Apolipoprotein E4 association with metabolic syndrome depends on body fatness

Torres-Pérez, Elena; Ledesma, Marta; García-Sobreviela, Maria Pilar; León-Latre, Montserrat; Arbonés-Mainar, José M.

doi:10.1016/j.atherosclerosis.2015.11.029

Cited by 36 publications

(43 citation statements)

References 37 publications

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“…While decreased fat mass traditionally carries positive connotations, the reduced adipogenesis in APOE4 mice, as well as APOE*4 carrying humans, appears to be detrimental. The failure to store lipids in adipose tissue is a potential contributor to obesity-induced IR and glucose intolerance among APOE4 carriers, both in mice 12 and humans 5 . In the current study, we confirm and expand upon these APOE effects on adiposity and glucose metabolism in diet-induced and genetic models of obesity, as both DIO- and ob/ob-APOE3 mice increased their WAT mass and maintained enhanced insulin sensitivity compared to their APOE4 counterparts.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously provided evidence in mice 12,13 and humans 5,14 suggesting that APOE plays an important role in WAT function. However, the specific metabolic signatures of the APOE isoforms – and their pathophysiologycal contributions during obesity – remain unclear.…”

Section: Introductionmentioning

confidence: 99%

“…A wealth of studies show that plasma lipids are higher in individuals who carry an APOE*4 allele (15–20% of the population) when compared to individuals with only APOE*3 alleles 2 . In addition to hyperlipidemia, APOE*4 has also been linked to metabolic syndrome (MetS) and impaired ability to properly manage postprandial glucose and carbohydrates 3–5 . Interestingly, impaired glucose metabolism in the brain is a hallmark of Alzheimer's disease (AD) 6 , and the APOE*4 allele is associated with reduced neuronal glucose utilization 7 and increased risk of developing AD 8 .…”

Section: Introductionmentioning

confidence: 99%

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Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4

et al. 2016

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Background The Apolipoprotein E (APOE) gene encodes for three isoforms in the human population (APOE2, APOE3, and APOE4). While the role of APOE in lipid metabolism is well characterized, the specific metabolic signatures of the APOE isoforms, during metabolic disorders, remain unclear. Objective To elucidate the molecular underpinnings of APOE-directed metabolic alterations, we tested the hypothesis that APOE4 drives a whole-body metabolic shift toward increased lipid oxidation. Methods We employed humanized mice in which Apoe gene has been replaced by the human APOE*3 or APOE*4 allele to produce human APOE3 or APOE4 proteins and characterized several mechanisms of fatty acid oxidation, lipid storage, substrate utilization and thermogenesis in those mice. Results We show that while APOE4 mice gained less body weight and mass than their APOE3 counterparts on a Western-type diet (p<0.001), they displayed elevated insulin and HOMA, markers of insulin resistance (p=0.004 and p=0.025, respectively). APOE4 mice also demonstrated a reduced respiratory quotient during the postprandial period (0.95±0.03 vs. 1.06±0.03, p<0.001), indicating increased usage of lipids as opposed to carbohydrates as a fuel source. Finally, APOE4 mice showed increased body temperature (37.30 ± 0.68 vs 36.9 ± 0.58 °C, p=0.039), augmented cold tolerance, and more metabolically active brown adipose tissue compared to APOE3 mice. Conclusion These data suggest that APOE4 mice may resist weight gain via an APOE4-directed global metabolic shift toward lipid oxidation and enhanced thermogenesis, and may represent a critical first step in the development of APOE-directed therapies for a large percentage of the population affected by disorders with established links to APOE and metabolism.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4

et al. 2016

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“…This may be related to oxidative stress, inflammation, and other factors caused by abnormal lipid metabolism in obese individuals, which may lead to myocardial fibrosis atrial remodeling followed by AF [30] . Some studies suggest that ApoE ε4 is one cause of hyperlipidemia [31] . The association between obesity and hyperlipidemia may indirectly indicate that ApoEε4 is a high risk factor for AF.…”

Section: Discussionmentioning

confidence: 99%

Correlation between Apolipoprotein E genetic polymorphism and atrial fibrillation

Lou¹,

Wang²,

Sun³

et al. 2019

Preprint

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Background： We speculated that there was a correlation between apolipoprotein E (ApoE) genetic polymorphisms and the occurrence of atrial fibrillation (AF) based on the AF inflammatory mechanism. The high-risk alleles of ApoE were examined in patients with AF and controls to determine the distribution of genotype and allele frequencies. Methods： From January 2017 to January 2019, 64 patients with AF in the department of cardiovascular medicine of the Lianyungang Second People's Hospital, and 49 healthy outpatient volunteers, were enrolled. ApoE gene polymorphisms were examined using allele-specific polymerase chain reaction. Statistical analyses were performed to identify high-risk ApoE alleles. Results： A total of 113 patients were enrolled in this study. Among them, 64 patients were in the AF group (38 male and 26 female), with an average age of 74.38 ± 8.37 years. The control group consisted of 49 cases (29 male and 20 female), with an average age of 65.24 ± 12.14 years. The six ApoE phenotypes ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and 4/ε4 were observed in 0.9% , 13.2%, 2.7%, 58.4% , 19.5%, and 5.3% . The proportions of our study population with ApoE protective, general, and risk genotypes accounted for 14.1%，61.1% , and 24.8% , respectively. There was no statistically significant difference in ApoE gene polymorphism frequencies related to gender, height, weight, smoking status, hypertension, type 2 diabetes mellitus, and coronary heart disease (P＞0.05). There were significant differences in age, body mass index（BMI）, larger left atrial diameter（LAD）, and left ventricle ejection fraction(LVEF) (P＜0.05). The observed genotype frequencies were in Hardy–Weinberg equilibrium and were representative of the population. Conclusion： There is a correlation between the ApoE genetic polymorphism and the occurrence of AF, and ApoEε4 is a high-risk genotype for AF.

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“…APOE4 have greater affinity for very low-density lipoprotein, and it is less efficient at homeostatic maintenance ( Huang and Mahley, 2014 ). However, APOE4 was associated with higher fasting glucose and insulin levels, as well as an increased metabolic syndrome risk with younger age onset ( Torres-Perez et al, 2016 ). In obese men, APOE4 carriers have elevated levels of plasma cholesterol, triglycerides, glucose, and insulin and presents IR ( Elosua et al, 2003 ; Jones and Rebeck, 2019 ).…”

Section: Genes Associated With Obesity and Neurodegenerative And Neurmentioning

confidence: 99%

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

2020

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Obesity is a multifactorial disease in which environmental conditions and several genes play an important role in the development of this disease. Obesity is associated with neurodegenerative diseases (Alzheimer, Parkinson, and Huntington diseases) and with neurodevelopmental diseases (autism disorder, schizophrenia, and fragile X syndrome). Some of the environmental conditions that lead to obesity are physical activity, alcohol consumption, socioeconomic status, parent feeding behavior, and diet. Interestingly, some of these environmental conditions are shared with neurodegenerative and neurodevelopmental diseases. Obesity impairs neurodevelopment abilities as memory and fine-motor skills. Moreover, maternal obesity affects the cognitive function and mental health of the offspring. The common biological mechanisms involved in obesity and neurodegenerative/neurodevelopmental diseases are insulin resistance, pro-inflammatory cytokines, and oxidative damage, among others, leading to impaired brain development or cell death. Obesogenic environmental conditions are not the only factors that influence neurodegenerative and neurodevelopmental diseases. In fact, several genes implicated in the leptin–melanocortin pathway ( LEP , LEPR , POMC , BDNF , MC4R , PCSK1 , SIM1 , BDNF , TrkB , etc.) are associated with obesity and neurodegenerative and neurodevelopmental diseases. Moreover, in the last decades, the discovery of new genes associated with obesity ( FTO, NRXN3, NPC1, NEGR1, MTCH2, GNPDA2 , among others) and with neurodegenerative or neurodevelopmental diseases ( APOE, CD38, SIRT1, TNF α, PAI-1, TREM2, SYT4, FMR1, TET3 , among others) had opened new pathways to comprehend the common mechanisms involved in these diseases. In conclusion, the obesogenic environmental conditions, the genes, and the interaction gene–environment would lead to a better understanding of the etiology of these diseases.

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Apolipoprotein E4 association with metabolic syndrome depends on body fatness

Cited by 36 publications

References 37 publications

Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4

Metabolic shifts toward fatty-acid usage and increased thermogenesis are associated with impaired adipogenesis in mice expressing human APOE4

Correlation between Apolipoprotein E genetic polymorphism and atrial fibrillation

Environment and Gene Association With Obesity and Their Impact on Neurodegenerative and Neurodevelopmental Diseases

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