflected the lipid composition of Lp-X with increased PC 32:1, PC 34:1, PE 32:1, PE 34:1 and FC accompanied by decreased CE compared to controls. Comparison of Lp-X and biliary lipid composition clearly indicates that Lp-X does not originate from a sole release of bile lipids. Moreover, these data present evidence for increased hepatic fatty acid and PL synthesis which may represent a reaction to high hepatic FC level observed during cholestasis.
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Bilis/metabolismo , Colestasis/metabolismo , Dislipidemias/metabolismo , Lipoproteína X/metabolismo , Bilis/química , Humanos , Lipoproteína X/químicaRESUMEN
Human familial lecithin:cholesterol acyltransferase (LCAT) deficiency (FLD) is characterized by low HDL, accumulation of an abnormal cholesterol-rich multilamellar particle called lipoprotein-X (LpX) in plasma, and renal disease. The aim of our study was to determine if LpX is nephrotoxic and to gain insight into the pathogenesis of FLD renal disease. We administered a synthetic LpX, nearly identical to endogenous LpX in its physical, chemical and biologic characteristics, to wild-type and Lcat-/- mice. Our in vitro and in vivo studies demonstrated an apoA-I and LCAT-dependent pathway for LpX conversion to HDL-like particles, which likely mediates normal plasma clearance of LpX. Plasma clearance of exogenous LpX was markedly delayed in Lcat-/- mice, which have low HDL, but only minimal amounts of endogenous LpX and do not spontaneously develop renal disease. Chronically administered exogenous LpX deposited in all renal glomerular cellular and matrical compartments of Lcat-/- mice, and induced proteinuria and nephrotoxic gene changes, as well as all of the hallmarks of FLD renal disease as assessed by histological, TEM, and SEM analyses. Extensive in vivo EM studies revealed LpX uptake by macropinocytosis into mouse glomerular endothelial cells, podocytes, and mesangial cells and delivery to lysosomes where it was degraded. Endocytosed LpX appeared to be degraded by both human podocyte and mesangial cell lysosomal PLA2 and induced podocyte secretion of pro-inflammatory IL-6 in vitro and renal Cxl10 expression in Lcat-/- mice. In conclusion, LpX is a nephrotoxic particle that in the absence of Lcat induces all of the histological and functional hallmarks of FLD and hence may serve as a biomarker for monitoring recombinant LCAT therapy. In addition, our studies suggest that LpX-induced loss of endothelial barrier function and release of cytokines by renal glomerular cells likely plays a role in the initiation and progression of FLD nephrosis.
Asunto(s)
Glomérulos Renales/efectos de los fármacos , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lipoproteína X/toxicidad , Proteinuria/etiología , Animales , Apolipoproteína A-I/metabolismo , Células Cultivadas , Citoesqueleto/efectos de los fármacos , Citoesqueleto/ultraestructura , Células Endoteliales/metabolismo , Células Endoteliales/patología , Matriz Extracelular/metabolismo , Perfilación de la Expresión Génica , Membrana Basal Glomerular/efectos de los fármacos , Membrana Basal Glomerular/patología , Mesangio Glomerular/citología , Mesangio Glomerular/metabolismo , Mesangio Glomerular/patología , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interleucina-6/metabolismo , Glomérulos Renales/patología , Deficiencia de la Lecitina Colesterol Aciltransferasa/patología , Lipoproteína X/metabolismo , Lipoproteína X/farmacocinética , Lipoproteínas HDL/metabolismo , Lisosomas/metabolismo , Tasa de Depuración Metabólica , Ratones , Ratones Endogámicos C57BL , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Fosfolipasas A2/metabolismo , Pinocitosis , Podocitos/metabolismo , Podocitos/patología , Proteinuria/inducido químicamente , Proteinuria/genética , Proteinuria/patologíaRESUMEN
Lecithin cholesterol acyl transferase (LCAT) is a plasma enzyme which esterifies cholesterol, and plays a key role in the metabolism of high-density lipoprotein cholesterol (HDL-C). Genetic disorders of LCAT are associated with lipoprotein abnormalities including low levels of HDL-C and presence of lipoprotein X, and clinical features mainly corneal opacities, changes in erythrocyte morphology and renal failure. Recombinant LCAT is being developed for the treatment of patients with LCAT deficiency.
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HDL-Colesterol/metabolismo , Deficiencia de la Lecitina Colesterol Aciltransferasa/diagnóstico , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Aterosclerosis/enzimología , Aterosclerosis/genética , Aterosclerosis/metabolismo , Humanos , Deficiencia de la Lecitina Colesterol Aciltransferasa/enzimología , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lipoproteína X/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/genéticaRESUMEN
Familial lecithin:cholesterol acyltransferase deficiency (FLD) is a monogenic autosomal recessive condition, affecting cholesterol esterification and leads to progressive renal impairment and end-stage renal failure, probably due to the abnormal lipoprotein (X) (Lp(X)). We report a case of FLD, whom we treated with a combination of nicotinic acid 1.5g nocte and fenofibrate M/R 160mg od and report changes in lipid profile and Lp(X), after six weeks and serum creatinine and urine albumin/creatinine ratio after 12 months. We assessed the cardiovascular risk using electron beam computed tomography. At baseline total cholesterol was 6.61mmol/L; HDL cholesterol 0.57mmol/L; Lp(X) cholesterol 3.24mmol/L; triglyceride 4.13mmol/L; apolipoprotein A1 46mg/dL; and apolipoprotein B 53mg/dL. After six weeks of treatment his total cholesterol was 4.16; HDL cholesterol 0.52; Lp(X) cholesterol 1.73mmol/L; triglyceride 1.80mmol/L; apolipoprotein A1 36mg/dL; and apolipoprotein B 50mg/dL. Baseline serum creatinine was 106micromol/L and urine albumin/creatinine ratio was 127.3mg/mmol and after 12 months was 101micromol/L and 31.5mg/mmol respectively. His coronary artery calcification score was zero. We have shown, we believe for the first time, that combination lipid modifying therapy in FLD leads to a reduction in Lp(X) concentration and an associated reduction in urine albumin excretion at 12 months.
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Albúminas/análisis , Deficiencia de la Lecitina Colesterol Aciltransferasa/sangre , Deficiencia de la Lecitina Colesterol Aciltransferasa/genética , Deficiencia de la Lecitina Colesterol Aciltransferasa/orina , Lipoproteínas/sangre , Adulto , Calcio/metabolismo , Colesterol/metabolismo , Vasos Coronarios/patología , Fenofibrato/farmacología , Humanos , Hipolipemiantes/uso terapéutico , Lipoproteína X/metabolismo , Masculino , Niacina/farmacología , Tomografía Computarizada por Rayos X/métodos , Triglicéridos/metabolismoRESUMEN
INTRODUCTION: Cryoglobulins are abnormal immune complexes where both the antigens and the antibodies are immunoglobulins. The ability of cryoglobulins to bind C-reactive protein and low density lipoproteins, activate complement, and stimulate production of tumor necrosis factor-alpha generates interest in studying cryoglobulins in ischemic stroke. MATERIALS AND METHODS: We determined blood levels of cryoglobulins in patients with ischemic stroke at different time points of stroke onset and identified the composition of cryoglobulins isolated from the blood on the first day of stroke onset. RESULTS: On days 1-14, significantly elevated levels of cryoglobulins were detected with the maximum level on day 3. DISCUSSION: Determination of immunoglobulin (Ig) content of cryoglobulins revealed the presence of a mixture of polyclonal IgG, IgA, and IgM, C3 complement protein and its activation split products, C1q complement protein, pathogenic lipoprotein-X, and beta-lipoprotein. CONCLUSION: We suggest that cryoglobulins are involved in post-ischemic inflammatory response through activation of the complement cascade and cytokines production.
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Complejo Antígeno-Anticuerpo/metabolismo , Crioglobulinas/metabolismo , Accidente Cerebrovascular/metabolismo , Anciano , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/inmunología , Complemento C1q/química , Complemento C1q/inmunología , Complemento C1q/metabolismo , Complemento C3/química , Complemento C3/inmunología , Complemento C3/metabolismo , Crioglobulinas/química , Crioglobulinas/inmunología , Femenino , Humanos , Inmunoquímica , Lipoproteína X/química , Lipoproteína X/inmunología , Lipoproteína X/metabolismo , Lipoproteínas LDL/química , Lipoproteínas LDL/inmunología , Lipoproteínas LDL/metabolismo , Masculino , Persona de Mediana Edad , Daño por Reperfusión/inmunología , Daño por Reperfusión/metabolismo , Accidente Cerebrovascular/inmunología , Accidente Cerebrovascular/fisiopatología , Factores de TiempoRESUMEN
Primary Biliary Cirrhosis (PBC) is a chronic, progressive liver disease associated with markedly elevated serum lipids, but it is not clear if PBC is associated with accelerated atherosclerosis. The present systematic review examined the relationship of PBC to atherosclerotic risk. The lipid abnormalities in PBC are complex, depend on the stage of hepatic dysfunction and affect most lipoprotein classes. Increased cholesterol levels in PBC are primarily due to LP-X, an abnormal LDL particle. LP-X has anti-atherogenic properties and may reduce the atherosclerotic risk. Few studies have examined coronary artery disease (CAD) events in PBC, and none have sufficient sample size of follow-up to determine CAD risk in PBC patients. Nevertheless, one study suggested that 12% of PBC patients died from circulatory system diseases suggesting that lipid treatment is appropriate in some patients. Additional larger scale, prospective studies are required to determine the necessity of lipid treatment in this patient group. In the interim, decisions on the use of lipid lowering agents depend largely on the prognosis of the PBC and physician and patient preference for treatment.
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Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/complicaciones , Lipoproteína X/metabolismo , Cirrosis Hepática Biliar/complicaciones , HDL-Colesterol/metabolismo , Enfermedad de la Arteria Coronaria/epidemiología , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Hipercolesterolemia , Hipolipemiantes/farmacología , Cirrosis Hepática Biliar/epidemiología , Cirrosis Hepática Biliar/fisiopatología , Estudios Longitudinales , Factores de RiesgoRESUMEN
OBJECTIVE: Lecithin:cholesterol acyltransferase deficiency (LCAT-def) is characterized by low levels of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) and the accumulation of lipoprotein-X (LpX). Despite the low HDL, atherosclerosis is uncommon in LCAT-def. The decreased LDL would be a possible explanation but the underlying mechanism is not clear. In addition, the mechanism(s) for LpX accumulation is not known. The aim of the present study is to elucidate the mechanism(s) responsible for the low LDL and determine the plasma kinetics of LpX in LCAT-def. METHODS AND RESULTS: We conducted a radiotracer study in LCAT-def (n=2) and normal controls (n=10) and a stable isotope study in one patient and other controls (n=7). LCAT-def LDL was catabolized faster than control LDL in the control subjects as well as in LCAT-def patients. Control LDL was catabolized faster in LCAT-def patients than the controls. The production rate of LDL apolipoprotein B-100 was normal in LCAT-def. The increased LDL apoB-100 catabolism was confirmed by a stable isotope study. LpX was catabolized more slowly in LCAT-def. CONCLUSIONS: The decreased LDL in LCAT-def is attributable to an increased catabolism caused by a rapid catabolism of abnormal LDL and an upregulation of LDL receptor pathway. The decreased catabolism of LpX contributes to its accumulation in LCAT-def.
Asunto(s)
Deficiencia de la Lecitina Colesterol Aciltransferasa/sangre , Lipoproteína X/sangre , Lipoproteínas LDL/sangre , Adulto , Apolipoproteína B-100 , Apolipoproteínas B/biosíntesis , Apolipoproteínas B/sangre , Estudios de Casos y Controles , Cromatografía Liquida , Femenino , Humanos , Cinética , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lípidos/sangre , Lipoproteína X/metabolismo , Lipoproteínas LDL/metabolismo , Masculino , Persona de Mediana Edad , Trazadores RadiactivosRESUMEN
Complete lecithin cholesterol acyltransferase (LCAT) deficiency is a rare genetic cause of extreme reduction in high density lipoproteins and there is a high prevalence of chronic renal dysfunction that may progress to renal failure. Previous in vitro studies suggest the vesicular lipoprotein X (LpX) particles commonly seen in LCAT-deficient plasmas may be causative. To test this hypothesis, we have generated a novel murine model that selectively accumulate LpX in the circulation by cross breeding the sterol regulatory element binding protein (SREBP) 1a transgenic mice (S+) with the LCAT knockout (lcat-/-) mice. Fast protein liquid chromatography fractionation of pooled plasma lipids revealed that virtually all cholesterol is concentrated in the very low density lipoprotein (VLDL)-sized fractions. These fractions are enriched in free cholesterol and phospholipid but extremely poor in triglyceride. Electron microscopy of the d <1.063 g/ml fraction of the S+lcat-/- mice revealed abnormal large vesicular particles, suggestive of LpX. The S+lcat-/- mice developed glomerular lesions spontaneously evident at 6 months with glomerular and tubulointerstitial lipid-deposits. Immunohistochemical staining with RhoA showed marked positive focal staining in glomeruli in the S+lcat-/- mice and undetectable in the S+/lcat+/+ control. By 10 months of age, the kidneys showed progressive glomerular injury including segmental foam cell infiltrates, mesangial expansion, and hyalinosis. Renal abnormalities are very similar to those seen in human LCAT deficiency. We conclude that the selective high-level accumulation of plasma LpX in the S+lcat-/- mice is strongly associated with a spontaneous glomerulopathy, providing in vivo evidence that LpX contributes to the LCAT deficiency-related nephropathy.
Asunto(s)
Glomérulos Renales/patología , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lípidos/sangre , Lipoproteína X/metabolismo , Animales , Modelos Animales de Enfermedad , Electroforesis en Gel de Poliacrilamida , Inmunohistoquímica , Glomérulos Renales/ultraestructura , Deficiencia de la Lecitina Colesterol Aciltransferasa/genética , Lipoproteína X/sangre , Lipoproteínas/sangre , Ratones , Ratones Noqueados , Ratones Transgénicos , Microscopía ElectrónicaRESUMEN
Hypercholesterolemic human LDL contains oxidized subfractions that have atherogenic properties. Paradoxically, atherosclerosis incidence is low in patients with primary biliary cirrhosis (PBC), a disease characterized by marked increases in plasma LDL, including the LDL subfraction lipoprotein-X (Lp-X). To investigate the mechanisms underlying this paradox, we first examined the propensity to oxidation of unfractionated LDL isolated from PBC patients. After prolonged incubation with copper, PBC-LDL failed to increase the oxidation index or electrophoretic mobility noted in control LDL. An admixture of PBC-LDL or Lp-X with control LDL prevented oxidation of the latter in a dose-dependent manner. PBC-LDL was also noncompetitive against copper-oxidized LDL (oxLDL) for binding with a murine monoclonal anti-oxLDL antibody in a competitive ELISA. OxLDL exerts its proapoptotic and antiangiogenic effects in part by inhibiting fibroblast growth factor 2 (FGF2) expression. Preincubation of oxLDL with PBC-LDL, but not control LDL, attenuated the inhibitory effects of oxLDL on FGF2 expression in cultured bovine aortic endothelial cells (ECs). The antioxidant and prosurvival properties of PBC-LDL diminished after the patients underwent orthotopic liver transplantation. These results suggest that Lp-X reduces LDL atherogenicity by preventing LDL oxidation to protect EC integrity in the presence of hypercholesterolemia. They also suggest that altering LDL composition may be as important as reducing LDL concentration in preventing or treating atherosclerosis.
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Lipoproteína X/metabolismo , Cirrosis Hepática Biliar/metabolismo , Oxígeno/metabolismo , Animales , Aorta/citología , Apoptosis , Bovinos , Células Cultivadas , Cromatografía en Gel , Regulación hacia Abajo , Electroforesis en Gel de Agar , Endotelio Vascular/citología , Ensayo de Inmunoadsorción Enzimática , Factor 2 de Crecimiento de Fibroblastos/metabolismo , Historia del Siglo XX , Ligandos , Lipoproteínas LDL/metabolismo , Péptidos/química , ARN Mensajero/metabolismo , Factores de TiempoRESUMEN
Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis caused by deficiency of the mitochondrial enzyme ferrochelatase. EPP in humans is associated with liver disease, hypertriglyceridemia, and a low level of high density lipoprotein (HDL) cholesterol. To explore consequences of ferrochelatase deficiency in lipid metabolism, we have analyzed hepatic lipid content and plasma lipoprotein levels in chow-fed BALB/c mice homozygous ( fch/fch) or heterozygous ( fch/1) for a point mutation in the ferrochelatase gene and in wild-type controls (1/1). Livers of fch/fch mice show bile duct proliferation and biliary fibrosis, but bile formation is not impaired. The free cholesterol content of fch/fch livers is significantly increased when compared with fch/1 and 1/1 livers. Plasma cholesterol in fch/fch mice (9.9 +/- 6.4 mM) is elevated when compared with fch/1 and 1/1 mice (2.9 +/- 0.2 and 2.5 +/- 0.3 mM, respectively), because of an increased cholesterol content in the very low density lipoprotein-sized fractions, whereas HDL cholesterol is reduced. The ratio of cholesteryl ester to free cholesterol is 4.3 +/- 0.6, 3.3 +/- 0.3, and 0.3 +/- 0.1 in the plasma of 1/1, fch/1, and fch/fch mice, respectively. The latter is not due to reduced lecithin:cholesterol acyltransferase activity in plasma of fch/fch mice but to the presence of lipoprotein-X (Lp-X), a particle composed of bile-type lipids usually seen only in cholestatic conditions. Expression of mdr2, essential for biliary phospholipid/cholesterol secretion, is increased in fch/fch livers. In spite of this, biliary phospholipid/cholesterol secretion is reduced relative to that of bile salts. It is postulated that an inability of bile salts to stimulate lipid secretion adequately leads to formation of Lp-X in this noncholestatic condition. Distinct atherosclerotic lesions were found in aged fch/fch mice.Thus, ferrochelatase deficiency in mice leads to liver disease associated with altered hepatic lipid metabolism, a characteristic hyperlipidemia, and development of atherosclerosis.-Bloks, V. W., T. Plösch, H. van Goor, H. Roelofsen, J. Baller, R. Havinga, H. J. Verkade, A. van Tol, P. L. M. Jansen, and F. Kuipers. Hyperlipidemia and atherosclerosis associated with liver disease in ferrochelatase-deficient mice. J. Lipid Res. 2001. 42: 41;-50.
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Arteriosclerosis/enzimología , Ferroquelatasa/farmacología , Hiperlipidemias/enzimología , Hepatopatías/enzimología , Animales , Arteriosclerosis/etiología , Arteriosclerosis/metabolismo , Hígado Graso/enzimología , Hígado Graso/etiología , Hígado Graso/metabolismo , Ferroquelatasa/genética , Hiperlipidemias/etiología , Hiperlipidemias/metabolismo , Metabolismo de los Lípidos , Lípidos/análisis , Lípidos/sangre , Lipoproteína X/sangre , Lipoproteína X/metabolismo , Lipoproteínas HDL/sangre , Lipoproteínas HDL/efectos de los fármacos , Lipoproteínas HDL/metabolismo , Hígado/metabolismo , Hígado/patología , Hepatopatías/etiología , Hepatopatías/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Mutantes , Protoporfiria EritropoyéticaRESUMEN
1. In the present study, the effect of reconstituted lipoprotein-X (rLp-X) on lipid accumulation and foam cell formation in rat peritoneal macrophages was evaluated. Furthermore, the combined effect of rLp-X and macrophages on mesangial cell proliferation was examined. 2. Incubation of macrophages with rLp-X (177 and 387 nmol unesterified cholesterol (FC)/mL) resulted in an increase of cellular cholesterol (162%) and cholesteryl esters (223 to 245%) relative to control. 3. Oil Red O staining of macrophages treated with rLp-X revealed the presence of foam cells. 4. In conclusion, rLp-X had no effect on the proliferation of mesangial cells incubated in macrophage-conditioned medium.
Asunto(s)
Células Espumosas/citología , Mesangio Glomerular/citología , Lipoproteína X/fisiología , Macrófagos Peritoneales/citología , Animales , Comunicación Celular/fisiología , División Celular/fisiología , Células Cultivadas , Células Espumosas/efectos de los fármacos , Células Espumosas/metabolismo , Mesangio Glomerular/efectos de los fármacos , Mesangio Glomerular/metabolismo , Lípidos/farmacocinética , Lipoproteína X/metabolismo , Lipoproteína X/farmacología , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratas , Ratas Sprague-DawleyRESUMEN
Progressive glomerulosclerosis is a major complication in patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. The lack of LCAT activity results in the accumulation of an abnormal lipoprotein, lipoprotein-X (Lp-X), in the plasma of these patients. Lipoprotein-X contains high levels of unesterified cholesterol and phosphatidylcholine. Lp-X may play a role in the accumulation of lipids in the kidney, which in turn may lead to glomerulosclerosis. The objective of this study is to examine the uptake and metabolism of Lp-X by rat mesangial cells. Our results suggest that Lp-X is taken up by mesangial cells and that the lipids in Lp-X are metabolized. Lysosomes containing unesterified cholesterol and phosphatidylcholine, in a molar ratio similar to Lp-X, were synthesized to investigate the roles individual apolipoproteins (apo CI, II, III and E) play in the uptake of Lp-X. Both apo CI and CIII inhibited its uptake while apo CII (1.5 fold) and E (4 fold) stimulated the uptake of Lp-X. Very low density lipoprotein (VLDL) and low density lipoprotein (LDL) inhibited Lp-X uptake by mesangial cells. However, at higher concentrations of high density lipoprotein (HDL), the uptake of Lp-X was stimulated. Proteoglycans have an important role in regulating the uptake of Lp-X, while cytoskeleton-dependent phagocytosis and the scavenger receptor do not appear to be involved.
Asunto(s)
Mesangio Glomerular/metabolismo , Lipoproteína X/metabolismo , Lisosomas/metabolismo , Animales , Apolipoproteínas/farmacología , Apolipoproteínas/fisiología , Células Cultivadas , Colesterol/farmacología , Colesterol/fisiología , Cromatografía en Capa Delgada , Mesangio Glomerular/citología , Lipoproteína X/antagonistas & inhibidores , Lipoproteínas/farmacología , Lipoproteínas/fisiología , Fosfatidilcolinas/farmacología , Fosfatidilcolinas/fisiología , Ratas , Ratas Sprague-Dawley , Conteo por CintilaciónRESUMEN
The clinical significance of lipoprotein-X (Lp-X) induced by intravenous infusion of 10% fat emulsion was assessed, with special reference to atherogenesis, by in vitro experiment using purified Lp-X from the sera of patients receiving Intralipid 10%. Lp-X appeared after long-term intravenous infusion of 10% fat emulsion in the patients with intestinal fistula due to the anastomotic leakage. To clarify the role of Lp-X in terms of atherogenicity, the cholesterol metabolism of Lp-X in macrophages as scavenger cells and in hepatocytes as parenchymal cells was studied. When [3H]cholesterol-labeled Lp-X or oxidized low-density lipoprotein (o-LDL) was incubated with J-774 macrophages, the incorporation of Lp-X into macrophages was negligible compared with o-LDL. When Lp-X or high-density lipoprotein (HDL) was incubated with J-774 macrophages laden with [3H]cholesterol, the release of cholesterol from macrophages was enhanced by Lp-X as well as HDL. When [3H]cholesterol-labeled Lp-X LDL or HDL was incubated with the human hepatoma cell line of Hep G2 cells, the incorporation of Lp-X into Hep G2 cells was less than that of LDL, but similar to that of HDL. From these findings, it is suggested that the catabolism of Lp-X cholesterol generated with intravenous 10% fat emulsion was mediated by hepatocytes rather than by macrophages, indicating that the hyperlipidemia due to increased Lp-X may not be atherogenic.
Asunto(s)
Emulsiones Grasas Intravenosas/administración & dosificación , Lipoproteína X/metabolismo , Animales , Arteriosclerosis/etiología , Transporte Biológico Activo , Línea Celular , Colesterol/metabolismo , Emulsiones Grasas Intravenosas/efectos adversos , Humanos , Hiperlipidemias/etiología , Lipoproteína X/biosíntesis , Lipoproteína X/sangre , Lipoproteínas HDL/metabolismo , Lipoproteínas LDL/metabolismo , Hígado/metabolismo , Macrófagos/metabolismo , Ratones , Nutrición Parenteral Total/efectos adversos , TritioRESUMEN
In order to clarify the metabolism of Lipoprotein X (Lp-X) induced by intravenous Intralipid 10%, in vitro experiments using purified Lp-X from the sera of the patients receiving Intralipid 10% were carried out. 1) Lp-X or high density lipoprotein (HDL) was incubated with J-774 macrophages laden with [3H] cholesterol. Marked extraction of cholesterol from macrophages by Lp-X as well as HDL was observed. 2) [3H] cholesterol labelled Lp-X or oxidized LDL (o-LDL) was incubated with J-774 macrophages. Incorporation of Lp-X into macrophages was negligible comparing to o-LDL. 3) [3H] cholesterol labelled Lp-X, low density lipoprotein (LDL), or HDL was incubated with Hep G2 cells was less than LDL, but similar to that of HDL. These results indicated that Lp-X extracted cholesterol from peripheral tissues during its formation, and it was not catabolized by the scavenger pathway, but catabolized by the LDL pathway of hepatocytes.