Plasma ApoE elevations are associated with NAFLD: The PREVEND Study

Berg, Eline H. van den; Corsetti, James P.; Bakker, Stephan J. L.; Dullaart, Robin

doi:10.1371/journal.pone.0220659

Cited by 16 publications

(17 citation statements)

References 66 publications

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“…Beyond the association between fasting serum triacylglycerols and diabetes, evidence suggests that plasma concentrations of triacylglycerol-enriched remnant lipoproteins (TRLs) and the cholesterol content in TRL more accurately reflect the pathophysiological processes that underlie progression to diabetes [7][8][9]. Events such as hepatic and pancreatic steatosis and heightened systemic inflammation are strongly related to the presence of large VLDL particles, namely VLDL1 [10,11].…”

Section: Introductionmentioning

confidence: 99%

Increased particle size of triacylglycerol-enriched remnant lipoproteins, but not their plasma concentration or lipid content, augments risk prediction of incident type 2 diabetes

Carvalho

Nogueira²,

Duncan

et al. 2020

Diabetologia

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Aims/hypothesis Type 2 diabetes prevention requires the accurate identification of those at high risk. Beyond the association of fasting serum triacylglycerols with diabetes, triacylglycerol-enriched remnant lipoproteins (TRLs) more accurately reflect pathophysiological changes that underlie progression to diabetes, such as hepatic insulin resistance, pancreatic steatosis and systemic inflammation. We hypothesised that TRL-related factors could improve risk prediction for incident diabetes. Methods We included individuals from the Brazilian Longitudinal Study of Adult Health cohort. We trained a logistic regression model for the risk of incident diabetes in 80% of the cohort using tenfold cross-validation, and tested the model in the remaining 20% of the cohort (test set). Variables included medical history and traits of the metabolic syndrome, followed by TRL-related measurements (plasma concentration, TRL particle diameter, cholesterol and triacylglycerol content). TRL features were measured using NMR spectroscopy. Discrimination was assessed using the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AUPRC). Results Among 4463 at-risk individuals, there were 366 new cases of diabetes after a mean (±SD) of 3.7 (±0.63) years of follow-up. We derived an 18-variable model with a global AUROC of 0.846 (95% CI: 0.829, 0.869). Overall TRL-related markers were not associated with diabetes. However, TRL particle diameter increased the AUROC, particularly in individuals with HbA 1c <39 mmol/ mol (5.7%) (hold-out test set [n = 659]; training-validation set [n = 2638]), but not in individuals with baseline HbA 1c 39-46 mmol/mol (5.7-6.4%) (hold-out test set [n = 233]; training-validation set [n = 933]). In the subgroup with baseline HbA 1c <39 mmol/mol (5.7%), AUROC in the test set increased from 0.717 (95% CI 0.603, 0.818) to 0.794 (95% CI 0.731, 0.862), and AUPRC in the test set rose from 0.582 to 0.701 when using the baseline model and the baseline model plus TRL particle diameter, respectively. TRL particle diameter was highly correlated with obesity, insulin resistance and inflammation in those with impaired fasting glucose at baseline, but less so in those with HbA 1c <39 mmol/mol (5.7%).

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Section: Introductionmentioning

confidence: 99%

Increased particle size of triacylglycerol-enriched remnant lipoproteins, but not their plasma concentration or lipid content, augments risk prediction of incident type 2 diabetes

Carvalho

Nogueira²,

Duncan

et al. 2020

Diabetologia

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“…Previously, numerous studies have implicated ApoE in the regulation of VLDL secretion. (11)(12)(13)(14) Indeed, we observed a reduction in VLDL-TAG secretion in ApoE knockout mice compared with wild-type mice. This phenotype is partially rescued by overexpression of exogenous ApoE (Supporting Fig.…”

Section: Pnpla7 Interacts With Apoe and Modulates Its Stabilitymentioning

confidence: 63%

“…(9,10) ApoB is an obligated structural component of VLDL, whereas apolipoprotein E (ApoE) plays an important role in the secretion of VLDL as well as in their clearance. (11)(12)(13)(14) In humans and mice, ApoE deficiency results in fatty liver and hypercholesterolemia associated with reduced VLDL ApoB production. (11,(15)(16)(17) Interestingly, large amounts of lipid are found to accumulate as numerous small ER-derived vesicles in the cytosol, indicating that the early or intermediary components of the VLDL secretory pathway is impaired in the livers of ApoE-deficient mice.…”

Section: Background and Aimsmentioning

confidence: 99%

The Patatin‐Like Phospholipase Domain Containing Protein 7 Facilitates VLDL Secretion by Modulating ApoE Stability

et al. 2020

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Background and Aims The regulation of hepatic very‐low‐density lipoprotein (VLDL) secretion is vital for lipid metabolism whose pathogenetic status is involved in fatty liver disease and dyslipidemia seen in hepatic steatosis. Accumulated evidence suggest that apolipoprotein E (ApoE) is closely related to hepatic VLDL secretion. Here, we report that the expression of patatin‐like phospholipase domain containing protein 7 (PNPLA7) is strongly induced by hepatic steatosis and positively correlates with plasma triacylglycerol (TAG) levels in the human subjects, whereas the role of PNPLA7 in hepatic VLDL secretion is unknown. Approach and Results Herein, with genetic manipulation in the mice, the deficiency of hepatic PNPLA7 expression resulted in reduced VLDL secretion accompanied by enhanced hepatic lipid accumulation and decreased hepatic ApoE expression. Furthermore, knockdown of PNPLA7 in the livers of the db/db mice also resulted in significant reduction in plasma TAG level but aggravated hepatic steatosis. Importantly, we observed that PNPLA7 interacted with ApoE and presumably at the site of endoplasmic reticulum. Mechanistically, we have shown that PNPLA7 could modulate polyubiquitination and proteasomal‐mediated degradation of ApoE. Overexpressed ApoE restored the impaired VLDL‐TAG metabolism in PNPLA7‐knockdown primary hepatocytes. Conclusion PNPLA7 plays a critical role in regulating hepatic VLDL secretion by modulating ApoE stability through its interaction with ApoE.

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“…The authors suggest based on conditional analysis that rs429358 in APOE is the causal variant with the C allele conferring protection (40). Candidate genes studies have previously shown a decreased risk with the ∈ 4 allele (41-43) and the ∈ 2 allele (42,44) although some studies reported no difference in the risk of NAFLD (45,46). Elevated serum levels of APOE appear to correlate with higher fatty liver index regardless of genotype (46).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E

Fairfield

Pius

et al. 2021

Preprint

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Background & Aims Genome-wide association studies (GWAS) have identified several risk loci for non-alcoholic fatty liver disease (NAFLD). Previous studies have largely relied on small sample sizes and have assessed quantitative traits. We performed a case-control GWAS in the UK Biobank using recorded diagnosis of NAFLD based on diagnostic codes recommended in recent consensus guidelines. Approach & Results We performed a GWAS of 4,761 cases of NAFLD and 373,227 healthy controls without evidence of NAFLD. Sensitivity analyses were performed excluding other co-existing hepatic pathology, adjusting for BMI and adjusting for alcohol intake. 9,723,654 variants were assessed by logistic regression adjusted for age, sex, genetic principal components and genotyping batch. We performed a GWA meta-analysis using available summary association statistics from two previously published case-control GWAS of NAFLD. Six risk loci were identified (P<5*10-8) of which one is novel in GWAS (rs429358 in APOE) and five are known (PNPLA3, TM6SF2, GCKR, MARC1 and TRIB1). Rs429358 (P=2.17*10-11) is a missense variant within the APOE gene determining ϵ4 vs ϵ2/ϵ3 alleles. All loci retained significance in sensitivity analyses without co-existent hepatic pathology and after adjustment for BMI. PNPLA3 and TM6SF2 remained significant after adjustment for alcohol (alcohol intake was known in only 158,388 individuals) with others demonstrating consistent direction and magnitude of effect. All 6 loci were significant on meta-analysis including APOE P=3.42*10-13 with consistent direction and magnitude of effect in all 6 loci in all three studies. The ϵ4 allele of APOE offered protection against NAFLD (odds ratio for heterozygotes 0.84 [95%CI 0.78-0.90] and homozygotes 0.64 [0.50-0.79]). Conclusions This GWAS demonstrates that the ϵ4 allele of APOE is strongly associated with protection against NAFLD.

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Plasma ApoE elevations are associated with NAFLD: The PREVEND Study

Cited by 16 publications

References 66 publications

Increased particle size of triacylglycerol-enriched remnant lipoproteins, but not their plasma concentration or lipid content, augments risk prediction of incident type 2 diabetes

Increased particle size of triacylglycerol-enriched remnant lipoproteins, but not their plasma concentration or lipid content, augments risk prediction of incident type 2 diabetes

The Patatin‐Like Phospholipase Domain Containing Protein 7 Facilitates VLDL Secretion by Modulating ApoE Stability

Genome-Wide Association Study of Non-Alcoholic Fatty Liver Disease Identifies Association with Apolipoprotein E

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