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Ishibashi Y, Yoshida H, Kotani K, Akiyama Y, Fujii H, Harada-Shiba M, Ishida T, Ishigaki Y, Kabata D, Kihara Y, Kurisu S, Masuda D, Matoba T, Matsuki K, Matsumura T, Mori K, Nakagami T, Nakazato M, Taniuchi S, Ueno H, Yamashita S, Yano S, Yoshida H, Shoji T. Serum Values of Cholesterol Absorption and Synthesis Biomarkers in Japanese Healthy Subjects: The CACHE Study HEALTHY Analysis. J Atheroscler Thromb 2023; 30:1336-1349. [PMID: 36740276 PMCID: PMC10564639 DOI: 10.5551/jat.63943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 12/06/2022] [Indexed: 02/06/2023] Open
Abstract
AIM Blood cholesterol absorption and synthesis biomarkers predict cardiovascular risk. This study aimed to determine the values of serum non-cholesterol sterol markers [lathosterol (Latho), campesterol (Campe), and sitosterol (Sito)] in healthy individuals and factors affecting these markers. METHODS The CACHE Consortium compiled clinical data, including serum Latho (cholesterol synthesis marker), and Campe and Sito (cholesterol absorption markers), by a gas chromatography method in 2944 individuals. Healthy subjects were selected by excluding those with prior cardiovascular disease, diabetes mellitus, hypertension, chronic kidney disease, familial hypercholesterolemia, sitosterolemia, current smokers, those with low (＜17 kg/m2) or high (≥ 30 kg/m2) body mass index (BMI), and those with treatment for dyslipidemia or hyperuricemia. Nonlinear regression stratified by sex was used to examine the associations of cholesterol metabolism markers with age, BMI, and serum lipid levels. RESULTS Of 479 individuals selected, 59.4% were female; the median age was 48 years in females and 50 years in males. The three markers showed positively skewed distributions, and sex differences were present. Age was associated positively with Latho, inversely with Campe, but not significantly with Sito. BMI was associated positively with Latho, but not significantly with Campe or Sito. High-density lipoprotein cholesterol (HDL-C) was positively associated with Campe and Sito, but not significantly with Latho. Non-HDL-C was positively associated with the three markers. CONCLUSION Our study results in the healthy subjects help to interpret the non-cholesterol sterol markers for cardiovascular risk assessment in patients with cardiovascular risk factors.
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Affiliation(s)
- Yutaka Ishibashi
- Department of General Medicine, Shimane University Faculty of Medicine, Shimane, Japan
- Jinjukai Education & Training Center for Healthcare Professionals, Shimane, Japan
| | - Hiroshi Yoshida
- Department of Laboratory Medicine, The Jikei University Kashiwa Hospital, Chiba, Japan
| | - Kazuhiko Kotani
- Division of Community and Family Medicine, Jichi Medical University, Tochigi, Japan
| | - Yusuke Akiyama
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hisako Fujii
- Department of Health and Medical Innovation, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Mariko Harada-Shiba
- Cardiovascular Center, Osaka Medical and Pharmaceutical University, Takatsuki, Japan
| | - Tatsuro Ishida
- Division of Cardiovascular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Yasushi Ishigaki
- Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Daijiro Kabata
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Yasuki Kihara
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Satoshi Kurisu
- Department of Cardiovascular Medicine, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Daisaku Masuda
- Department of Cardiology, Rinku General Medical Center, Izumisano, Osaka, Japan
| | - Tetsuya Matoba
- Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kota Matsuki
- Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori, Japan
| | - Takeshi Matsumura
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan
| | - Kenta Mori
- Department of General Internal Medicine, Kobe University Hospital, Kobe, Japan
| | - Tomoko Nakagami
- Division of Diabetology and Metabolism, Department of Internal Medicine, Tokyo Women fs Medical University School of Medicine, Tokyo, Japan
| | - Masamitsu Nakazato
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Satsuki Taniuchi
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Ueno
- Division of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Shizuya Yamashita
- Department of Cardiology, Rinku General Medical Center, Izumisano, Osaka, Japan
| | - Shozo Yano
- Department of Laboratory Medicine, Shimane University Faculty of Medicine, Shimane, Japan
| | - Hisako Yoshida
- Department of Medical Statistics, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
| | - Tetsuo Shoji
- Department of Vascular Medicine, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
- Vascular Science Center for Translational Research, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan
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Therapeutic Potential of Brazilian Cerrado Campomanesia Species on Metabolic Dysfunctions. Molecules 2018; 23:molecules23092336. [PMID: 30216974 PMCID: PMC6225494 DOI: 10.3390/molecules23092336] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/03/2018] [Accepted: 09/04/2018] [Indexed: 12/25/2022] Open
Abstract
Obesity, in conjunction with other metabolic disorders such as insulin resistance and dyslipidemia, is a feature of metabolic syndrome which is characterized by a pro-inflammatory state and increased oxidative stress. Therefore, antioxidant foods are proposed to prevent and treat these disorders. Medicinal plants are one of the main strategies in this regard. Guavira, a Brazilian Cerrado plant, contains different bioactive compounds with a high antioxidant capacity and without clinical or reproductive toxicity effects. Though there are different varieties of guavira, the principal Brazilian Cerrado guaviras demonstrated hypoglycemic, anti-inflammatory, and hypocholesterolemic actions. There is also a potential antiplatelet agent in C. xanthocarpa, while C. adamantium displayed hypocholesterolemic actions in animal models and human clinical trials. On the other hand, even with a lack of studies related to C. pubescens, it demonstrated anti-inflammatory effects and an antioxidant capacity in in vitro studies. Despite the fact that most of the studies were not performed to evaluate pathological conditions specific to obese animal models or obese subjects, guavira demonstrated effects in metabolic disorders that are commonly related to the obesity context, such as cardiovascular disturbances and hyperglycemia status. This suggests that guavira is a potential therapeutic approach to obesity-induced metabolic syndrome.
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Vinagre CG, Freitas FR, de Mesquita CH, Vinagre JC, Mariani AC, Kalil-Filho R, Maranhão RC. Removal of Chylomicron Remnants from the Bloodstream is Delayed in Aged Subjects. Aging Dis 2018; 9:748-754. [PMID: 30090662 PMCID: PMC6065288 DOI: 10.14336/ad.2017.1003] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 10/03/2017] [Indexed: 12/22/2022] Open
Abstract
Dietary fats absorbed in the intestine are transported in the circulation as chylomicrons and remnants that have atherogenic potential. Although postprandial lipidemia is increased in older subjects, the specific chylomicron metabolism has not been explored in older subjects nor compared to young subjects, which is the focus of this study. After a 12 h fast, artificially-made emulsions similar to lymph chylomicrons and doubly labeled with radioactive cholesteryl esters and triglycerides were intravenously injected in 23 older (66±4 years) and 20 young (24±3 years) subjects. Sequential blood samples were collected to determine fractional clearance rates (FCR, in min-1) by compartmental analysis. Older subjects had higher LDL-cholesterol (p<0.001) and triglycerides (p<0.0001) than young subjects; HDL-cholesterol presented no difference. The emulsion cholesteryl-ester FCR was lower in older subjects compared to the young (p=0.0001). The emulsion triglyceride FCR did not differ in the two groups. Tested in vitro, however, the lipolysis of the emulsion triglycerides was less intense in the older than in the young subjects. As delayed removal of remnants, indicated by the pronouncedly smaller cholesteryl ester FCR, is related to the presence of cardiovascular diseases, this can be a risk factor which could accelerate atherogenic complications occurring in aged subjects
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Affiliation(s)
- Carmen G Vinagre
- 1Heart Institute (InCor) of Medical School Hospital, University of São Paulo, São Paulo, Brazil.,2University of Santo Amaro, São Paulo, Brazil
| | - Fatima R Freitas
- 1Heart Institute (InCor) of Medical School Hospital, University of São Paulo, São Paulo, Brazil
| | | | - Juliana C Vinagre
- 1Heart Institute (InCor) of Medical School Hospital, University of São Paulo, São Paulo, Brazil
| | | | - Roberto Kalil-Filho
- 1Heart Institute (InCor) of Medical School Hospital, University of São Paulo, São Paulo, Brazil
| | - Raul C Maranhão
- 1Heart Institute (InCor) of Medical School Hospital, University of São Paulo, São Paulo, Brazil.,4Faculty of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
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Bizzarri R, Cerbai E, Solaro R, Chiellini E. A Convenient Method for the Synthesis of (S)-Dolichol and (S)-Nordolichol. J BIOACT COMPAT POL 2016. [DOI: 10.1177/0883911503040435] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A procedure for the preparation of (S)-dolichol and (S)-nor-dolichol starting from the polyprenyl fraction extracted from Gingko Biloba integer or extracted leaves is described. Two chiral isoprenoid compounds in good yields and high degree of enantiomeric excess were obtained. The (S)-nordolichol appears to be a good chiral precursor for the preparation of 14C-labeled (S)-dolichol which is to be used in investigations aimed at gaining further information with respect to the role of dolichol in the function of living cells.
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Affiliation(s)
| | | | | | - Emo Chiellini
- Department of Chemistry and Industrial Chemistry UdR of the Consortium INSTM University of Pisa via Risorgimento 35, 56123–Pisa, Italy
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Molińska nee Sosińska E, Klimczak U, Komaszyło J, Derewiaka D, Obiedziński M, Kania M, Danikiewicz W, Swiezewska E. Double bond stereochemistry influences the susceptibility of short-chain isoprenoids and polyprenols to decomposition by thermo-oxidation. Lipids 2015; 50:359-70. [PMID: 25739731 PMCID: PMC4365272 DOI: 10.1007/s11745-015-3998-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Accepted: 01/04/2015] [Indexed: 11/26/2022]
Abstract
Isoprenoid alcohols are common constituents of living cells. They are usually assigned a role in the adaptation of the cell to environmental stimuli, and this process might give rise to their oxidation by reactive oxygen species. Moreover, cellular isoprenoids may also undergo various chemical modifications resulting from the physico-chemical treatment of the tissues, e.g., heating during food processing. Susceptibility of isoprenoid alcohols to heat treatment has not been studied in detail so far. In this study, isoprenoid alcohols differing in the number of isoprene units and geometry of the double bonds, β-citronellol, geraniol, nerol, farnesol, solanesol and Pren-9, were subjected to thermo-oxidation at 80 °C. Thermo-oxidation resulted in the decomposition of the tested short-chain isoprenoids as well as medium-chain polyprenols with simultaneous formation of oxidized derivatives, such as hydroperoxides, monoepoxides, diepoxides and aldehydes, and possible formation of oligomeric derivatives. Oxidation products were monitored by GC-FID, GC-MS, ESI-MS and spectrophotometric methods. Interestingly, nerol, a short-chain isoprenoid with a double bond in the cis (Z) configuration, was more oxidatively stable than its trans (E) isomer, geraniol. However, the opposite effect was observed for medium-chain polyprenols, since Pren-9 (di-trans-poly-cis-prenol) was more susceptible to thermo-oxidation than its all-trans isomer, solanesol. Taken together, these results experimentally confirm that both short- and long-chain polyisoprenoid alcohols are prone to thermo-oxidation.
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Affiliation(s)
- Ewa Molińska nee Sosińska
- Department of Lipid Biochemistry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106, Warsaw, Poland,
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Klionsky DJ, Bergamini E. Searching for the fountain of autophagy-dependent youth. Autophagy 2014; 8:1169-74. [DOI: 10.4161/auto.20788] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
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Viecili PRN, Borges DO, Kirsten K, Malheiros J, Viecili E, Melo RD, Trevisan G, da Silva MA, Bochi GV, Moresco RN, Klafke JZ. Effects of Campomanesia xanthocarpa on inflammatory processes, oxidative stress, endothelial dysfunction and lipid biomarkers in hypercholesterolemic individuals. Atherosclerosis 2014; 234:85-92. [PMID: 24632042 DOI: 10.1016/j.atherosclerosis.2014.02.010] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2013] [Revised: 02/02/2014] [Accepted: 02/12/2014] [Indexed: 11/18/2022]
Abstract
In Brazil, the edible plant Campomanesia xanthocarpa Berg. (Myrtaceae), popularly known as "guavirova," has been studied in hypercholesterolemic individuals. The present work investigated the effects of C. xanthocarpa on inflammatory processes, oxidative stress, endothelial dysfunction and lipid biomarkers in hypercholesterolemic individuals. A total of 156 individuals were selected in a double-blind fashion and randomly divided into two groups in accordance with the intervals used in the criteria for hypercholesterolemia: individuals with total cholesterol (TC) levels between 200 and 240 mg/dL (undesirable level individuals - UL) and individuals with TC levels >240 mg/dL (hypercholesterolemic individuals - HL). Both groups had a control group (CG), which received placebo treatment, an encapsulated excipient group (lactose) and an experimental group that received 500 mg (EG 500), 750 mg (EG 750) or 1000 mg (EG 1000) of encapsulated C. xanthocarpa. The inflammatory processes (high-sensitivity C-reactive protein - hs-CRP), oxidative stress (advanced oxidation protein products-AOPPs; ischemia-modified albumin-IMA), endothelial dysfunction (nitric oxide - NOx) and biochemical (TC, triglycerides, high-density lipoprotein - HDL, low-density lipoproteins - LDL, and very low-density lipoprotein - VLDL) parameters were measured before and 90 days after the initiation of treatment. A significant decrease in TC and LDL levels was observed in HL individuals from the EG 500 group (reduction of 29 ± 3% and 41 ± 5% to levels before treatment) compared to the CG group individuals. A significant reduction in oxidative stress and inflammatory process components (reduction of 52 ± 11% in AOPPs, 32 ± 10% in IMA and 57 ± 7% in hs-CRP) and a significant increase in NOx (increase of 84 ± 27%) was observed in HL individuals in the EG 1000 group when compared to the CG group individuals. Treatment with encapsulated C. xanthocarpa reduced blood TC and LDL levels in hypercholesterolemic individuals. In addition to its effect on cholesterol levels, this plant reduced oxidative stress in hypercholesterolemic individuals and improved the levels of NOx.
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Affiliation(s)
- Paulo Ricardo Nazário Viecili
- Programa de Pós-Graduação em Atenção Integral à Saúde, Universidade de Cruz Alta, 98020-290 Cruz Alta, RS, Brazil; Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil
| | - Diego Olschowsky Borges
- Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil; Fundação Universidade Federal de Ciências da Saúde de Porto Alegre, 90050-170 Porto Alegre, Brazil
| | - Karina Kirsten
- Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil
| | - Jênifer Malheiros
- Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil
| | - Eduardo Viecili
- Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil
| | - Rodolfo Dahlem Melo
- Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil
| | - Gabriela Trevisan
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Mariane Arnoldi da Silva
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Guilherme Vargas Bochi
- Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Rafael Noal Moresco
- Programa de Pós-Graduação em Ciências Farmacêuticas, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil
| | - Jonatas Zeni Klafke
- Programa de Pós-Graduação em Atenção Integral à Saúde, Universidade de Cruz Alta, 98020-290 Cruz Alta, RS, Brazil; Centro de Ensino e Pesquisa, Instituto de Cardiologia de Cruz Alta, 98010-110 Cruz Alta, RS, Brazil.
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Trapani L, Segatto M, Pallottini V. New compounds able to control hepatic cholesterol metabolism: Is it possible to avoid statin treatment in aged people? World J Hepatol 2013; 5:676-684. [PMID: 24432184 PMCID: PMC3879689 DOI: 10.4254/wjh.v5.i12.676] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2013] [Accepted: 11/16/2013] [Indexed: 02/06/2023] Open
Abstract
Aging is characterized by the loss of homeostasis that leads to changes in the biochemical composition of tissues, reduced ability to respond adaptively to environmental stimuli, and increased susceptibility and vulnerability to diseases including coronary artery diseases, carotid artery disease and brain vessel disease. Hypercholesterolemia is one of the primary risk factors for these pathologies, whose incidence is highly related to aging. Almost 25% of men and 42% of women older than 65 years have a serum total cholesterol level greater than 240 mg/dL. The mechanisms behind this age-related increase in plasma cholesterol are still incompletely understood, thus, the control of plasma cholesterol content in aged people is more challenging than in adults. In this review the different pharmacological approaches to reduce plasma cholesterol levels, particularly in aged people, will be discussed. In brief, current therapies are mostly based on the prescription of statins (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors) that are pretty effective but that exert several side effects. More attention should be given to potential drug interactions, potential age-related changes in drug pharmacokinetics, adverse effects such as myopathy and competing risks when statins are prescribed to old patients. In combination or in alternative to statin therapy, other agents might be required to reduce low density lipoprotein (LDL) cholesterol levels. Among the available drugs, the most commonly prescribed are those addressed to reduce cholesterol absorption, to modulate lipoprotein lipase activity and bile acid sequestrants: even these pharmacological interventions are not exempt from side effects. The use of antioxidants or organoselenium compounds and the discovery of new proteins able to modulate exclusively LDL receptor recycling such as Proprotein convertase subtilisin kexin 9 and SEC24 offer new pharmacological approaches to selectively reduce the main causes of dyslipidemia.
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Jia YJ, Liu J, Guo YL, Xu RX, Sun J, Li JJ. Dyslipidemia in rat fed with high-fat diet is not associated with PCSK9-LDL-receptor pathway but ageing. J Geriatr Cardiol 2013; 10:361-8. [PMID: 24454330 PMCID: PMC3888919 DOI: 10.3969/j.issn.1671-5411.2013.04.007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Revised: 08/06/2013] [Accepted: 08/11/2013] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Obesity is associated with unfavorable alternations in plasma lipid profile and a broad spectrum of cardio-metabolic disorders. Proprotein convestase subtilisin kexin type 9 (PCSK9) is a novel circulating protein that promotes hypercholesterolemia by decreasing hepatic low lipoprotein density receptor (LDLR) protein. However, the relationship between PCSK9 concentration and lipid profile in an obesity condition has less been investigated. OBJECTIVE To examine the changes of plasma PCSK9 concentration in a rat model fed with high fat diet (HFD) and its correlation to lipid profile, body weight and ageing. METHODS Twenty male Sprague Dawley (SD) rats were divided into two groups, control group (fed with normal pellet for 4 weeks), and high-fat diet group (fed with 3% cholesterol enrich diet for 4 weeks). Blood samples of rats were obtained before and at days 14, 21, and 28 in both groups. The body weight, plasma metabolic parameters (glucose, lipid profile) and PCSK9 were determined at indicated time points. RESULTS The body weights were significantly increased in rats fed with HFD compared to that in rats with normal pellets at day 28. Additionally, total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) levels in rat fed with HFD were also higher than that in rats fed with control diet while decreased high density lipoprotein cholesterol (HDL-C) levels were found in rats with HFD at day 28. More interesting, there were no differences of plasma PCSK9 concentrations as well as hepatic expression of LDLR between the two groups at day 28. CONCLUSIONS Although the body weight and LDL-C were significantly increased in rats fed with HFD at 4 weeks, there were no differences of changes in plasma PCSK9 concentration and LDLR expression of liver tissue in both groups at baseline and day 28, suggesting that dyslipidemia in the rat model with HFD appears not to be associated with PCSK9-LDLR pathway but ageing.
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Affiliation(s)
- Yan-Jun Jia
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Jun Liu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Yuan-Lin Guo
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Rui-Xia Xu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Jiang Sun
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
| | - Jian-Jun Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing 100037, China
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Pisapia L, Del Pozzo G, Barba P, Caputo L, Mita L, Viggiano E, Russo GL, Nicolucci C, Rossi S, Bencivenga U, Mita DG, Diano N. Effects of some endocrine disruptors on cell cycle progression and murine dendritic cell differentiation. Gen Comp Endocrinol 2012; 178:54-63. [PMID: 22531466 DOI: 10.1016/j.ygcen.2012.04.005] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2011] [Revised: 03/21/2012] [Accepted: 04/09/2012] [Indexed: 12/24/2022]
Abstract
Endocrine disruptor chemicals (EDCs), which are predominantly present in the environment, are able to mimic or antagonise the biological activity of hormones primarily through the interaction with specific receptors. The main consequences are adverse effects on the growth and development of reproductive organs, the induction of cancer and effects on neuronal differentiation. In this study, we investigated the ability of certain EDCs, Bisphenol A (BPA), Bisphenol B (BPB), Bisphenol F (BPF), 4-n Nonylphenol (NP) and Octylphenol (OP), belonging to a homogeneous group of phenol origin, to interfere with specific cellular processes, namely, proliferation, by using MCF-7 breast carcinoma cells, and differentiation, by using murine bone marrow dendritic cells. We correlated the data on cell growth with the stimulation of cell cycle progression, which could become a step in the development of cancer, and we established a proliferation ranking between the tested EDCs: NP>BPA>OP>BPB>BPF. In addition, we investigated the ability of NP, BPA and OP to induce the differentiation of dendritic cells, the powerful antigen-presenting cells of the immune system. The differentiation and activation of these cells could affect a well-regulated immune response and determine an allergic sensitisation. We found that BPA and NP were active in determining differentiation.
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Affiliation(s)
- L Pisapia
- Institute of Genetics and Biophysics of CNR, Naples, Italy
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Segatto M, Trapani L, Marino M, Pallottini V. Age- and sex-related differences in extra-hepatic low-density lipoprotein receptor. J Cell Physiol 2011; 226:2610-6. [PMID: 21792919 DOI: 10.1002/jcp.22607] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
To determine whether differences in LDLr behavior in extra-hepatic tissues and whether extra-hepatic receptors could differentially contribute to cholesterol homeostasis under physiological conditions, we evaluated the presence and regulation of LDLr from both a gender and an aging perspective. We used the brain cortex, the gastrocnemius, and the heart ventricle of 3- and 12-month-old male and female rats. We observed a protein decrease of total LDLr in 12-month-old female rat brains that was completely restored by 17-β estradiol treatment. In the gastrocnemius, LDLr accumulates in the skeletal muscle in both male and female aged rats as a precursor probably due to a glycosylation impairment. In the heart, no modifications were observed in either older rats or rats of a specific gender. These data highlight a tissue-specific dysregulation of LDLr that is age- and gender-dependent.
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Affiliation(s)
- Marco Segatto
- Department of Biology, University of Roma Tre, Rome, Italy
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Trapani L, Segatto M, Simeoni V, Balducci V, Dhawan A, Parmar VS, Prasad AK, Saso L, Incerpi S, Pallottini V. Short- and long-term regulation of 3-hydroxy 3-methylglutaryl coenzyme A reductase by a 4-methylcoumarin. Biochimie 2011; 93:1165-71. [PMID: 21530605 DOI: 10.1016/j.biochi.2011.04.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2010] [Accepted: 04/11/2011] [Indexed: 12/16/2022]
Abstract
Dyslipidemia is one of the most significant risk factors for cardiovascular diseases. Cholesterol homeostasis is regulated by both the receptor-mediated endocytosis of Low Density Lipoproteins by LDL receptors and de novo cholesterol synthesis via the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase. Although statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase substrate competitors, have revolutionized the management of cardiovascular diseases by lowering serum LDL, their side effects range from myalgia to rhabdomyolysis. Treatment with antioxidant compounds could represent an efficient alternative in the modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. Indeed it has already been demonstrated that the rise in reactive oxygen species levels causes the complete dephosphorylation and, in turn activation of the enzyme. Many coumarins and their derivatives have the special ability to scavenge reactive oxygen species or show a lipid lowering potential. Here we evaluated whether the coumarin, 4-methylesculetin could exert both the ability to scavenge ROS and to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase in HepG2 cell line where the enzyme activity dysregulation induced by reactive oxygen species has already been reported. The antioxidant property of 4-methylesculetin led to the reduction of 3-hydroxy-3-methylglutaryl coenzyme A reductase activation state through the increase of the enzyme phosphorylation. In addition, this coumarin showed the ability to modulate 3-hydroxy-3-methylglutaryl coenzyme A reductase protein levels both by transcriptional and degradational events independent of its antioxidant activity.
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Affiliation(s)
- Laura Trapani
- Department of Biology, University Roma Tre, Viale Marconi, Rome, Italy
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Age-Related Hypercholesterolemia and HMG-CoA Reductase Dysregulation: Sex Does Matter (A Gender Perspective). Curr Gerontol Geriatr Res 2010:420139. [PMID: 20454643 PMCID: PMC2863156 DOI: 10.1155/2010/420139] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/26/2010] [Accepted: 02/18/2010] [Indexed: 02/07/2023] Open
Abstract
Although cardiovascular diseases are less prevalent in premenopausal women than in men, their occurrence in women increases at the onset of menopause, and the loss of female sex hormones contributes to the striking increase in cardiovascular morbidity and mortality in postmenopausal women. We present here a description of age-related disruption of lipid homeostasis, which particularly affects 3-hydroxy 3-methylglutaryl Coenzyme A reductase, the key rate-limiting enzyme in the cholesterol biosynthetic pathway. We further discuss the age- and gender-related dysregulation of this enzyme, providing new evidence for the different mechanisms driving dyslipidemia in elderly men and women. In addition, we introduce pharmacological methods of regulating HMGR and maintaining cholesterol homeostasis.
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Klafke JZ, da Silva MA, Panigas TF, Belli KC, de Oliveira MF, Barichello MM, Rigo FK, Rossato MF, Soares dos Santos AR, Pizzolatti MG, Ferreira J, Viecili PRN. Effects of Campomanesia xanthocarpa on biochemical, hematological and oxidative stress parameters in hypercholesterolemic patients. JOURNAL OF ETHNOPHARMACOLOGY 2010; 127:299-305. [PMID: 19914369 DOI: 10.1016/j.jep.2009.11.004] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2009] [Revised: 10/28/2009] [Accepted: 11/02/2009] [Indexed: 05/28/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE In Southern Brazil, the plant Campomanesia xanthocarpa Berg. (Myrtaceae), popularly known as "guavirova", has been empirically used for its potential effect in reducing blood cholesterol levels. AIM OF THE STUDY Since there are no scientific data confirming its popular use, the aim of the present study was to investigate the effect of Campomanesia xanthocarpa on biochemical, hematological, anthropometrical and oxidative stress parameters in hypercholesterolemic patients. MATERIALS AND METHODS Thirty three patients were selected according to total cholesterol (TC) levels: 200-240 mg/dL, undesirable level (UL), and >240 mg/dL, hypercholesterolemic level (HL). UL or HL patients were randomly divided into control group (CG), which received placebo capsules, and experimental group 250 (EG 250) or 500 (EG 500), which received either 250 or 500 mg of encapsulated Campomanesia xanthocarpa. All groups received a cholesterol restriction diet and capsules once a day. The biochemical (TC, triglycerides, HDL, LDL and VLDL), hematological (hematocrit and hemoglobin), anthropometrical (weight and abdominal circumference) and oxidative stress (protein carbonyl) parameters were measured before, 45 and 90 days after the treatment started. RESULTS There was no alteration on biochemical, hematological, anthropometric or oxidative stress parameters in UL patients of all groups. However, a significant decrease in TC and LDL levels was observed in HL patients from EG 500 group (reduction of 28+/-3% and 45+/-4% to levels before treatment) in relation to CG group patients (reduction of 12+/-2% and 29+/-4%). Moreover, a significant reduction in oxidative stress was observed in HL patients of EG 250 (51+/-12%) and EG 500 groups (34+/-18%) when compared to levels before treatment. A positive correlation between plasma oxidative stress PC and TC levels was observed. Finally, we found that Campomanesia xanthocarpa extract possesses anti-oxidant properties and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitory activity in vitro. CONCLUSION Confirming its popular use, the treatment with Campomanesia xanthocarpa encapsulated reduced blood TC and LDL levels in hypercholesterolemic patients.
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Trapani L, Violo F, Pallottini V. Hypercholesterolemia and 3-hydroxy-3-methylglutaryl coenzyme A reductase regulation in aged female rats. Exp Gerontol 2009; 45:119-28. [PMID: 19895880 DOI: 10.1016/j.exger.2009.10.014] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2009] [Revised: 10/12/2009] [Accepted: 10/29/2009] [Indexed: 12/14/2022]
Abstract
Coronary heart disease is less prevalent in pre-menopausal women than in men, but increases at the onset of menopause. This delay is due to estrogen protective effects. The rise of cholesterolemia is one of the main risk factors for coronary disease. Since 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme of the cholesterol biosynthetic pathway, it plays a pivotal role in cholesterol homeostasis maintenance. Aim of this study is to investigate whether HMGR is involved in the cholesterolemia increase that occurs during aging, and to consider its potential role as a target for estrogen protective effects. "In vivo" studies have been performed using the livers of 12-month-old female rats (whose estrogen level decrease is comparable to the one detected at the occurrence of human menopause), 12-month-old female rats treated with 17-beta-estradiol, and 3-month-old untreated male and female rats. The results indicated hypercholesterolemic status and a significant increase of HMGR activity according to a reduced activation of AMPK detected in treated rats compared to controls. Furthermore, 17-beta estradiol treatment reduced HMGR activity restoring AMPK activation. These findings highlight the correlation between estrogen and HMGR short-term regulation, and suggest the presence of another mechanism underlying the protective role of estrogen in age-related diseases.
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Affiliation(s)
- Laura Trapani
- Department of Biology, University Roma Tre, Viale Marconi 446, Rome, Italy
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16
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Straniero S, Cavallini G, Donati A, Pallottini V, Martini C, Trentalance A, Bergamini E. Stimulation of autophagy by antilipolytic drugs may rescue rodents from age-associated hypercholesterolemia. Rejuvenation Res 2009; 12:77-84. [PMID: 19419245 DOI: 10.1089/rej.2008.0806] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Aging is characterized by several metabolic changes responsible for the decline of certain functions and the appearance of age-related diseases, including hypercholesterolemia, which is the main risk factor for atherosclerosis and cardiovascular disease. Similar changes in a number of morphological and biochemical parameters were observed in rats. Caloric restriction (CR) was shown to increase longevity and prevent age-related diseases in various organisms, and to counteract the age-associated increase in plasma cholesterol. CR was thought to operate through the stimulation of the process of macroautophagy. The aim of this work was to investigate the effect of the stimulation of macroautophagy on age-associated cholesterolemia. Mature Sprague-Dawley rats were fasted overnight and given the antilipolytic agent 3,5-dimethylpyrazole (DMP; 12 mg/kg b.w. in 0.2 mL of saline, intraperitoneally). The age-related changes in cholesterol plasma level, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA-R) activity, and lipoperoxidation were determined. Low-density lipoprotein (LDL) receptor expression was determined by immunoblot of sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE)-separated liver membranes. Results show that the stimulation of macroautophagy reduces the total LDL and high-density lipoprotein (HDL) cholesterol plasma level to juvenile values, and triglycerides levels even lower. The hypocholesterolemic action of DMP requires neither the counteraction of the age-related changes in the HMG-CoA-R activation state and regulation, nor the counteraction of the age-related increase in lipoperoxidation, and only involves a restoration of the numbers of LDL receptors on liver membranes to juvenile levels.
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Affiliation(s)
- Sara Straniero
- Centro di Ricerca di Biologia e Patologia dell'Invecchiamento, Università di Pisa, Pisa, Italy
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17
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Deficiency and supplementation of PUFA in the diet have similar effects on the age-associated changes in rat-plasma cholesterol levels. Mech Ageing Dev 2008; 129:759-62. [DOI: 10.1016/j.mad.2008.09.009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2008] [Revised: 08/19/2008] [Accepted: 09/15/2008] [Indexed: 02/05/2023]
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Martini C, Pallottini V, De Marinis E, Marino M, Cavallini G, Donati A, Straniero S, Trentalance A. Omega-3 as well as caloric restriction prevent the age-related modifications of cholesterol metabolism. Mech Ageing Dev 2008; 129:722-7. [PMID: 18930075 DOI: 10.1016/j.mad.2008.09.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 09/08/2008] [Accepted: 09/17/2008] [Indexed: 12/23/2022]
Abstract
Intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake; endogenous synthesis is subject to feedback control of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, while the exogenous supply is mainly controlled by the modulation of the low-density lipoprotein receptor. During ageing, hepatic lipid modifications occur and caloric restriction are able to prevent these changes. So, the aim of this work was to evaluate the mechanisms underlying the effect exerted both by caloric restrictions and by a diet enriched with Omega-3 fatty acids, on the cholesterol plasma levels during ageing, by studying the regulation of the protein involved in cholesterol homeostasis maintenance. Livers from diet restricted and Omega-3 supplemented diet fed 24-month-old rat were used to analyze, the protein complex of cholesterol homeostasis maintenance and those ones that are able to modulate 3-hydroxy-3-methyl-glutaryl-CoA reductase. The data obtained demonstrate that both caloric restriction and Omega-3 supplemented diets are able to prevent hypercholesterolemia, by regulating HMG-CoAR activation state by controlling ROS production and p38 phosphorylation. Moreover also the age-dependent loss of LDLr membrane exposition is prevented.
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Affiliation(s)
- Chiara Martini
- Department of Biology, University of Roma Tre, Viale Marconi 446, 00146 Rome, Italy
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Skorupinska-Tudek K, Wojcik J, Swiezewska E. Polyisoprenoid alcohols--recent results of structural studies. CHEM REC 2008; 8:33-45. [PMID: 18302278 DOI: 10.1002/tcr.20137] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Polyisoprenoid alcohols (polyprenols and dolichols) are linear polymers of from several up to more than 100 isoprene units identified in almost all living organisms. Studies of their chemical structures have resulted in the discovery of new variants such as the recently described alloprenols with reversed configuration of the double bond in the alpha-isoprene unit. In parallel, structural elucidation of metabolically labeled plant dolichols has indicated that both the mevalonate and methylerythritol phosphate pathways are involved in the biosynthesis of dolichols in roots, leading to the construction of a spatial model of their biosynthesis. According to this model, in root cells, synthesis of the dolichol molecule is initiated in the plastids, and the resulting intermediates, oligoprenyl diphosphates, are exported to the cytoplasm and are elongated up to the desired chain length. The metabolic consequences of this putative model are discussed in the context of the enzymatic machinery involved.
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Affiliation(s)
- Karolina Skorupinska-Tudek
- Department of Lipid Biochemistry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5a, 02-106 Warsaw, Poland
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20
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Martini C, Pallottini V, Cavallini G, Donati A, Bergamini E, Trentalance A. Caloric restrictions affect some factors involved in age-related hypercholesterolemia. J Cell Biochem 2007; 101:235-43. [PMID: 17203467 DOI: 10.1002/jcb.21158] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Ageing has been defined as a progressive decrease in physiological capacity and a reduced ability to respond to environmental stresses. It has been observed that diet-restricted animals show a minor morbidity in age-related disease. Among these age-related diseases, hypercholesterolemia is the most recurring one and it is often associated with cardiac failure. Several studies have been published indicating age-dependent changes in circulating levels of cholesterol in both humans and in rodents; recently changes have also been reported in the proteins involved in cholesterol homeostasis, that is, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR), Insig-induced gene (Insig) protein, SREBP cleavage activating protein (SCAP), sterol regulatory element binding protein (SREBP), and low density lipoprotein receptor (LDLr). Most age-related modifications of biochemical parameters are normalized or very improved in food-restricted animals, so the aim of this work is to examine whether or not alterations of the factors involved in cholesterol homeostasis which occur during ageing could be counteracted by caloric restriction (CR). The data show that the diet restrictions used attenuate the age-related effects on the factors involved in the synthesis and the degradation rate of HMG-CoAR; in spite of this, CRs have a good effect on the age-related hypercholesterolemia whose reduction seems to depend both on the correct membrane LDLr localization and on the proper restored HMG-CoAR activity.
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Affiliation(s)
- Chiara Martini
- Department of Biology, University of Rome Roma Tre, 446 Viale Marconi, 00146 Rome, Italy
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21
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Pallottini V, Martini C, Cavallini G, Donati A, Bergamini E, Notarnicola M, Caruso MG, Trentalance A. Modified HMG-CoA reductase and LDLr regulation is deeply involved in age-related hypercholesterolemia. J Cell Biochem 2006; 98:1044-53. [PMID: 16741953 DOI: 10.1002/jcb.20951] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
During the ageing process in rats hypercholesterolemia occurs in concert with full activation, lowered degradation rate and an unchanged level of the rate limiting cholesterol biosynthesis enzyme, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR). The molecular bases of the HMG-CoAR unchanged level and lowered degradation rate in aged rats is not clear. In fact no data are available during ageing, on transcription and degradation of HMG-CoAR, so well defined in adult animal. So, aim of this work was to measure mRNA levels of the enzyme and the level of the proteins of the regulatory complex responsible of the cholesterol metabolism. To complete the picture, the level of sterol regulatory element binding proteins (SREBPs), SREBP cleavage activating protein, and insulin-induced gene has been measured. The levels of other related proteins, whose transcription is SREBP dependent, that is low density lipoprotein receptor (LDLr) and Caveolin 1, have been also measured. The age-related reduced Insigs levels, joined to a reduced insulin sensitivity, could explain the decreased degradation rate of the HMG-CoAR and the increased active SREBP-2. The SREBP-2 in particular seems to be committed in multiple way to gene transcription. The obtained data represent a good contribution to explain the age-related hypercholesterolemia.
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Affiliation(s)
- Valentina Pallottini
- Department of Biology, University of Rome "Roma Tre", Viale Marconi 446, 00146 Rome, Italy.
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22
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Quiles JL, Ochoa JJ, Ramirez-Tortosa MC, Huertas JR, Mataix J. Age-related mitochondrial DNA deletion in rat liver depends on dietary fat unsaturation. J Gerontol A Biol Sci Med Sci 2006; 61:107-14. [PMID: 16510854 DOI: 10.1093/gerona/61.2.107] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
We fed male Wistar rats lifelong on virgin olive (rich in the monounsaturated oleic acid) or sunflower (rich in the polyunsaturated linoleic acid) oil-based diets. At 6 and 24 months, liver mitochondria were analyzed for a mitochondrial DNA (mtDNA) deletion, reactive oxygen species, antioxidants, and ultrastructural alterations. An aging-related increase in the relative amount of the deletion was observed for both dietary groups, being higher in animals fed sunflower oil. Oxidative stress was lower in virgin olive oil-fed animals. Aging led to higher superoxide dismutase, catalase, and glutathione peroxidase activities and increased alpha-tocopherol and coenzyme Q. Mitochondria from aged animals fed sunflower oil exhibited a lower number of cristae and a higher circularity. Results suggest that the age-related increase of the relative amount of deleted mtDNA depends on fat unsaturation. Moreover, the studied mtDNA deletion was correlated with mitochondrial oxidative stress and ultrastructural alterations.
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Affiliation(s)
- José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology, University of Granada, Spain.
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Pallottini V, Martini C, Bassi AM, Romano P, Nanni G, Trentalance A. Rat HMGCoA reductase activation in thioacetamide-induced liver injury is related to an increased reactive oxygen species content. J Hepatol 2006; 44:368-74. [PMID: 16140414 DOI: 10.1016/j.jhep.2005.06.011] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2005] [Revised: 05/11/2005] [Accepted: 06/13/2005] [Indexed: 12/15/2022]
Abstract
BACKGROUND/AIMS In thioacetamide-induced liver injury a modification of isoprenoid content and an increase of reactive oxygen species has been described. We have examined how reactive oxygen species influence the 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate limiting enzyme of the isoprenoid biosynthetic pathway, to verify if changes of that enzyme activity are involved in the changed lipid composition of the liver. METHODS In chronic and acute thioacetamide-treated rat liver we measured the reactive oxygen species content, the activation state and K(M), the level and degradation rate of the hepatic reductase, its short term regulatory enzymes and the liver lipid profile. RESULTS In thioacetamide-treated rat liver, the reactive oxygen species content is high and the reductase is fully activated with no modifications in its K(M) and its short term regulatory enzymes. The reductase level is reduced in chronic thioacetamide treated rats and its degradation rate is altered. CONCLUSIONS The data show a relationship between reactive oxygen species production and altered 3-hydroxy-3-methylglutaryl coenzyme A reductase activity. It is suggested that reducing the levels of reactive oxygen species may improve the altered lipid profile found in liver injury.
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Affiliation(s)
- Valentina Pallottini
- Department of Biology, University of Rome Roma Tre, Viale Marconi 446, 00146-Rome, Italy.
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Pallottini V, Montanari L, Cavallini G, Bergamini E, Gori Z, Trentalance A. Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver. Mech Ageing Dev 2005; 125:633-9. [PMID: 15491682 DOI: 10.1016/j.mad.2004.08.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2004] [Revised: 07/22/2004] [Accepted: 08/04/2004] [Indexed: 12/14/2022]
Abstract
As the main risk factor for cardiovascular disease, hypercholesterolemia is one of the most studied age-related metabolic alterations. In the liver, cholesterol homeostasis is strictly regulated through the modulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. With ageing, hepatic HMG-CoA reductase becomes completely activated and cholesterol content increases in the blood. The research reported in this paper uses the regulatory enzymes of reductase (i.e., the AMP-dependent kinase (AMPK) and the protein phosphatase 2A (PP2A)), the HMG-CoA reductase thermodependent activity and the "in vitro" enzyme degradation to elucidate the role played by the HMG-CoA reductase regulation and its membrane interaction. Related experiments were performed on 3 and 24 months "ad libitum" (AL) fed rats and 24 months caloric-restricted rats. The results show no changes in the PP2A level and the activation state of AMP dependent kinase in aged "ad libitum" fed rats. By contrast, the activation state of the kinase is enhanced in the aged caloric-restricted animals. With respect to the adult, the thermodependent activity of reductase remains unchanged, while the degradation rate of the HMG-CoA reductase is slower and independent on proteasome. These findings support the hypothesis that a different arrangement of the HMG-CoA reductase membrane domain in aged rats is a cause of reductase deregulation.
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Affiliation(s)
- Valentina Pallottini
- Department of Biology, University Roma Tre, Viale Marconi 446, 00146 Rome, Italy
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25
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Pallottini V, Martini C, Pascolini A, Cavallini G, Gori Z, Bergamini E, Incerpi S, Trentalance A. 3-Hydroxy-3-methylglutaryl coenzyme A reductase deregulation and age-related hypercholesterolemia: a new role for ROS. Mech Ageing Dev 2005; 126:845-51. [PMID: 15992608 DOI: 10.1016/j.mad.2005.02.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2004] [Revised: 02/16/2005] [Accepted: 02/25/2005] [Indexed: 01/28/2023]
Abstract
The microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCoAR) is the rate-limiting enzyme in cholesterol synthesis and is highly regulated by a variety of factors. We have recently reported increased reductase activity during ageing, attributed to a higher activation state and impaired degradation of the hepatic enzyme. One of the widely recognized causes of age-related metabolic modifications is the large increase of reactive oxygen species (ROS). Therefore, the effect of ROS increase on the activity and the regulation of the HMGCoAR has been investigated in two different experimental models of ROS enriched tissue: liver from rats fed on diets deprived of either Vitamin E (Vit. E) or polyunsaturated fatty acids (Pufa). The results show that in these models, compared to that of old rats, full activation the HMGCoAR was detected while a different degradation rate is observed with the respect to old rats. Thus, our data show full correlation between ROS production and increased HMGCoAR activity. The possible therapeutic implications of these results are discussed.
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Affiliation(s)
- Valentina Pallottini
- Department of Biology, University of Roma Tre, Viale Marconi 446, 00146 Rome, Italy.
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26
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Parentini I, Cavallini G, Donati A, Gori Z, Bergamini E. Accumulation of Dolichol in Older Tissues Satisfies the Proposed Criteria To Be Qualified a Biomarker of Aging. J Gerontol A Biol Sci Med Sci 2005; 60:39-43. [PMID: 15741281 DOI: 10.1093/gerona/60.1.39] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Criteria for defining biomarkers have been suggested. Accumulation of dolichol in tissues of older animals meets the following criteria: (a) levels of dolichol exhibit a quantitative correlation with age in all tissues and are not altered by several age-dependent diseases in the same direction as that of aging; (b) accumulation is not secondary to metabolic changes of aging and is altered appropriately by factors that modulate the aging rate like caloric restriction and physical exercise; (c) biomarker is applicable to different tissues across mammalian species, including humans, and to trisomy 21 and its hypothalamic digoxin-mediated model. Reliable changes in tissue dolichol levels are seen in relatively short intervals of time compared to over a life span, and levels can be tested on a small amount of tissue without causing death of the animal. In this article, we show applications to the study of host-graft interaction and detection of gender-related differences in biological age, and we discuss mechanism(s) of accumulation.
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Affiliation(s)
- Ilaria Parentini
- Centro di Ricerca di Biologia e Patologia dell'Invecchiamento, Via Roma 55-Scuola Medica, 56126 Pisa, Italy
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27
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Quiles JL, Ochoa JJ, Ramirez-Tortosa C, Battino M, Huertas JR, Martín Y, Mataix J. Dietary fat type (virgin olive vs. sunflower oils) affects age-related changes in DNA double-strand-breaks, antioxidant capacity and blood lipids in rats. Exp Gerontol 2004; 39:1189-98. [PMID: 15288693 DOI: 10.1016/j.exger.2004.05.002] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2004] [Revised: 04/13/2004] [Accepted: 05/04/2004] [Indexed: 01/01/2023]
Abstract
This study was designed to investigate the possible effect on DNA double-strand breaks, antioxidant capacity and blood lipids of feeding rats lifelong with two different dietary fat sources: virgin olive oil (rich in the monounsaturated oleic acid) or sunflower oil (rich in the polyunsaturated linoleic acid). No changes in mean or maximal lifespan were observed. Overall, aging led to increased levels of plasma cholesterol, triglycerides, phospholipids, total lipids, polyunsaturated fatty acids and DNA double-strand breaks. All these parameters were higher in animals fed on sunflower oil diet. Aging diminished total antioxidant capacity with both diets, but in a lower extension for virgin olive oil diet. A very good inverse correlation (r= -0.715; P < 0.01, for sunflower oil group and r= -0.535; P < 0.01 for virgin olive oil group) between DNA damage and total antioxidant capacity was found. These results allow to conclude that dietary fat type should be considered in studies on aging, since the intake of oils with different polyunsaturation levels directly modulates total antioxidant capacity of plasma, DNA damage to peripheral blood lymphocytes and lead to important changes at the lipid metabolism level. In the present study best results were found after intake of virgin olive oil, which suggest the possible use of that edible oil to provide a healthier aging.
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Affiliation(s)
- José L Quiles
- Department of Physiology, Institute of Nutrition and Food Technology, University of Granada, C/Ramón y Cajal 4 Edificio Fray Luis, Granada 18071, Spain.
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Wang JF, Guo YX, Niu JZ, Liu J, Wang LQ, Li PH. Effects of Radix Puerariae flavones on liver lipid metabolism in ovariectomized rats. World J Gastroenterol 2004; 10:1967-70. [PMID: 15222048 PMCID: PMC4572242 DOI: 10.3748/wjg.v10.i13.1967] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To study the effects of Radix Puerariae flavones (RPF) on liver lipid metabolism in ovariectomized (OVX) rats.
METHODS: Forty adult female Wistar rats were randomly divided into four groups: OVX group; sham-OVX group; OVX + estrogen group and OVX + RPF group. One week after operation rats of the first two groups were treated with physiological saline, rats of OVX + estrogen group with estrogen (1 mg/kg·b.w.) and rats of OVX + RPF group with RPF (100 mg/kg·b.w.), respectively for 5 weeks. After the rats were killed, their body weight, the weight of the abdominal fat and uterus were measured, and the levels of total cholesterol (TC) and triglyceride (TG) in liver homogenate were determined.
RESULTS: Compared with the sham-OVX group, the body mass of the rats in OVX group was found increased significantly; more abdominal fat in store; TC and TG in liver increased and uterine became further atrophy. As a result, the RPF was found to have an inhibitive action on those changes of various degrees.
CONCLUSION: RPF has estrogen-like effect on lipid metabolism in liver and adipose tissue.
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Affiliation(s)
- Ji-Feng Wang
- Department of Biochemistry, Beijing University of Chinese Medicine, Beijing 100029, China
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Cavallini G, Parentini I, Di Stefano R, Maccheroni M, Masini M, Pollera M, Gori Z, Mosca F, Bergamini E. Dolichol levels in younger and older rat hearts heterotopically transplanted in younger recipients. Lipids 2002; 37:913-6. [PMID: 12458628 DOI: 10.1007/s11745-002-0979-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Dolichol (D) levels increase dramatically in older tissue. An understanding of the exchangeability of D between tissues may be essential in order to understand the mechanism of the abnormal accumulation associated with aging. The question was investigated by the use of organ transplantation. D-poor hearts donated by 3-mon-old and D-rich by 22-mon-old male Lewis rats were transplanted heterotopically in 3-mon-old syngenic recipients, whose peripheral tissues and liver were poor in D. Native and transplanted hearts were taken 7 and 21 d after surgery. Native hearts of 3-mon- and 22-mon-old male Lewis rats served as control. D concentration and quantity were higher in older than in younger native hearts as expected. In the transplanted hearts, the quantity of D was unchanged, irrespective of the age of the donor and of the time of transplantation, whereas D concentration increased because of the remarkable disuse atrophy. No changes in D were observed in recipients' tissues. It is concluded that dolichol is not redistributed via circulation from the transplanted heart to the tissues and liver of the younger recipient.
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Affiliation(s)
- Gabriella Cavallini
- Dipartimento di Patologia sperimentale, Biotecnologie mediche, Infettivologia e Epidemiologia, University of Pisa, Italy
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