Regulation of p27 and cdk2 expression in different adipose tissue depots in aging and obesity

Aging usually comes associated with increased visceral fat accumulation, reaching even an obesity state, and favoring its associated comorbidities. One of the processes involved in aging is cellular senescence, which is highly dependent on the activity of the regulators of the cell cycle. The aim of this study was to analyze the changes in the expression of p27 and cdk2 in different adipose tissue depots during aging, as well as their regulation by obesity in mice. Changes in the expression of p27 and CDK2 in visceral and subcutaneous white adipose tissue (WAT) biopsies were also analyzed in a human cohort of obesity and type 2 diabetes. p27, but not cdk2, exhibits a lower expression in subcutaneous than in visceral WAT in mice and humans. p27 is drastically downregulated by aging in subcutaneous WAT (scWAT), but not in gonadal WAT, of female mice. Obesity upregulates p27 and cdk2 expression in scWAT, but not in other fat depots of aged mice. In humans, a significant upregulation of p27 was observed in visceral WAT of subjects with obesity. Taken together, these results show a differential adipose depot-dependent regulation of p27 and cdk2 in aging and obesity, suggesting that p27 and cdk2 could contribute to the adipose-tissue depot’s metabolic differences. Further studies are necessary to fully corroborate this hypothesis

Alteraciones del metabolismo lipídico producidas por el virus de la hepatitis c en pacientes con infección crónica

Background: Chronic infection with the hepatitis C virus (HCV) is known to generate an apparently favorable lipid profile. Paradoxically, these patients present an increase in concomitant cardiovascular events. The objectives of the present review were to analyze and synthesize studies that inquired into the changes produced by hepatitis C virus (HCV) in the lipid metabolism of patients with chronic infection, and about whether these modifications can be associated with subsequent episodes of cardiovascular diseases. Methods: A bibliographic search was carried out in the Medline and Scopus databases of the articles published from January 2008 to February 2019. A total of 901 publications were identified, of which 10 studies that fulfilled the inclusion and exclusion criteria were reviewed. Results: It was found that the levels of total cholesterol and its lipid fractions were decreased in patients with chronic HCV infection. There was no clear association with triglyceride levels. In addition, there seemed to be an association between chronic HCV infection and an increased risk of developing atherosclerosis and cardiovascular diseases. Conclusions: Chronic HCV infection has a lipid- lowering effect and increases cardiovascular risk. Prospective studies are needed to analyze the effect of new therapies with direct-acting antivirals on lipid metabolism and cardiovascular risk.Fundamentos: Es conocido que la infección crónica por el virus de la hepatitis C (VHC) genera un perfil lipídico aparentemente favorable. Paradójicamente, estos pacientes presentan un aumento de eventos cardiovasculares concomitantes. Los objetivos de la presente revisión fueron analizar y sintetizar los estudios que indagasen en las modificaciones que produce el VHC sobre el metabolismo lipídico de los pacientes con infección crónica, así como estudiar si esas modificaciones pueden asociarse a episodios posteriores de enfermedad cardiovascular. Métodos: Se realizó una búsqueda bibliográfica en las bases de datos de Medline y Scopus de los artículos publicados desde enero de 2008 hasta febrero de 2019. Se identificaron un total de 901 publicaciones, de las cuales se revisaron 10 estudios que cumplieron con los criterios de inclusión y exclusión propuestos. Resultados: Se encontró que en los pacientes con infección crónica por el VHC estaban disminuidos los niveles de colesterol total y sus fracciones lipídicas. No existió una clara asociación con los niveles de triglicéridos. Además, parecía haber una asociación entre la infección crónica por VHC y un aumento del riesgo de padecer aterosclerosis y de desarrollar enfermedades cardiovasculares. Conclusiones: La infección crónica por el VHC tiene un efecto hipolipemiante y aumenta el riesgo cardiovascular. Se precisan estudios prospectivos que analicen el efecto de las nuevas terapias con antivirales de acción directa sobre el metabolismo lipídico y el riesgo cardiovascular

Microarray analysis of hepatic genes differentially expressed in the presence of the unsaponifiable fraction of olive oil in apolipoprotein E-deficient mice

The hypothesis that the unsaponifiable fraction of olive oil dramatically influences hepatic gene expression was tested in mice. Two olive oils, obtained from the same olive cultivar but by different technological procedures, were characterized to show that they differed mainly in terms of the composition/quantity of this unsaponifiable fraction. Using DNA microarrays, hepatic gene expression was analysed in apoE-deficient mice fed one of two isoenergetic, isonitrogenous diets containing either 10% (w/w) olive oil or unsaponifiable fraction-enriched olive oil. To provide an initial screening of potential candidate genes involved in a differential response, only genes with remarkably modified expression (signal log2 ratio ≥3 or < -3) were further considered. The eleven genes fulfilling these prerequisites were confirmed by quantitative RT-PCR, and then analysed in apoE-deficient mice with a C57BL/6J genetic background. Orosomucoid and serum amyloid A2 were upregulated (to variable extents depending on the genetic background) in the absence of hepatic steatosis and inflammation. Fabp5 and Mt2 were also strongly upregulated. Several proteases were highly suppressed by the unsaponifiable-enriched olive diet, independent of the genetic background. The findings indicate that change in the expression of these genes is a good marker of the intake of the unsaponifiable fraction of olive oil. The results highlight the important biological effects of the unsaponifiable fraction of olive oil. The term 'monounsaturated fatty acid-enriched oil' no longer appears appropriate for describing all the oils to which it is currently applied since it does not adequately reflect that they have different biological effects. © The Authors 2007.This research was supported by grants FEGA-FEOGA (CAO99-014), Ministerio de Educación y Ciencia, CICYT (SAF2004-08 173-C03-02 and AGL2005-00 572), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes FISS de investigación cooperativa C03-01 and G03-140 and by the Fundación Española del Corazón.Peer Reviewe

Efecto de la administracion de escualeno sobre el desarrollo aterosclerotico asociado con el contenido hepatico de lipidos dependiente del sexo

Trabajo presentado en el XXXI Congreso Sociedad Española de Bioquímica y Biología Molecular SEBBM, celebrado en Bilbao (España) el 10 de septiembre de 2008.[Objective]: To investigate the effect of this isoprenoid on the development of atherosclerosis.[Methods and Results]: Two groups of apoE-knockout mice, separated according to sex, were fed on standard chow diet: the control group receiving only vehicle and the second group an aqueous solution of squalene to provide a dose of 1 g/kg/day for 10 weeks. At the end of this period, plasma lipid parameters, oxidative stress markers and hepatic fat were measured as well as cross-sectional lesion area of aortic root in both groups. Data showed that in males squalene feeding reduced atherosclerotic lesion area independently of plasma lipids and activation of circulating monocytes. In contrast, squalene intake did not decrease lesion area in females, despite reducing plasma cholesterol and triglycerides, isoprostane and percentage of Mac-1 expressing white cells. In males, atherosclerotic lesion area was positively and signifi cantly associated with hepatic fat content and the plasma triglycerides were also strongly associated with liver weight.[Conclusions]: These results indicate that administration of squalene modulate lesion development in a gender specifi c manner, and that accumulation of hepatic fat by liver

Sex-dependent effect of liver growth factor on atherosclerotic lesions and fatty liver disease in apolipoprotein E knockout mice

Objective: Since the hepatic mitogen, liver growth factor (LGF), improves vascular structure and function in a hypertensive rat model and exhibits antioxidant activity, it may play a role in the development of atherosclerosis. Methods: To test this hypothesis, 14 male and 11 female apolipoprotein E (apoE)-deficient mice with a C57BL/6J genetic background were injected intraperitoneally twice a week with 1.7 µg of LGF per mouse for ten weeks. Plasma carbohydrates, inflammatory and lipid parameters, apolipoproteins A-I and A-II and paraoxonase activity were assessed at the end of the experimental period. Histological and chemical analyses of the livers and quantification of aortic atherosclerotic lesions were also carried out. Results: LGF administration changed neither plasma lipid nor inflammatory parameters. ApoA-I and arylesterase activity were not affected by LGF either, while apoA-II decreased significantly in males but not in females. Plasma apoA-II correlated positively with liver fat in males but negatively in females. Atherosclerotic area lesions in males receiving LGF were 25% lower than in control mice. Likewise, a significant reduction of fatty liver disease was also observed in males in association with decreased levels of insulin, leptin and resistin. Conclusion: These results indicate that administration of LGF modulates atherosclerotic lesions in a sex-dependent manner. This effect is independent of plasma cholesterol, triglycerides, IL-6, MCP-1 and TNF-α and is related to a remodelling of HDL particles characterised by a decrease in apoA-II induced by changes in hepatic mRNA expression. Hence, LGF administration could be used as a safe alternative to control fatty liver disease and atherosclerosis in male

Squalene in a sex-dependent manner modulates atherosclerotic lesion which correlates with hepatic fat content in apoE-knockout male mice

BACKGROUND: Squalene is an intermediate of cholesterol biosynthesis which can be obtained from the diet where it is abundant, for example, in olive oil. The effect of this isoprenoid on the development of atherosclerosis was investigated on apoE-knockout mice. METHODS AND RESULTS: Two groups of animals, separated according to sex, were fed on standard chow diet: the control group receiving only vehicle and the second group an aqueous solution of squalene to provide a dose of 1g/kg/day in male and female mice. This treatment was maintained for 10 weeks. At the end of this period, plasma lipid parameters, oxidative stress markers and hepatic fat were measured as well as cross-sectional lesion area of aortic root in both groups. Data showed that in males squalene feeding reduced atherosclerotic lesion area independently of plasma lipids and activation of circulating monocytes. In contrast, squalene intake did not decrease lesion area in females, despite reducing plasma cholesterol and triglycerides, isoprostane and percentage of Mac-1 expressing white cells. In males, atherosclerotic lesion area was positively and significantly associated with hepatic fat content and the plasma triglycerides were also strongly associated with liver weight. CONCLUSIONS: These results indicate that administration of squalene modulates lesion development in a gender specific manner, and that accumulation of hepatic fat by liver is highly correlated with lesion progression in males. Hence, squalene administration could be used as a safe alternative to correct hepatic steatosis and atherosclerosis particularly in males.Peer reviewe

Hydroxytyrosol administration enhances atherosclerotic lesion development in apo E deficient mice

Hydroxytyrosol is a phenol found in olive oil. To verify the effect of hydroxytyrosol on the development of atherosclerosis, two groups of apo E deficient male mice on a standard chow diet were used: the control group receiving only water, and the second group an aqueous solution of hydroxytyrosol in order to provide a dose of 10 mg/kg/day to each mouse. This treatment was maintained for 10 weeks. At the moment of sacrifice, blood was drawn and heart removed. Plasma lipids, apolipoproteins and monocyte Mac-1 expression were assayed as well as aortic atherosclerotic areas in both groups. Data showed no significant changes in HDL cholesterol, paraoxonase, apolipoprotein B or triglyceride levels. However, hydroxytyrosol administration decreased apolipoprotein A-I and increased total cholesterol, atherosclerotic lesion areas and circulating monocytes expressing Mac-1. The latter was highly correlated with lesion areas (r = 0.65, P < 0.01). These results indicate that administration of hydroxytyrosol in low cholesterol diets increases atherosclerotic lesion associated with the degree of monocyte activation and remodelling of plasma lipoproteins. Our data supports the concept that phenolic-enriched products, out of the original matrix, could be not only non useful but also harmful. Our results suggest that the formulation of possible functional foods should approximate as much as possible the natural environment in which active molecules are found.This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón.This research was supported by grants FEGA-FEOGA (CAO99-0014), CICYT (SAF2004-08173-C03-02 and AGL2002-00495), Junta de Andalucía (CAO01-002), FISS 01/0202, Redes DGA (A-26) and FISS de investigación cooperativa C03-01 and G03-140 and by Fundación Española del Corazón. R.C., S.A., M.A.N. and N.G. were recipient of DGA, FEGA-FEOGA and Fundación Cuenca Villoro fellowships.Peer reviewe

CLAs in Animal Source Foods: Healthy Benefits for Consumers

Conjugated linoleic acid (CLA) is a group of polyunsaturated fatty acids that exist as positional and stereo-isomers of octadecadienoate (18:2). Among these isomers, the most studied two isomers are cis 9, trans 11-CLA and trans 10, cis 12- CLA due to their biological effects. CLA can be naturally synthesized in the rumen of ruminant animals by bacteria Butyrivibrio fibrisolvens via the Δ-9- desaturase of trans 11 octadecanoic acid pathway. The major dietary sources of CLA are represented by meat and milk from ruminant animals. Although references to CLA can be traced back to the 1950s, current interest in the health benefits of CLA started in the late 1980s, after it was identified as the anticarcinogenic component present in fried ground beef. Since then, an extensive literature has documented the anticarcinogenic effects of CLA. In addition, there is some evidence that CLA is also anti-atherosclerotic, has beneficial effects on type 2 diabetes, and may play a key role in helping to regulate body fat. The fact that the richest natural sources of CLA, meat and dairy products, are consumed by people worldwide has very interesting implications for public health