Browsing by Author "Rigotti, Attilio"

Now showing 1 - 14 of 14
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    Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition
    (ELSEVIER SCIENCE INC, 2009) Chang, Eric H.; Rigotti, Attilio; Huerta, Patricio T.
    Dysregulated cholesterol metabolism is a major risk factor for atherosclerosis and other late-onset disorders, such as Alzheimer's disease. The scavenger receptor, class B, type I (SR-BI) is critical in maintaining the homeostasis of cholesterol and alpha-tocopherol. SR-BI binds high-density lipoproteins (HDL) and mediates the selective transfer of cholesteryl esters and alpha-tocopherol from circulating HDL to cells. SR-BI is also involved in reverse cholesterol transport from peripheral tissues into the liver. Previous studies using SR-BI genetic knockout mice indicated that the deletion of SR-BI resulted in an accelerated onset of atherosclerosis. We hypothesized that SR-BI-dependent lipid dysregulation might disrupt brain function leading to cognitive impairment. Here, we report that very old SR-BI knockout mice show deficient synaptic plasticity (long-term potentiation) in the CA 1 region of the hippocampus. Very old SR-BI KO mice also display selective impairments in recognition memory and spatial memory. Thus, SR-BI influences neural and cognitive processes, a finding that highlights the contribution of cholesterol and alpha-tocopherol homeostasis in proper cognitive function. (C) 2007 Elsevier Inc. 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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    Gallbladder disease is associated with insulin resistance in a high risk Hispanic population
    (ELSEVIER SCIENCE BV, 2006) Nervi, Flavio; Miquel, Juan Francisco; Alvarez, Manuel; Ferreccio, Catterina; Garcia Zattera, Maria Jose; Gonzalez, Robinson; Perez Ayuso, Rosa Maria; Rigotti, Attilio; Villarroel, Luis
    Background/Aims: We tested whether cholesterol gallstone disease (GS) is associated to insulin resistance and serum C-reactive protein (CRP) in a high risk population.
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    Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2007) Mella, Juan G.; Schirin Sokhan, Ramin; Rigotti, Attilio; Pimentel, Fernando; Villarroel, Luis; Wasmuth, Hermann E.; Sauerbruch, Tilman; Nervi, Flavio; Lammert, Frank; Miquel, Juan Francisco
    Apolipoprotein E (apoE) isoforms are genetic determinants of interindividual variations in lipid metabolism. To assess whether apoE is a genetic risk factor for cholesterol gallstone disease (GD), we analyzed apoE variants in populations from Chile and Germany, two countries with very high prevalence rates of this disease. ApoE genotypes were determined in Chilean gallstone patients (n = 117) and control subjects (n = 122) as well as in German gallstone patients ( n 5 184) and matched controls (n = 184). In addition, we studied apoE variants in subgroups of Chilean patients with strong differences in their susceptibility to acquire gallstones: 50 elderly subjects without gallstones in spite of well-known risk factors for this disease (gallstone-resistant) and 32 young individuals with gallstones but without risk factors (gallstone-susceptible). Furthermore, correlation analysis of apoE genotypes with cholesterol crystal formation times, biliary cholesterol saturation index (CSI), and gallstone cholesterol contents was performed in 81 cholecystectomized patients. In this study analyzing the largest sample set available, apoE4 genotype was not associated with an increased frequency of GD in either population. Moreover, in the Chilean population after adjusting for risk factors such as gender, age, body mass index, serum lipids, and glucose, the odds ratio for the association of the apoE4 allele and GD was significantly (P < 0.05) < 1. Also, genotypes were not correlated with cholesterol crystal formation time, CSI, or gallstone cholesterol content. In contrast to previous smaller studies, apoE polymorphisms were not associated with susceptibility to cholesterol GD in high-risk populations.
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    Intake of red wine grape pomace decreased atherosclerosis, attenuated myocardial damage and increased survival in a murine model of lethal coronary heart disease
    (MDPI, 2019) Salas Perez, Francisca Lorena; Rivera Vega, Katherine Solange; Echeverria, Guadalupe; Urquiaga, Ines; Dicenta, Sara; Perez, Druso; Andia, Marcelo; Uribe, Sergio; Tejos, Cristian; Busso, Dolores; Irarrazaval Mena, Pablo; Rigotti, Attilio
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    Molecular diagnosis and combined lipid lowering therapy of heterozygous familial hypercholesterolemia. Report of one case
    (SOC MEDICA SANTIAGO, 2007) Arteaga, Antonio; Cuevas, Ada; Rigotti, Attilio; Gonzalez, Francisco; Castillo, Sergio; Mata, Pedro; Alonso, Rodrigo
    Heterozygous familial hypercholesterolemia affects one every 400 individuals, is caused by mutations in the LDL receptor gene and is associated with premature coronary artery disease. Nowadays, LDL cholesterol can be efficiently reduced with the new therapies to reduce blood lipids. We report a female patient who consulted in 1975, when she was 46 years old, for severe hypercbolesterolemia. In 2003, a sample of leukocyte DNA was obtained and the uncommon 1705 + 1G > A mutation of the LDL receptorgene was detected. No mutations in the apolipoprotein B gene were,found. The patient was treated successfully with simvastatin SO mg/day and ezetimibe 10 mg/day and LDL cholesterol levels were reduced below 200 mg/dl.
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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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    Non-alcoholic fatty liver disease and its association with obesity, insulin resistance and increased serum levels of C-reactive protein in Hispanics
    (WILEY, 2009) Riquelme Pérez, Arnoldo; Arrese Jiménez, Marco; Soza, Alejandro; Morales, Arturo; Baudrand Biggs, René; Pérez Ayuso, Rosa María; González Donoso, Robinson; Álvarez Lobos, Manuel; Marshall Rivera, Guillermo; Garcia Zattera, María José; Otarola, Francisco; Medina, Brenda; Rigotti, Attilio; Miquel P., Juan Francisco; Nervi, Flavio; Hernández, María José
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    Normal Hepatic Cell Surface Localization of the High Density Lipoprotein Receptor, Scavenger Receptor Class B, Type I, Depends on All Four PDZ Domains of PDZK1
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2009) Fenske, Sara A.; Yesilaltay, Ayce; Pal, Rinku; Daniels, Kathleen; Barker, Caroline; Quinones, Veronica; Rigotti, Attilio; Krieger, Monty; Kocher, Olivier
    PDZK1 is a four PDZ domain-containing scaffold protein that binds to scavenger receptor class B, type I (SR-BI), the high density lipoprotein receptor, by its first PDZ domain (PDZ1). PDZK1 knock-out mice exhibit a >95% decrease in hepatic SR-BI protein and consequently an similar to 70% increase in plasma cholesterol in abnormally large high density lipoprotein particles. These defects are corrected by hepatic overexpression of full-length PDZK1 but not the PDZ1 domain alone, which partially restores SR-BI protein abundance but not cell surface expression or function. We have generated PDZK1 knock-out mice with hepatic expression of four PDZK1 transgenes encoding proteins with nested C-terminal truncations: pTEM, which lacks the three C-terminal residues (putative PDZ-binding motif), and PDZ1.2, PDZ1.2.3, or PDZ1.2.3.4, which contain only the first two, three, or four N-terminalPDZ domains, respectively, but not the remaining C-terminal sequences. Hepatic overexpression of pTEM restored normal hepatic SR-BI abundance, localization, and function. Hepatic overexpression of PDZ1.2 or PDZ1.2.3 partially restored SR-BI abundance (similar to 12 or similar to 30% of wild type, respectively) but did not (PDZ1.2) or only slightly (PDZ1.2.3) restored hepatic SR-BI cell surface localization and function. Hepatic overexpression of PDZ1.2.3.4 completely restored SR-BI protein abundance, cell surface expression, and function (normalization of plasma cholesterol levels). Thus, all four PDZ domains in PDZK1, but not PDZ1-3 alone, are sufficient for its normal control of the abundance, localization, and therefore function of hepatic SR-BI, whereas the residues C-terminal to the PDZ4 domain, including the C-terminal putative PDZ-binding domain, are not required.
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    Overexpression of the PDZ1 domain of PDZK1 blocks the activity of hepatic scavenger receptor, class B, type I by altering its abundance and cellular localization
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2008) Fenske, Sara A.; Yesilaltay, Ayce; Pal, Rinku; Daniels, Kathleen; Rigotti, Attilio; Krieger, Monty; Kocher, Olivier
    PDZK1 is a four-PDZ domain-containing scaffold protein that, via its first PDZ domain (PDZ1), binds to the C terminus of the high density lipoprotein (HDL) receptor scavenger receptor, class B, type I (SR-BI). Abolishing PDZK1 expression in PDZK1 knock-out (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally large HDL particles. Here we show that, although hepatic overexpression of PDZK1 restored normal SR-BI protein abundance and function in PDZK1 KO mice, hepatic overexpression of only the PDZ1 domain was not sufficient to restore normal SR-BI function. In wild-type mice, overexpression of the PDZ1 domain overcame the activity of the endogenous hepatic PDZK1, resulting in a 75% reduction in hepatic SR-BI protein levels and intracellular mislocalization of the remaining SR-BI. As a consequence, the plasma lipoproteins in PDZ1 transgenic mice resembled those in PDZK1 KO mice (hypercholesterolemia due to large HDL). These results indicate that the PDZ1 domain can control the abundance and localization, and therefore the function, of hepatic SR-BI and that structural features of PDZK1 in addition to its SR-BI-binding PDZ1 domain are required for normal hepatic SR-BI regulation.
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    PDZK1 is required for maintaining hepatic scavenger receptor, class B, type I (SR-BI) steady state levels but not its surface localization or function
    (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2006) Yesilaltay, Ayce; Kocher, Olivier; Pal, Rinku; Leiva, Andrea; Quinones, Veronica; Rigotti, Attilio; Krieger, Monty
    PDZK1 is a multi-PDZ domain-containing adaptor protein that binds to the C terminus of the high density lipoprotein receptor, scavenger receptor, class B, type I (SR-BI), and controls the posttranscriptional, tissue-specific expression of this lipoprotein receptor. In the absence of PDZK1 (PDZK1(-/-) mice), murine hepatic SR-BI protein levels are very low (< 5% of control). As a consequence, abnormal plasma lipoprotein metabolism (similar to 1.5-1.7-fold increased total plasma cholesterol carried in both normal size and abnormally large high density lipoprotein particles) resembles, but is not as severely defective as, that in SR-BI(-/-) mice. Here we show that the total plasma cholesterol levels and size distribution of lipoproteins are virtually identical in SR-BI(-/-) and SR-BI(-/-)/ PDZK1(-/-) mice, indicating that most, if not all of the effects of PDZK1 on lipoprotein metabolism are likely because of the effects of PDZK1 on SR-BI. Hepatic overexpression of wild-type SR-BI in PDZK1(-/-) mice restored near or greater than normal levels of cell surface-expressed, functional SR-BI protein levels in the livers of SR-BI(-/-)/ PDZK1(-/-) mice and consequently restored apparently normal lipoprotein metabolism in the absence of PDZK1. Thus, PDZK1 is important for maintaining adequate steady state levels of SR-BI in the liver but is not essential for cell surface expression or function of hepatic SR-BI.
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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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    Validation of self-applicable questionnaire for a Mediterranean dietary index in Chile
    (SOC MEDICA SANTIAGO, 2016) Echeverria, Guadalupe; Urquiaga, Ines; Jose Concha, Maria; Dussaillant, Catalina; Villarroel, Luis; Velasco, Nicolas; Leighton, Federico; Rigotti, Attilio
    Background: Availability of brief dietary indexes that can effectively evaluate dietary patterns and their association with health is critical for prevention and management of several chronic disease conditions. Aim: To adapt a self-applicable Mediterranean Dietary Index in Chile (Chilean-MDI). Material and Methods: The Chilean-MDI was developed based on a previous Mediterranean eating score that was adapted to Chilean dietary habits. This index was further validated in a sample of 153 adults by comparing the concordance between the results obtained by self-application of the Chilean-MDI with those obtained by a trained nutritionist. Additionally, the index was applied in a sample of 53,366 Chilean adults in order to describe the diet quality of our population. Results: There was an adequate concordance between findings obtained by self-application of the Chilean-MDI and those achieved by the nutritionist. The application of the index in Chilean adult population showed abetter diet quality (high Mediterranean diet adherence) among women, with advanced age and among people with higher educational levels. Conclusions: The Chilean-MDI can be successfully self-applied to portray the overall diet quality in the Chilean adult population. Additionally, this dietary index describes overall food intake in Chilean adults, showing demographic trends that are comparable to those obtained with similar indexes applied in other populations.