Browsing by Author "Amigo, Ludwig"

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    CETP expression enhances liver HDL-cholesteryl ester uptake but does not alter VLDL and biliary lipid secretion
    (ELSEVIER IRELAND LTD, 2007) Harada, Lila M.; Amigo, Ludwig; Cazita, Patricia M.; Salerno, Alessandro G.; Rigotti, Attilio A.; Quintao, Eder C. R.; Oliveira, Helena C. F.
    The aim of this work was to study how CETP expression affects whole body cholesterol homeostasis. Thus, tissue uptake and plasma removal rates of labeled HDL-cholesteryl ester (CE), VLDL secretion rates, and biliary lipid secretion and fecal bile acid content were compared between human CETP transgenic (Tg) and non-transgenic (nTg) mice fed with a standard diet. CETPTg mice exhibited increased HDL-CE plasma fractional catabolic rate and uptake by the liver, adrenalls, adipose tissue and spleen. HDL fractions from both CETP Tg and from nTg mice were removed faster from the plasma of CETP expressing than from nTg mice, suggesting a direct role of CETP in accelerating tissue CE uptake. However, neither hepatic output of VLDL cholesterol and triglycerides nor biliary lipid and fecal bile acid excretion were changed in CETP Tg compared to nTg mice. CETP Tg mice also showed enhanced hepatic cholesterol content. Steady state cholesterol homeostasis was probably preserved through the downregulation of hepatic HMG-CoA reductase and LDL receptor expression. In conclusion, although CETP expression facilitates cholesteryl ester tissue uptake, it does not alter biliary lipid and fecal bile acid excretion, the mandatory final step of the reverse cholesterol transport. (c) 2006 Elsevier Ireland Ltd. All rights reserved.
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    Cholecystectomy increases hepatic triglyceride content and very-low-density lipoproteins production in mice
    (WILEY, 2011) Amigo, Ludwig; Husche, Constanze; Zanlungo, Silvana; Luetjohann, Dieter; Arrese, Marco; Miquel, Juan F.; Rigotti, Attilio; Nervi, Flavio
    Background & aims: Bile acid (BA) pool size remains unchanged after cholecystectomy (XGB) but it circulates faster, exposing the enterohepatic system to an increased flux of BA. Triglyceride (TG) and BA metabolisms are functionally inter-related. We investigated whether ablation of the gallbladder (GB) modifies hepatic TG metabolism. Methods: Male mice were subjected to XGB and fed a normal diet. In some experiments, mice received a 1% nicotinic acid diet to block lipolysis. Parameters of BA and TG metabolism, and microsomal triglyceride transfer protein (MTTP) activity were measured 1-2 months after XGB. Serum parameters, hepatic lipids and mRNA expression of genes of lipid metabolism were determined. Results: BA pool size and synthesis were normal, but biliary BA secretion doubled during the diurnal light phase in XGB mice. Serum and hepatic TG concentrations increased 25% (P < 0.02), and hepatic very-low-density lipoproteins (VLDL)-TG and apoB-48 productions increased 15% (P < 0.03) and 50% (P < 0.01), respectively, after XGB. Feeding a 1% nicotinic acid did normalize VLDL production. MTTP activity increased 15% (P < 0.005) after XGB. Hepatic free fatty acid (FFA) synthesis and content, and mRNA levels of lipid metabolism-related genes remained normal in XGD mice. Conclusions: XGB increased serum and hepatic TG levels, and VLDL production, which were restored to normal by nicotinic acid. The results suggest that FFA flux from adipose tissue to the liver is increased in XGB mice. They support the hypothesis that the GB has a role in the regulation of hepatic TG metabolism and that XGB may favour the accumulation of fat in the liver.
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    Gugulipid causes hypercholesterolemia leading to endothelial dysfunction, increased atherosclerosis, and premature death by ischemic heart disease in male mice.
    (2017) Contreras Duarte, Susana de las Mercedes; Leiva Mendoza, Andrea Alejandra; Amigo, Ludwig; Sepulveda, Esteban; Boric P., Mauricio; Quinones, Veronica; Busso, Dolores; Rigotti Rivera, Attilio
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    Inactivation of hepatic microsomal triglyceride transfer protein protects mice from diet-induced gallstones
    (W B SAUNDERS CO-ELSEVIER INC, 2006) Amigo, Ludwig; Castro, Juan; Miquel, Juan Francisco; Zanlungo, Silvana; Young, Stephen G.; Nervi, Flavio
    Background & Aims: Microsomal triglyceride transfer protein (MTTP) is critical for the production of very-low-density lipoproteins (VLDL). The current studies were undertaken to examine the in vivo role of MTTP in hepatic cholesterol and fatty acid metabolism, as well as in biliary lipid secretion. We also tested whether MTTP plays a role in diet-induced cholelithiasis in mice. Methods: We used mice in which Mttp had been inactivated in the liver (Mttp(Delta/Delta) mice). We measured several parameters of cholesterol metabolism, fatty acid synthesis, and biliary lipid levels in mice fed a normal or a lithogenic diet. We also assessed the incidence of diet-associated gallstones. Results: Hepatic Mttp inactivation markedly decreased plasma triglyceride and cholesterol levels and increased biliary cholesterol and bile acid output. Hepatic cholesterogenesis and fatty acid synthesis were significantly decreased in Mttp(Delta/Delta), mice compared with control mice. The incidence of gallstones decreased from 90% in control mice to 33% in Mttp(Delta/Delta) mice after 8 weeks of a lithogenic diet (P < .0001). The mechanism of the protective effect appears to be increased biliary phospholipid output in Mttp(Delta/Delta) mice, leading to significant unsaturation of gallbladder bile. Conclusions: These results indicate that modulation of Map expression in the liver affects hepatic lipid svnthesis and storage as well as biliary lipid secretion. Our findings further indicate that inhibition of hepatic MTTP activity decreases the risk of experimental cholelithiasis by favoring phospholipid output into the bile.
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    Increased activity of hepatic microsomal triglyceride transfer protein and bile acid synthesis in gallstone disease
    (JOHN WILEY & SONS INC, 2007) Castro, Juan; Amigo, Ludwig; Miquel, Juan Francisco; Galman, Cecilia; Crovari, Fernando; Raddatz, Alejandro; Zanlungo, Silvana; Jalil, Roberto; Rudling, Mats; Nervi, Flavio
    A strong interrelationship exists between the regulation of bile acid (BA) metabolism and hepatic very low density lipoprotein (VLDL) production. We have recently shown that BA synthesis is increased in gallstone disease. We investigated the activity of hepatic microsomal triglyceride transfer protein (MTTP) as a surrogate of VLDL production, BA synthesis, and mRNA expression levels of proteins that regulate fatty acid (FA) metabolism in the liver of gallstone (GS) patients compared with GS-free patients. Twenty-seven volunteers subjected to elective surgery; 9 were GS-free and 18 with GS agreed to have a liver biopsy. We quantified by a fluorescence assay the activity of MTTP and by quantitative reverse-transcription PCR (RT-PCR) the mRNA content of hepatic MTTP and genes that regulate hepatic sterol and FA metabolism. Plasma was assayed for lathosterol and 7 alpha-hydroxy-4-cholesten-3-one. Liver histology was normal in GS and GS-free patients. Serum VLDL triglycerides and apoB were significantly increased in GS. Hepatic triglycerides tripled in GS (P < 0.001) compared with GS-free. MTTP activity increased 70% (P < 0.001). Serum lathosterol and hepatic cholesterol concentrations, and mRNA expressions of MTTP, CD36, and FABP1 were similar in GS-free and GS patients. Hepatic mRNA expression of hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and 3-hydroxyl-3-methyl-glutaryl-CoA synthase (HMGS) were significantly decreased- 40% and 27%, respectively in GS. Serum 7a-hydroxy-4-cholesten-3-one was 75% higher, and mRNA expression of CYP7A1 was increased sevenfold (P < 0.001) in GS. Conclusion: Hepatic MTTP activity and BA synthesis are increased in GS. Results suggest that hepatic VLDL production and trafficking of BA are increased in gallstone patients.
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    Niemann-Pick C2 Protein Expression Regulates Lithogenic Diet-Induced Gallstone Formation and Dietary Cholesterol Metabolism in Mice
    (SPRINGER HEIDELBERG, 2012) Balboa, Elisa; Morales, Gabriela; Aylwin, Paula; Carrasco, Gonzalo; Amigo, Ludwig; Castro, Juan; Rigotti, Attilio; Zanlungo, Silvana
    Niemann-Pick C2 protein (NPC2) is a lysosomal soluble protein that is highly expressed in the liver; it binds to cholesterol and is involved in intracellular cholesterol trafficking, allowing the exit of lysosomal cholesterol obtained via the lipoprotein endocytic pathway. Thus, this protein may play an important role in controlling hepatic cholesterol transport and metabolism. The aim of this work was to study the relevance of NPC2 protein expression in hepatic cholesterol metabolism, biliary lipid secretion and gallstone formation by comparing NPC2 hypomorph [NPC2 (h/h)] and wild-type mice fed control, 2% cholesterol, and lithogenic diets. NPC2 (h/h) mice exhibited resistance to a diet-induced increase in plasma cholesterol levels. When consuming the chow diet, we observed increased biliary cholesterol and phospholipid secretions in NPC2 (h/h) mice. When fed the 2% cholesterol diet, NPC2 (h/h) mice exhibited low and high gallbladder bile cholesterol and phospholipid concentrations, respectively. NPC2 (h/h) mice fed with the lithogenic diet showed reduced biliary cholesterol secretion, gallbladder bile cholesterol saturation, and cholesterol crystal and gallstone formation. This work indicates that hepatic NPC2 expression is an important factor in the regulation of diet-derived cholesterol metabolism and disposal as well as in diet-induced cholesterol gallstone formation in mice.
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    P450CYP2C epoxygenase and CYP4A omega-hydroxylase mediate ciprofibrate-induced PPAR alpha-dependent peroxisomal proliferation
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007) Gatica, Arnaldo; Aguilera, Mauricio C.; Contador, David; Loyola, Gloria; Pinto, Claudio O.; Amigo, Ludwig; Tichauer, Juan E.; Zanlungo, Silvana; Bronfman, Miguel
    Peroxisomal proliferators, such as ciprofibrate, are used extensively as effective hypolipidemic drugs. The effects of these compounds on lipid metabolism require ligand binding activation of the peroxisome proliferator-activated receptor (PPAR) alpha subtype of nuclear receptors and involve transcriptional activation of the metabolic pathways involved in lipid oxidative metabolism, transport, and disposition. omega-Hydroxylated-eicosatrienoic acids (HEETs), products of the sequential metabolism of arachidonic acid (AA) by the cytochrome P450 CYP2C epoxygenase and CYP4A omega-hydroxylase gene subfamilies, have been identified as potent and high-affinity ligands of PPAR alpha in vitro and as PPAR alpha activators in transient transfection assays. Using isolated rat hepatocytes in culture, we demonstrate that specific inhibition of either the CYP2C epoxygenase or the CYP4A omega-hydroxylase abrogates ciprofibrate-induced peroxisomal proliferation, whereas inhibition of other eicosanoid-synthesizing pathways had no effect. Conversely, overexpression of the rat liver CYP2C11 epoxygenase leads to spontaneous peroxisomal proliferation, an effect that is reversed by a CYP inhibitor. Based on these results, we propose that HEETs may serve as endogenous PPAR alpha ligands and that the P450 AA monooxygenases participate in ciprofibrate-induced peroxisomal proliferation and the activation of PPAR alpha downstream targets.
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    Role of plasma and liver cholesterol- and lipoprotein-metabolism determinants in LpX formation in the mouse
    (ELSEVIER SCIENCE BV, 2007) Bravo, Ignacio; Amigo, Ludwig; Cohen, David E.; Nervi, Flavio; Rigotti, Attilio; Francone, Omar; Zanlungo, Silvana
    Cholestasis is characterized by hypercholesterolemia and the appearance of an abnormal lipoprotein, lipoprotein X (LpX), in plasma. The mechanisms responsible for this cholestatic plasma lipid phenotype are not fully understood. We used ATP-binding cassette A1 (ABCA1)((-/-)) and scavenger receptor class B type I (SR-BI)((-/-)) mice to test the hypothesis that hepatic sinusoidal cholesterol transporters contribute to LpX formation and hypercholesterolemia during cholestasis. Bile-duct ligation (BDL) of both ABCA1((-/-)) and SR-BI((-/-)) mice, as well as their respective controls, induced a dramatic increase in plasma cholesterol and phospholipid concentrations. Plasma fractionation revealed the presence of LpX in plasma of cholestatic mice, irrespective of their genetic background. We observed that the presence of HDL before cholestasis, a decrease in the activity of LCAT, and an increase in VLDL synthesis were not required for hypercholesterolemia and lipoprotein modifications induced by obstructive cholestasis in mice. In addition, murine cholestasis resulted in increased hepatic cholesterol synthesis that may contribute to the higher plasma free cholesterol levels found during the early hours after BDL. Together these findings indicate that hypercholesterolemia and LpX formation associated with obstructive cholestasis are correlated with an increase in hepatic cholesterol synthesis and are independent of plasma HDL levels, LCAT activity, VLDL synthesis, and ABCA1 and SR-BI expression. (c) 2007 Elsevier B.V. All rights reserved.
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    The consumption of beef burgers prepared with wine grape pomace flour improves fasting glucose, plasma antioxidant levels, and oxidative damage markers in humans : a controlled trial
    (2018) Urquiaga Reus, Inés; Troncoso, Danitza; Mackenna, María José; Urzúa, Catalina; Pérez, Druso; Dicenta, Sara; De la Cerda, Paula María; Amigo, Ludwig; Carreño, Juan Carlos; Echeverría Errázuriz, Guadalupe; Rigotti Rivera, Attilio
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    Transgenic overexpression of Niemann-Pick C2 protein promotes cholesterol gallstone formation in mice
    (2016) Acuña, Mariana; González Hódar, Lila Alejandra; Amigo, Ludwig; Castro, Juan; Morales, M. Gabriela; Cancino, Gonzalo I.; Groen, Albert K.|Young, Juan; Miquel P., Juan Francisco; Zanlungo Matsuhiro, Silvana