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Joëlle Magné,
Anna Aminoff,
Jeanna Perman Sundelin,
Maria Nastase Mannila,
Peter Gustafsson,
Kjell Hultenby,
Annika Wernerson,
Greta Bauer,
Laura Listenberger,
Matt J Neville,
Fredrik Karpe, Jan Borén,
Ewa Ehrenborg
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ABSTRACT: Perilipin 2 (PLIN2) is the most abundant lipid droplet (LD)-associated protein in nonadipose tissue, and its expression correlates with intracellular lipid accumulation. Here we identified a missense polymorphism, Ser251Pro, that has major effect on protein structure and function, along with an influence on human plasma triglyceride concentration. The evolutionarily conserved Ser251Pro polymorphism was identified with the ClustalW program. Structure modeling using 3D-JigSaw and the Chimera package revealed that the Pro251 allele disrupts a predicted α-helix in PLIN2. Analyses of macrophages from individuals carrying Ser251Pro variants and human embryonic kidney 293 (HEK293) cells stably transfected with either of the alleles demonstrated that the Pro251 variant causes increased lipid accumulation and decreased lipolysis. Analysis of LD size distribution in stably transfected cells showed that the minor Pro251 allele resulted in an increased number of small LDs per cell and increased perilipin 3 protein expression levels as compared with cells carrying the major Ser251 allele. Genotyping of 2113 individuals indicated that the Pro251 variant is associated with decreased plasma triglyceride and very low-density lipoprotein concentrations. Altogether, these data provide the first evidence of a polymorphism in PLIN2 that affects PLIN2 function and may influence the development of metabolic and cardiovascular diseases.-Magné, J., Aminoff, A., Perman Sundelin, J., Mannila, M. N., Gustafsson, P., Hultenby, K., Wernerson, A., Bauer, G., Listenberger, L., Neville, M. J., Karpe, F., Borén, J., Ehrenborg, E. The minor allele of the missense polymorphism Ser251Pro in perilipin 2 (PLIN2) disrupts an α-helix, affects lipolysis, and is associated with reduced plasma triglyceride concentration in humans.
The FASEB Journal 04/2013; · 5.71 Impact Factor
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ABSTRACT: Obesity increases the risk of metabolic diseases, including insulin resistance and type 2 diabetes, as well as cardiovascular disease. In addition to lipid accumulation in adipose tissue, obesity is associated with increased lipid storage in ectopic tissues, such as skeletal muscle and liver. Furthermore, lipid accumulation in the heart may result in cardiac dysfunction and heart failure. It has recently been demonstrated that intracellular lipid accumulation in ectopic tissues leads to pathological responses and impaired insulin signalling. Here, we will review the current understanding of how lipid storage and lipid droplet physiology affect the risk of developing metabolic diseases. © 2013 The Association for the Publication of the Journal of Internal Medicine.
Journal of Internal Medicine 04/2013; · 5.48 Impact Factor
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Rosellina Margherita Mancina,
Maria Antonella Burza,
Cristina Maglio,
Carlo Pirazzi,
Federica Sentinelli,
Michela Incani,
Tiziana Montalcini,
Arturo Pujia,
Tiziana Congiu,
Sandro Loche,
Sabrina Pilia,
Olov Wiklund, Jan Borén,
Stefano Romeo,
Marco Giorgio Baroni
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ABSTRACT: BACKGROUND: Childhood obesity is a growing epidemic worldwide and it is associated with metabolic complications, such as insulin resistance. Recently, a genetic variation (rs7607980) in the cordon-bleu protein-like 1 (COBLL1) gene has been associated with lower insulin resistance in adults. The aim of the study was to investigate if the association between COBLL1 rs7607980 genetic variant and lower insulin resistance was present early in life. METHODS: This sequence variant was genotyped in 878 overweight and obese children (mean age: 10 years) from Sardinia, Italy, from the outpatient clinic of the Pediatric Endocrine Unit, at the Regional Hospital for Microcitaemia in Cagliari. Insulin resistance was assessed by measurement of fasting circulating insulin levels before and after an oral glucose tolerance test (OGTT) and by homeostatic model assessment of insulin resistance (HOMA-IR). RESULTS: The COBLL1 rs7607980 C allele was associated with lower fasting insulin and HOMA-IR levels (P = 0.002 and P = 0.035, respectively) in overweight and obese children. Importantly, lower insulin levels were also observed two hours after OGTT in C allele carriers (P = 0.009). CONCLUSIONS: The present study shows for the first time the association between COBLL1 rs7607980 C allele, lower serum insulin levels and lower insulin resistance in overweight and obese children. Copyright © 2013 John Wiley & Sons, Ltd.
Diabetes/Metabolism Research and Reviews 03/2013; · 3.37 Impact Factor
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Cristina Maglio,
Ulrika Ericson,
Maria Antonella Burza,
Rosellina Margherita Mancina,
Carlo Pirazzi,
Johanna Andersson Assarsson,
Kajsa Sjöholm,
Marco Giorgio Baroni,
Per-Arne Svensson,
Tiziana Montalcini,
Arturo Pujia,
Lars Sjöström,
Olov Wiklund,
Lena M S Carlsson, Jan Borén,
Marju Orho-Melander,
Stefano Romeo
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ABSTRACT: Context:Obesity and insulin resistance are risk factors for cancer development. The IRS1 rs2943641 genetic variant has been widely associated with insulin resistance.Objective:The aim of the study was to examine whether the IRS1 rs2943641 associates with cancer incidence in obese individuals.Design, Setting and Patients:The IRS1 rs2943641 was genotyped in participants from the Swedish Obese Subjects (SOS) study, an intervention trial on the effect of bariatric surgery on mortality and morbidity compared with usual care and in the population-based Malmö Diet and Cancer (MDC) cohort. In both studies, the median follow-up for cancer incidence was about 15 years.Intervention and Main Outcome Measure:Cancer incidence was assessed in both the SOS and the MDC cohorts through national and local registers.Results:The IRS1 T allele was associated with lower insulin resistance in both the SOS and the MDC studies. A lower cancer incidence was found in T allele carriers from the SOS control group (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.62-0.96; P = .021) and was restricted to morbidly obese individuals (HR 0.67, 95% CI 0.50-0.91; P = .011). No evidence of such association was detected in the surgery group (interaction P = .005). In the MDC cohort, a nonsignificant tendency for lower cancer incidence in T allele carriers was observed only in morbidly obese individuals. A meta-analysis of morbidly obese individuals (body mass index > 40 kg/m(2)) from the two cohorts strengthened the evidence for the association (HR 0.66, 95% CI 0.50-0.87; P = .004).Conclusions:Our results suggest that the T allele of rs2943641 near IRS1 may associate with lower cancer incidence in morbidly obese individuals.
The Journal of clinical endocrinology and metabolism 02/2013; · 6.50 Impact Factor
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ABSTRACT: BACKGROUND: Stress-induced cardiomyopathy (SIC), also known as Takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular akinesia involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC but the pathophysiological pathways and receptors involved are unknown. METHODS: Sprague Dawley rats (~300g) were injected with a single dose of the β-adrenergic agonist isoprenaline (ISO, i.p.) and echocardiography was used to study cardiac function. The akinetic part of the left ventricle was biopsied in six SIC patients. Amount of intracellular lipid and glycogen as well as degree of permanent cardiac damage were assessed by histology. RESULTS: In rats, ISO at doses ≥50mg/kg induced severe SIC-like regional akinesia that completely resolved within seven days. Intracellular lipid content was higher in akinetic, but not in normokinetic myocardium in both SIC patients and rats. β2-receptor blockade or Gi-pathway inhibition was associated with less widespread akinesia and low lipid accumulation but significantly increased acute mortality. CONCLUSIONS: We provide a novel rat model of SIC that supports the hypothesis of circulating catecholamines as initiators of SIC. We propose that the β-adrenoreceptor pathway is important in the setting of severe catecholamine overstimulation and that perturbations of cardiac metabolism occur in SIC.
International journal of cardiology 01/2013; · 7.08 Impact Factor
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ABSTRACT: BACKGROUND: Statins have anti-inflammatory and antiatherogenic effects that have been attributed to inhibition of RHO protein geranylgeranylation in inflammatory cells. The activity of protein geranylgeranyltransferase type I (GGTase-I) is widely believed to promote membrane association and activation of RHO family proteins. However, we recently showed that knockout of GGTase-I in macrophages activates RHO proteins and proinflammatory signaling pathways, leading to increased cytokine production and rheumatoid arthritis. In this study, we asked whether the increased inflammatory signaling of GGTase-I-deficient macrophages would influence the development of atherosclerosis in LDL receptor-deficient mice. METHODS AND RESULTS: Aortic lesions in mice lacking GGTase-I in macrophages (Pggt1b(Δ/Δ)) contained significantly more T lymphocytes than the lesions in controls. Surprisingly, however, mean atherosclerotic lesion area in Pggt1b(Δ/Δ) mice was reduced by ~60%. GGTase-I deficiency reduced the accumulation of cholesterol esters and phospholipids in macrophages incubated with minimally modified and acetylated LDL. Analyses of GGTase-I-deficient macrophages revealed upregulation of the COX2-PPARγ pathway and increased SR-B1- and CD36-mediated basal and HDL-stimulated cholesterol efflux. Lentivirus-mediated knockdown of RHOA, but not RAC1 or CDC42, normalized cholesterol efflux. The increased cholesterol efflux in cultured cells was accompanied by high levels of macrophage reverse cholesterol transport and slightly reduced plasma lipid levels in vivo. CONCLUSIONS: Targeting GGTase-I activates RHOA and leads to increased macrophage reverse cholesterol transport and reduced atherosclerosis development despite a significant increase in inflammation.
Circulation 01/2013; · 14.74 Impact Factor
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ABSTRACT: Cadmium exposure has been found to be associated with atherosclerotic plaques in the carotid arteries and with circulating levels of the proatherogenic intercellular adhesion molecule-1 (ICAM-1). The research questions were (1) if blood and urinary cadmium levels are associated with low ankle-brachial index (ABI) as a measure of peripheral artery disease in a longitudinal study and (2) if ICAM-1 mediates proatherogenic effects of cadmium exposure.
A prospective, observational cohort study with a 5-year follow-up and an experimental study of cultured human aortic endothelial cells exposed to cadmium.
Research unit at a university hospital.
A cohort of 64-year-old women (n=489) recruited by stratified sampling of similarly sized groups with normal, impaired and diabetic glucose tolerance as assessed in a population-based screening examination. PRIMARY AND SECONDARY OUTCOME MEASURES: ABI (ratio of the systolic blood pressures in the tibial and brachial arteries ≤0.9 in any artery) in relation to cadmium exposure; ICAM-1 concentrations in the cell culture medium after cadmium incubation.
High (tertile 3 vs 1) concentrations of blood (B-Cd) or creatine-adjusted urinary cadmium (U-Cd) at baseline were found to predict low ABI after adjustment for smoking and other cardiovascular risk factors at baseline. For U-Cd the OR was 2.5 (95% CI 1.1 to 5.8). After exclusion of participants with ultrasound-assessed femoral atherosclerosis at baseline the OR for U-Cd was unchanged, and for B-Cd it was 3.7 (95% CI 1.05 to 13.3). Inclusion of serum ICAM-1 levels did not affect the cadmium-related ORs in multivariate analyses. The experimental study did not show any cadmium-induced increase of the production of ICAM-1 from human endothelial cells.
Cadmium exposure was associated with future peripheral artery disease, supporting the concept that cadmium exposure in the population has proatherogenic effects, although ICAM-1 mediated effects do not seem to be involved.
BMJ open. 01/2013; 3(3).
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ABSTRACT: The small GTPase ADP ribosylation factor 6 (ARF6) mediates endocytosis and has in addition been shown to regulate neuron differentiation. Here we investigated whether ARF6 promotes differentiation of Neuro-2a neuronal cells by modifying the cellular lipid composition. We showed that knockdown of ARF6 by siRNA in Neuro-2a cells increased neuronal outgrowth as expected. ARF6 knockdown also resulted in increased glucosylceramide levels and decreased sphingomyelin levels, but did not affect the levels of ceramide or phospholipids. We speculated that the ARF6 knockdown-induced increase in glucosylceramide was caused by an effect on glucosylceramide synthase and, in agreement, showed that ARF6 knockdown increased the mRNA levels and activity of glucosylceramide synthase. Finally, we showed that incubation of Neuro-2a cells with the glucosylceramide synthase inhibitor D-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (D-PDMP) normalized the increased neuronal outgrowth induced by ARF6 knockdown. Our results thus show that ARF6 regulates neuronal differentiation through an effect on glucosylceramide synthase and glucosylceramide levels.
PLoS ONE 01/2013; 8(3):e60118. · 4.09 Impact Factor
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ABSTRACT: Myocardial ischemia is associated with intracellular accumulation of lipids and increased depots of myocardial lipids are linked to decreased heart function. Despite investigations in cell culture and animal models, there is little data available on where in the heart the lipids accumulate after myocardial ischemia and which lipid species that accumulate. The aim of this study was to investigate derangements of lipid metabolism that are associated with myocardial ischemia in a porcine model of ischemia and reperfusion. The large pig heart enables the separation of the infarct area with irreversible injury from the area at risk with reversible injury and the unaffected control area. The surviving myocardium bordering the infarct is exposed to mild ischemia and is stressed, but remains viable. We found that cholesteryl esters accumulated in the infarct area as well as in the bordering myocardium. In addition, we found that expression of the low density lipoprotein receptor (LDLr) and the low density lipoprotein receptor-related protein 1 (LRP1) was up-regulated, suggesting that choleteryl ester uptake is mediated via these receptors. Furthermore, we found increased ceramide accumulation, inflammation and endoplasmatic reticulum (ER) stress in the infarcted area of the pig heart. In addition, we found increased levels of inflammation and ER stress in the myocardium bordering the infarct area. Our results indicate that lipid accumulation in the heart is one of the metabolic derangements remaining after ischemia, even in the myocardium bordering the infarct area. Normalizing lipid levels in the myocardium after ischemia would likely improve myocardial function and should therefore be considered as a target for treatment.
PLoS ONE 01/2013; 8(4):e61942. · 4.09 Impact Factor
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Yangzhen Shao,
Björn Redfors,
Marcus Ståhlman,
Margareta Scharin Täng,
Azra Miljanovic,
Helge Möllmann,
Christian Troidl,
Sebastian Szardien,
Christian Hamm,
Holger Nef, Jan Borén,
Elmir Omerovic
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ABSTRACT: AimStress-induced cardiomyopathy (SIC), also known as takotsubo cardiomyopathy, is an acute cardiac syndrome with substantial morbidity and mortality. The unique hallmark of SIC is extensive ventricular dysfunction (akinesia) involving apical segments with preserved function in basal segments. Adrenergic overstimulation plays an important role in initiating SIC, but the pathomechanisms involved are unknown. We tested the hypothesis that excessive catecholamines cause perturbation of myocardial lipid metabolism and that cardiac lipotoxicity is responsible for the pathogenesis of SIC. METHODS AND RESULTS: A single dose injection of isoprenaline (ISO; 400 mg/kg) induced SIC-like regional akinesia in mice. Oil red O staining revealed severe lipid accumulation in the heart 2 h post-ISO. Both intramyocardial lipid accumulation and cardiac function were normalized within 1 week post-ISO and no significant amount of fibrosis was detected. We found that gene expression of lipid importers and exporters (ApoB lipoprotein) was depressed 2 h post-ISO. These results were confirmed by similar findings in SIC patients and in ISO/patient serum-stressed HL-1 cardiomyocytes. Moreover, overexpression of ApoB in the heart was found to protect against the development of ISO-induced cardiac toxicity and cardiac dysfunction. We also found that ISO-induced intramyocardial lipid accumulation caused electrophysiological disturbance and stunning in ISO/patient serum-stressed HL-1 cardiomyocytes. CONCLUSIONS: The present study demonstrates that lipotoxicity is closely associated with catecholamine-induced myocardial dysfunction, including neurogenic stunning, metabolic stunning, and electrophysiological stunning. Cardiac lipotoxicity may originate from direct inhibition of myocardial ApoB lipoprotein and subsequent decreased lipid export, caused by supraphysiological levels of catecholamines.
European Journal of Heart Failure 10/2012; · 4.90 Impact Factor
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Carlo Pirazzi,
Martin Adiels,
Maria Antonella Burza,
Rosellina Margherita Mancina,
Malin Levin,
Marcus Ståhlman,
Marja-Riitta Taskinen,
Marju Orho-Melander,
Jeanna Perman,
Arturo Pujia,
Linda Andersson,
Cristina Maglio,
Tiziana Montalcini,
Olov Wiklund, Jan Borén,
Stefano Romeo
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ABSTRACT: BACKGROUND & AIMS: The robust association between non-alcoholic fatty liver disease (NAFLD) and the genetic variant I148M (rs738409) in PNPLA3 has been widely replicated. The aim of this study was to investigate the effect of the PNPLA3 I148M mutation on: (1) hepatic secretion of very low density lipoproteins (VLDL) in humans; and (2) secretion of apolipoprotein B (apoB) from McA-RH 7777 cells, which secrete VLDL-sized apoB-containing lipoproteins. METHODS: VLDL kinetics was analyzed after a bolus infusion of stable isotopes in 55 overweight/obese men genotyped for the PNPLA3 I148M variant. Intracellular lipid content, apoB secretion and glycerolipid metabolism were studied in McA-RH 7777 cells overexpressing the human 148I wild type or 148M mutant PNPLA3 protein. RESULTS: In humans, carriers of the PNPLA3 148M allele had increased liver fat compared to 148I homozygotes, and kinetic analysis showed a relatively lower secretion of the large, triglyceride-rich VLDL (VLDL(1)) in 148M carriers vs. 148I homozygotes for the same amount of liver fat. McA-RH 7777 cells overexpressing the 148M mutant protein showed a higher intracellular triglyceride content with a lower apoB secretion and fatty acid efflux, compared to cells overexpressing the 148I wild type protein. The responses with 148M matched those observed in cells expressing the empty vector, indicating that the mutation results in loss of function. CONCLUSIONS: We have shown that PNPLA3 affects the secretion of apoB-containing lipoproteins both in humans and in vitro and that the 148M protein is a loss-of-function mutation. We propose that PNPLA3 148M promotes intracellular lipid accumulation in the liver by reducing the lipidation of VLDL.
Journal of Hepatology 08/2012; · 9.26 Impact Factor
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Rajesh K Nallapalli,
Mohamed X Ibrahim,
Alex X Zhou,
Sashidar Bandaru,
Sai Naresh Sunkara,
Björn Redfors,
David Pazooki,
Yin Zhang, Jan Borén,
Yihai Cao,
Martin O Bergo,
Levent M Akyürek
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ABSTRACT: Many human cancer cells express filamin A (FLNA), an actin-binding structural protein that interacts with a diverse set of cell signaling proteins, but little is known about the biological importance of FLNA in tumor development. FLNA is also expressed in endothelial cells, which may be important for tumor angiogenesis. In this study, we defined the impact of targeting Flna in cancer and endothelial cells on the development of tumors in vivo and on the proliferation of fibroblasts in vitro.
First, we used a Cre-adenovirus to simultaneously activate the expression of oncogenic K-RAS and inactivate the expression of Flna in the lung and in fibroblasts. Second, we subcutaneously injected mouse fibrosarcoma cells into mice lacking Flna in endothelial cells.
Knockout of Flna significantly reduced K-RAS-induced lung tumor formation and the proliferation of oncogenic K-RAS-expressing fibroblasts, and attenuated the activation of the downstream signaling molecules ERK and AKT. Genetic deletion of endothelial FLNA in mice did not impact cardiovascular development; however, knockout of Flna in endothelial cells reduced subcutaneous fibrosarcoma growth and vascularity within tumors.
We conclude that FLNA is important for lung tumor growth and that endothelial Flna impacts local tumor growth. The data shed new light on the biological importance of FLNA and suggest that targeting this protein might be useful in cancer therapeutics.
Molecular Cancer 08/2012; 11:50. · 3.99 Impact Factor
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Rajesh K Nallapalli,
Mohamed X Ibrahim,
Alex X Zhou,
Sashidar Bandaru,
Sai Naresh Sunkara,
Björn Redfors,
David Pazooki,
Yin Zhang, Jan Borén,
Yihai Cao,
Martin O Bergo,
Levent M Akyürek
Molecular Cancer 08/2012; · 3.99 Impact Factor
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ABSTRACT: OBJECTIVES: There is currently widespread exposure to the toxic metal cadmium through the diet as well as through smoking, and it has been suggested that cadmium exposure may increase the risk of cardiovascular disease. Here we examined whether cadmium exposure is associated with prevalence and growth of atherosclerotic plaques in the carotid arteries. DESIGN AND SUBJECTS: The analyses were performed in a screening-based cohort of 64-year-old Caucasian women with stratified, random selection to groups with normal glucose tolerance, impaired glucose tolerance and diabetes (n = 599). We measured cadmium concentrations in blood and urine at baseline. In addition, we performed ultrasound examination to determine the prevalence and area of atherosclerotic plaques in the carotid arteries and assessed smoking history and other cardiovascular risk factors at baseline and at a follow-up examination after a mean of 5.4 years. RESULTS: At baseline, blood cadmium levels were associated with increased risk of plaque and a large plaque area after adjustment for confounders. In women who had never smoked, blood cadmium levels correlated positively with plaque area at baseline. The occurrence of large plaques and the change in plaque area at follow-up were associated with blood and creatinine-corrected urinary cadmium concentrations at baseline after adjustment for confounders. Blood and urine cadmium levels added information to established cardiovascular risk factors in predicting progress of atherosclerosis. CONCLUSIONS: We have shown that cadmium levels in blood and urine are independent factors associated with the development of atherosclerotic plaques at baseline as well as prospectively. This novel observation emphasizes the need to consider cadmium as a pro-atherogenic pollutant.
Journal of Internal Medicine 07/2012; · 5.48 Impact Factor
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ABSTRACT: Sudden death due to malignant ventricular arrhythmias is the most important cause of death in acute myocardial infarction. Improved knowledge about the pathophysiology underlying these arrhythmias is essential in the search for new anti-arrhythmic strategies. Lysophosphatidylcholine (LPC), a hydrolysis product of (membrane) phospholipid degradation, is one of the most potent pro-arrhythmic substances that accumulate in the human heart during myocardial ischemia. The aim of this study was to set up and validate an in vitro experimental system for studies on the effects of LPC on electrophysiological parameters in beating cardiomyocytes.
Spontaneously beating HL-1 cardiomyocytes were cultured on multielectrode array microchips for three days for the recording of electrical activities in the form of field potentials (FP). FPs were recorded at baseline and after addition of 2, 4, 8, 12, 16, 20, and 24 µM of LPC to the cell medium (n=9). We found that LPC could induce rapid effects on electrical parameters in the HL-1 cells. The overall half-maximal effective concentration (EC(50)) of LPC was around 12 µM. The beating rate and peak-peak amplitude of FP thus decreased at concentrations ≥ 12 µM and were inversely proportional to increased LPC concentration. The duration of FP was significantly prolonged with LPC above 12 µM and was concentration-dependent. LPC delayed signal propagation, an effect which was mimicked by blocking gap junctions with heptanol and attenuated by pre-treatment with isoprenaline and atropine. Finally, asynchronous activity was induced by LPC at >12 µM.
LPC induced prompt and pronounced electrophysiological alterations that may underlie its observed pro-arrhythmic properties. Our in vitro model with HL-1 cells and microelectrode array system may be a useful tool for preclinical studies of electrophysiological effects of various pathophysiological concepts.
Cellular Physiology and Biochemistry 07/2012; 30(2):477-88. · 2.86 Impact Factor
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Maria Antonella Burza,
Carlo Pirazzi,
Cristina Maglio,
Kajsa Sjöholm,
Rosellina Margherita Mancina,
Per-Arne Svensson,
Peter Jacobson,
Martin Adiels,
Marco Giorgio Baroni, Jan Borén,
Stefano Ginanni Corradini,
Tiziana Montalcini,
Lars Sjöström,
Lena Mariana Susann Carlsson,
Stefano Romeo
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ABSTRACT: BACKGROUND: Obesity is a risk factor for cancer, including hepatocellular carcinoma. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M (rs738409) genetic variant has been associated with hepatocellular carcinoma (HCC) in individuals with chronic alcohol abuse or hepatic viral infection. In the present study we examined the association between the PNPLA3 I148M genetic variant and hepatocellular carcinoma in obese individuals from the Swedish Obese Subjects cohort (n=4047). METHODS: We performed a matched, prospective, controlled, interventional trial, investigating the effect of bariatric surgery (surgery group) compared to conventional treatment (control group) for obesity. RESULTS: A total of 9 events were observed in the 15-year median follow up (5 in the control group and 4 in the surgery group). A significantly higher incidence of hepatocellular carcinoma in PNPLA3 148M allele carriers was found in obese individuals in the control group (log-rank P-value=0.001), but not in the surgery group (log-rank P-value=0.783). Consistently, an increased risk (for each PNPLA3 148M allele, hazard ratio: 5.9; 95% confidence interval 1.5-23.8; P-value=0.013) of developing hepatocellular carcinoma was observed only in the control group. CONCLUSION: The current study is the first prospective report showing the association of the PNPLA3 I148M genetic variant and hepatocellular carcinoma in severely obese individuals.
Digestive and Liver Disease 06/2012; · 3.05 Impact Factor
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ABSTRACT: In this short review, we discuss apolipoprotein B100 and the assembly of very low-density lipoproteins. In particular, we address the nature and importance of co- and posttranslational degradation of apolipoprotein B100 during the assembly process. We also provide a short historical background to the development of the current model for the degradation of apolipoprotein B100.
Arteriosclerosis Thrombosis and Vascular Biology 06/2012; 32(6):1334-8. · 6.37 Impact Factor
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ABSTRACT: To better understand the postprandial clearance of triglyceride-rich lipoproteins (TRLs) and its relation to the fasting kinetics of TRLs.
Two studies were performed on 30 male subjects: a fasting kinetic study to determine the fasting secretion and clearance rates of apolipoprotein B (apoB) 100 and triglycerides in the very low-density lipoprotein 1 and 2 (VLDL(1) and VLDL(2)) fractions; and a postprandial study to determine the postprandial accumulation of apoB48, apoB100 and triglycerides in the chylomicron, VLDL(1) and VLDL(2) fractions. Results from these two studies were combined to characterize the postprandial clearance of TRLs in a physiologically relevant setting.
Our results show that postprandial accumulation of the apoB48-carrying chylomicrons can be predicted from the clearance capacity of the lipolytic pathway, determined in the fasting state. Furthermore, we show that chylomicrons and VLDL(1) particles are not cleared equally by the lipoprotein lipase pathway, and that chylomicrons seem to be the preferred substrate. Subjects with a rapid fasting lipid metabolism accumulate lower levels of postprandial triglycerides with less accumulation of apoB100 in the VLDL(1) fraction and a faster transfer of apoB100 into the VLDL(2) fraction. In contrast, fasting VLDL(1) secretion does not predict postprandial triglyceride accumulation.
Non-fasting triglyceride levels have recently been identified as a major predictor of future cardiovascular events. Here we show that the capacity of the lipolytic pathway is a common determinant of both the fasting and non-fasting triglyceride levels and may thus play an important role in the development of dyslipemia and atherosclerosis.
Atherosclerosis 02/2012; 222(1):222-8. · 3.79 Impact Factor
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ABSTRACT: The heart produces apolipoprotein (apo) B-containing lipoproteins which enables cardiac export of potentially cardiotoxic lipids. We hypothesized that overexpression of apoB attenuates the pathologic cardiac remodeling and hypertrophic response following pathological stimuli such as chronic adrenergic overstimulation and myocardial infarction (MI).
Cardiac hypertrophy was induced by a chronic infusion of isoproterenol (ISO) 15 mg/kg/day for 3 weeks in human apoB transgenic mice (n = 9) and in non-transgenic wild-type mice (n = 10). As controls, apoB transgenic (n = 10) and wild-type mice (n = 10) saline infusions were used. Transthoracic echocardiography was performed at baseline and after 3 weeks of treatment to evaluate left ventricular (LV) function and morphology. To investigate the effects of expression on postinfarct hypertrophic response we induced MI in apoB transgenic mice (n = 8) and in wild-type controls (n = 11). The hearts were explanted and weighed 6 weeks post MI.
At baseline, WT mice had higher BW and LV mass (LVM) compared to the apoB mice. The increase in LV mass and dimensions after 3 weeks of treatment with ISO was significantly lower while systolic function was significantly better in the apoB group. Six weeks post MI the apoB mice had significantly lower heart weight and heart weight to body weight ratio. The infarct size was similar in both groups.
Overexpression of apoB attenuates the pathologic remodeling and hypertrophic response to chronic adrenergic stimulation and MI. Our results indicate that cardiac expression of apoB-containing lipoproteins might be an important regulator of myocardial structure and function.
Scandinavian journal of clinical and laboratory investigation 01/2012; 72(3):230-6. · 1.38 Impact Factor
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Colin N A Palmer,
Cristina Maglio,
Carlo Pirazzi,
Maria Antonella Burza,
Martin Adiels,
Lindsay Burch,
Louise A Donnelly,
Helen Colhoun,
Alexander S Doney,
John F Dillon, [......],
Andrew T Hattersley,
Tim Frayling,
Andrew D Morris,
Markku Peltonen,
Per-Arne Svensson,
Peter Jacobson, Jan Borén,
Lars Sjöström,
Lena M S Carlsson,
Stefano Romeo
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ABSTRACT: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity.
PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O.R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction = 0.002). This provides evidence for the obesity interaction with I48M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study.
Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.
PLoS ONE 01/2012; 7(6):e39362. · 4.09 Impact Factor
