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Metabolism of serum lipoproteins and the role of the latter in the development of vascular lesions

The principal interest of the laboratory is the metabolism of serum lipoproteins and the role of the latter in the development of vascular lesions, notably in diabetic patients. Lipoproteins are protein-lipid complexes whose primary task is the transport and re-distribution of triglycerides, the principal energy storage molecule, and cholesterol, an essential component of cell structure and the precursor of numerous hormones. Modifications to lipoprotein metabolism disrupt efficient transport of these lipids and favour their deposition, notably cholesterol, in the blood vessel wall. Our studies centre on the mechanisms by which a subclass of lipoproteins, high density lipoproteins (HDL), protect against the development of vascular lesions. HDL appear to act via various pathways, one of which is a reduction in the consequences of oxidative stress. They prevent or limit peroxidation of blood lipids, a pre-requisite for lesion development, and also protect the endothelium from oxidative stress. The anti-oxidative capacity of HDL is largely attributed to an associated enzyme, paraoxonase, which is the focus of our research. Animal models have clearly established that it prevents the onset of vascular lesions due to its anti-oxidant function. One area of study has been factors influencing expression of the paraoxonase gene. We reported promoter polymorphisms with a strong impact on serum paraoxonase concentrations, and, more recently, have identified transcription factors implicated in promoter activity. Other studies have investigated the pathway by which the enzyme is secreted by hepatocytes and associates with serum HDL. We proposed a process which involves insertion of the protein into the cell membrane prior to its desorption by HDL. It is a high affinity, saturable process that necessitates docking of HDL with the cell surface receptor. Complementing these projects are studies of paraoxonase in a clinical context. We have already demonstrated that diabetic patients are deficient in serum paraoxonase activity, and have identified additional, environmental factors, which influence its anti-oxidant capacity. These include cigarette smoking, and probably reflect the susceptibility of the enzyme itself to oxidative stress. Further studies of the anti-oxidant function of paraoxonase, and its consequent anti-inflammatory potential, are being undertaken in a transgenic mouse model.

Group's publications

Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2: role of sphingosine-1-phosphate.
CARDIOVASCULAR RESEARCH
2009 vol. 82(2) pp. 313-323
FRIAS MA, JAMES RW, GERBER-WICHT C, LANG U

Myeloperoxidase and paraoxonase-1 in type 2 diabetic patients
NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES
2009 vol. 19(9) pp. 613-619
JORNAYVAZ FR, BRULHART-MEYNET MC, JAMES RW

Anti-apolipoprotein A-1 IgG are associated with high oxidized low-density lipoprotein levels of in acute coronary syndrome
CLINICAL SCIENCE
2008 vol. 115(1) pp. 25-33
VUILLEUMIER NICOLAS ET AL.

Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism.
DIABETES
2008 vol. 57(5) pp. 1176-1185
CEDERROTH CR AND AL.

HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress.
JOURNAL OF LIPID RESEARCH
2008 vol. 49(6) pp. 1246-1253
MOREN X, DEAKIN S, LIU ML, TASKINEN MR, JAMES RW

Paraoxonase 1: genetics and activities during aging.
JOURNAL OF LIPID RESEARCH
2008 vol. 11(1) pp. 113-127
MARCHEGIANI F, MARRA M, OLIVIERI F, CARDELLI M, JAMES RW, BOEMI M, FRANCESCHI C

HDL oxidation compromises its influence on paraoxonase-1 secretion and its capacity to modulate enzyme activity
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2007 vol. 27 pp. 1146-1152
DEAKIN S, MOREN X, JAMES RW

Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction?
ATHEROSCLEROSIS
2007 vol. 191 pp. 355-361
WONG CW, CHRISTEN T, PFENNIGER A, JAMES RW, KWAK BR

Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study
DIABETES/METABOLISM RESEARCH AND REVIEWS
2007 vol. 23(5) pp. 392-399
CHAPPUIS B, BRAUN M, STETTLER C, ALLEMANN S, DIEM P, LUMB PJ, WIERZBICKI AS, JAMES R, CHRIST ER

Pharmacogenetic interaction between paraoxonase-1 gene promoter polymorphism C-107T and statin
PHARMACOGENETICS AND GENOMICS
2007 vol. 17(6) pp. 542-457
DEAKIN S, GUERNIER S, JAMES RW

A long and winding road: defining the biological role and clinical importance of paraoxonases
CLINICAL CHEMISTRY AND LABORATORY MEDICINE
2006 vol. 44 pp. 1052-1059
JAMES RW

Interleukin-8 secretion by fibroblasts induced by low density lipoproteins is p38 MAPK-dependent and leads to cell spreading and wound closure
JOURNAL OF BIOLOGICAL CHEMISTRY
2006 vol. 281 pp. 199-205
DOBREVA I, WAEBER G, JAMES RW, WIDMANN C

The PON1192RR genotype is associated with a higher prevalence of arterial hypertension
JOURNAL OF HYPERTENSION
2006 vol. 24(7) pp. 1293-1298
MARRA MAURIZIO ET AL.

Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I
JOURNAL OF LIPID RESEARCH
2006 vol. 47 pp. 515-520
GARIN MCB, MOREN X, JAMES RW

Association of paraoxonase-1 activity and concentration with angiographic severity and extent of coronary artery disease
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2006 vol. 47 pp. 2429-2435
GRANER M, JAMES RW, KAHRI J, NIEMINEN MS, SYVANNE M, TASKINEN MR

Paraoxonase activity and genotype predispose to successful aging
JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES
2006 vol. 61 pp. 541-546
MARCHEGIANI F, MARRA M, SPAZZAFUMO L, JAMES RW, BOEMI M, OLIVIERI F, CARDELLI M, CAVALLONE L, BONFIGLI AR, FRANCESCHI C

Postprandial modulation of serum paraoxonase activity and concentration in diabetic and non-diabetic subjects
NUTRITION, METABOLISM, AND CARDIOVASCULAR DISEASES : NMCD
2006 vol. 16(7) pp. 457-465
BEER SANDRA, MOREN XENIA, RUIZ JUAN, JAMES RICHARD

Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells.
ATHEROSCLEROSIS
2005 vol. 179 pp. 17-25
DEAKIN S, MOREN X, JAMES RICHARD

Small, dense lipoprotein particles and reduced paraoxonase-1 in patients with the metabolic syndrome.
JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM
2005 vol. 90 pp. 2264-2269
GARIN MCL, KALIX B, MORABIA ALFREDO, JAMES RICHARD

Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients.
JOURNAL OF HEPATOLOGY
2005 vol. 42 pp. 41-46
MUZZI ALBA ET AL.

Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position - 107, implicating the Sp1 transcription factor.
BIOCHEMICAL JOURNAL
2003 vol. 372 pp. 643-649
DEAKIN S, LEVIEV I, BRULHART, JAMES RW

Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high-affinity, saturable, desorption mechanism
JOURNAL OF BIOLOGICAL CHEMISTRY
2002 vol. 277 pp. 4301-4308
DEAKIN S, LEVIEV I, M. GOMARASCHI, L. CALABRESI, G. FRANCESCHINI, JAMES RW

The paraoxonase PON1 promoter polymorphism C(-107)T is associated with increased serum glucose concentrations in non-diabetic patients
DIABETOLOGIA
2001 vol. 44 pp. 1177-1183
LELIEV I, KALIX B, BRULHART-MEYNET, JAMES RICHARD

Smoking is associated with reduced serum paraoxonase activity and concentration in coronary artery disease patients
CIRCULATION
2000 vol. 101 pp. 2252-2257
JAMES RICHARD, LEVIEV ILIA, RIGHETTI ALBERTO

Research's domains

GENE EXPRESSION
ATHEROSCLEROSIS
METABOLISM OF LIPOPROTEINS




DATABASE-RESEARCH	GROUP OF CLINICAL PATIENT RESEARCH

Richard JAMES	Head of group CV	Research subject	Members of the group


	Links about the group Prof. R. JAMES HUG/Spécialités de Médecine Serv. Endocrino. Diabét.Nutri. Rue Gabrielle-Perret-Gentil 4 1211 Genève 14 Suisse Richard.James@hcuge.ch Tel.: 022/372.93.04 Fax: 022/372.93.09 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Metabolism of serum lipoproteins and the role of the latter in the development of vascular lesions The principal interest of the laboratory is the metabolism of serum lipoproteins and the role of the latter in the development of vascular lesions, notably in diabetic patients. Lipoproteins are protein-lipid complexes whose primary task is the transport and re-distribution of triglycerides, the principal energy storage molecule, and cholesterol, an essential component of cell structure and the precursor of numerous hormones. Modifications to lipoprotein metabolism disrupt efficient transport of these lipids and favour their deposition, notably cholesterol, in the blood vessel wall. Our studies centre on the mechanisms by which a subclass of lipoproteins, high density lipoproteins (HDL), protect against the development of vascular lesions. HDL appear to act via various pathways, one of which is a reduction in the consequences of oxidative stress. They prevent or limit peroxidation of blood lipids, a pre-requisite for lesion development, and also protect the endothelium from oxidative stress. The anti-oxidative capacity of HDL is largely attributed to an associated enzyme, paraoxonase, which is the focus of our research. Animal models have clearly established that it prevents the onset of vascular lesions due to its anti-oxidant function. One area of study has been factors influencing expression of the paraoxonase gene. We reported promoter polymorphisms with a strong impact on serum paraoxonase concentrations, and, more recently, have identified transcription factors implicated in promoter activity. Other studies have investigated the pathway by which the enzyme is secreted by hepatocytes and associates with serum HDL. We proposed a process which involves insertion of the protein into the cell membrane prior to its desorption by HDL. It is a high affinity, saturable process that necessitates docking of HDL with the cell surface receptor. Complementing these projects are studies of paraoxonase in a clinical context. We have already demonstrated that diabetic patients are deficient in serum paraoxonase activity, and have identified additional, environmental factors, which influence its anti-oxidant capacity. These include cigarette smoking, and probably reflect the susceptibility of the enzyme itself to oxidative stress. Further studies of the anti-oxidant function of paraoxonase, and its consequent anti-inflammatory potential, are being undertaken in a transgenic mouse model. Group's publications Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2: role of sphingosine-1-phosphate. CARDIOVASCULAR RESEARCH 2009 vol. 82(2) pp. 313-323 FRIAS MA, JAMES RW, GERBER-WICHT C, LANG U Myeloperoxidase and paraoxonase-1 in type 2 diabetic patients NUTRITION METABOLISM AND CARDIOVASCULAR DISEASES 2009 vol. 19(9) pp. 613-619 JORNAYVAZ FR, BRULHART-MEYNET MC, JAMES RW Anti-apolipoprotein A-1 IgG are associated with high oxidized low-density lipoprotein levels of in acute coronary syndrome CLINICAL SCIENCE 2008 vol. 115(1) pp. 25-33 VUILLEUMIER NICOLAS ET AL. Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism. DIABETES 2008 vol. 57(5) pp. 1176-1185 CEDERROTH CR AND AL. HDL subfraction distribution of paraoxonase-1 and its relevance to enzyme activity and resistance to oxidative stress. JOURNAL OF LIPID RESEARCH 2008 vol. 49(6) pp. 1246-1253 MOREN X, DEAKIN S, LIU ML, TASKINEN MR, JAMES RW Paraoxonase 1: genetics and activities during aging. JOURNAL OF LIPID RESEARCH 2008 vol. 11(1) pp. 113-127 MARCHEGIANI F, MARRA M, OLIVIERI F, CARDELLI M, JAMES RW, BOEMI M, FRANCESCHI C HDL oxidation compromises its influence on paraoxonase-1 secretion and its capacity to modulate enzyme activity ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 2007 vol. 27 pp. 1146-1152 DEAKIN S, MOREN X, JAMES RW Do allelic variants of the connexin37 1019 gene polymorphism differentially predict for coronary artery disease and myocardial infarction? ATHEROSCLEROSIS 2007 vol. 191 pp. 355-361 WONG CW, CHRISTEN T, PFENNIGER A, JAMES RW, KWAK BR Differential effect of pioglitazone (PGZ) and rosiglitazone (RGZ) on postprandial glucose and lipid metabolism in patients with type 2 diabetes mellitus: a prospective, randomized crossover study DIABETES/METABOLISM RESEARCH AND REVIEWS 2007 vol. 23(5) pp. 392-399 CHAPPUIS B, BRAUN M, STETTLER C, ALLEMANN S, DIEM P, LUMB PJ, WIERZBICKI AS, JAMES R, CHRIST ER Pharmacogenetic interaction between paraoxonase-1 gene promoter polymorphism C-107T and statin PHARMACOGENETICS AND GENOMICS 2007 vol. 17(6) pp. 542-457 DEAKIN S, GUERNIER S, JAMES RW A long and winding road: defining the biological role and clinical importance of paraoxonases CLINICAL CHEMISTRY AND LABORATORY MEDICINE 2006 vol. 44 pp. 1052-1059 JAMES RW Interleukin-8 secretion by fibroblasts induced by low density lipoproteins is p38 MAPK-dependent and leads to cell spreading and wound closure JOURNAL OF BIOLOGICAL CHEMISTRY 2006 vol. 281 pp. 199-205 DOBREVA I, WAEBER G, JAMES RW, WIDMANN C The PON1192RR genotype is associated with a higher prevalence of arterial hypertension JOURNAL OF HYPERTENSION 2006 vol. 24(7) pp. 1293-1298 MARRA MAURIZIO ET AL. Paraoxonase-1 and serum concentrations of HDL-cholesterol and apoA-I JOURNAL OF LIPID RESEARCH 2006 vol. 47 pp. 515-520 GARIN MCB, MOREN X, JAMES RW Association of paraoxonase-1 activity and concentration with angiographic severity and extent of coronary artery disease JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY 2006 vol. 47 pp. 2429-2435 GRANER M, JAMES RW, KAHRI J, NIEMINEN MS, SYVANNE M, TASKINEN MR Paraoxonase activity and genotype predispose to successful aging JOURNALS OF GERONTOLOGY SERIES A-BIOLOGICAL SCIENCES AND MEDICAL SCIENCES 2006 vol. 61 pp. 541-546 MARCHEGIANI F, MARRA M, SPAZZAFUMO L, JAMES RW, BOEMI M, OLIVIERI F, CARDELLI M, CAVALLONE L, BONFIGLI AR, FRANCESCHI C Postprandial modulation of serum paraoxonase activity and concentration in diabetic and non-diabetic subjects NUTRITION, METABOLISM, AND CARDIOVASCULAR DISEASES : NMCD 2006 vol. 16(7) pp. 457-465 BEER SANDRA, MOREN XENIA, RUIZ JUAN, JAMES RICHARD Very low density lipoproteins provide a vector for secretion of paraoxonase-1 from cells. ATHEROSCLEROSIS 2005 vol. 179 pp. 17-25 DEAKIN S, MOREN X, JAMES RICHARD Small, dense lipoprotein particles and reduced paraoxonase-1 in patients with the metabolic syndrome. JOURNAL OF CLINICAL ENDOCRINOLOGY AND METABOLISM 2005 vol. 90 pp. 2264-2269 GARIN MCL, KALIX B, MORABIA ALFREDO, JAMES RICHARD Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. JOURNAL OF HEPATOLOGY 2005 vol. 42 pp. 41-46 MUZZI ALBA ET AL. Paraoxonase-1 promoter haplotypes and serum paraoxonase: a predominant role for polymorphic position - 107, implicating the Sp1 transcription factor. BIOCHEMICAL JOURNAL 2003 vol. 372 pp. 643-649 DEAKIN S, LEVIEV I, BRULHART, JAMES RW Enzymatically active paraoxonase-1 is located at the external membrane of producing cells and released by a high-affinity, saturable, desorption mechanism JOURNAL OF BIOLOGICAL CHEMISTRY 2002 vol. 277 pp. 4301-4308 DEAKIN S, LEVIEV I, M. GOMARASCHI, L. CALABRESI, G. FRANCESCHINI, JAMES RW The paraoxonase PON1 promoter polymorphism C(-107)T is associated with increased serum glucose concentrations in non-diabetic patients DIABETOLOGIA 2001 vol. 44 pp. 1177-1183 LELIEV I, KALIX B, BRULHART-MEYNET, JAMES RICHARD Smoking is associated with reduced serum paraoxonase activity and concentration in coronary artery disease patients CIRCULATION 2000 vol. 101 pp. 2252-2257 JAMES RICHARD, LEVIEV ILIA, RIGHETTI ALBERTO Research's domains GENE EXPRESSION ATHEROSCLEROSIS METABOLISM OF LIPOPROTEINS