Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein

Berg, Eline H. van den; Flores‐Guerrero, Jose L.; Gruppen, Eke G.; Garcia, Erwin; Connelly, Margery A.; Meijer, Vincent E de; Bakker, Stephan J. L.; Blokzijl, Hans; Dullaart, Robin P. F.

doi:10.3390/jcm11051223

Cited by 6 publications

(10 citation statements)

References 61 publications

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“…Our findings in LTRs align with previous results showing a 2.4 fold increase in urinary TMAO concentrations in a small group of 40 LTRs, obtained 7 months after transplantation, compared with their levels before the procedure [36]. Complementary to the current report, we previously found that plasma TMAO concentrations tended to be lower in patients with cirrhosis compared with PREVEND participants [30]. Accordingly, circulating TMAO was lower in patients with PSC and impaired liver function compared with healthy controls and patients with ulcerative colitis [31].…”

Section: Discussionsupporting

confidence: 92%

“…In cirrhotic livers, FMO3 protein expression is progressively impaired with advancing disease severity [29]. In line, TMAO levels tend to be decreased in patients with endstage liver disease compared with the general population and are inversely associated with the Model for End-stage Liver Disease (MELD) score [30]. TMAO is also decreased in patients with primary sclerosing cholangitis (PSC) and compromised liver function compared with healthy controls [31].…”

Section: Introductionmentioning

confidence: 93%

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Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients

Trillos-Almanza,

Chvatal-Medina,

Connelly

et al. 2024

IJMS

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Liver transplant recipients (LTRs) have lower long-term survival rates compared with the general population. This underscores the necessity for developing biomarkers to assess post-transplantation mortality. Here we compared plasma trimethylamine-N-oxide (TMAO) levels with those in the general population, investigated its determinants, and interrogated its association with all-cause mortality in stable LTRs. Plasma TMAO was measured in 367 stable LTRs from the TransplantLines cohort (NCT03272841) and in 4837 participants from the population-based PREVEND cohort. TMAO levels were 35% higher in LTRs compared with PREVEND participants (4.3 vs. 3.2 µmol/L, p < 0.001). Specifically, TMAO was elevated in LTRs with metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, and polycystic liver disease as underlying etiology (p < 0.001 for each). Among LTRs, TMAO levels were independently associated with eGFR (std. β = −0.43, p < 0.001) and iron supplementation (std. β = 0.13, p = 0.008), and were associated with mortality (29 deaths during 8.6 years follow-up; log-rank test p = 0.017; hazard ratio of highest vs. lowest tertile 4.14, p = 0.007). In conclusion, plasma TMAO is likely elevated in stable LTRs, with impaired eGFR and iron supplementation as potential contributory factors. Our preliminary findings raise the possibility that plasma TMAO could contribute to increased mortality risk in such patients, but this need to be validated through a series of rigorous and methodical studies.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 93%

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients

Trillos-Almanza,

Chvatal-Medina,

Connelly

et al. 2024

IJMS

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“…The presence of LP-Z may reflect the inflammatory hepatitis and cholestasis described in both adult COVID-19 ( 66 , 67 ) and up to one third of SARS CoV-2 infections in youth ( 68 ). LP-Z in adults has specifically been linked to worse outcomes in alcoholic cirrhotic disease that also associates with poor HDL function ( 69 ). This is the first description of LP-Z in youth and the increased occurrence not only among youth with MIS-C, but among those with the lowest HDL parameters, is striking.…”

Section: Discussionmentioning

confidence: 99%

Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity

Mietus‐Snyder

Suslovic

Delaney

et al. 2022

Front. Cardiovasc. Med.

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BackgroundMyriad roles for high-density lipoprotein (HDL) beyond atheroprotection include immunologic functions implicated in the severity of coronavirus disease-2019 (COVID-19) in adults. We explored whether there is an association between HDL and COVID-19 severity in youth.MethodsA pediatric cohort (N = 102), who tested positive for COVID-19 across a range of disease manifestations from mild or no symptoms, to acute severe symptoms, to the multisystem inflammatory syndrome of children (MIS-C) was identified. Clinical data were collected from the medical record and reserve plasma aliquots were assessed for lipoproteins by NMR spectroscopy and assayed for HDL functional cholesterol efflux capacity (CEC). Findings were compared by COVID-19 status and symptom severity. Lipoprotein, NMR spectroscopy and CEC data were compared with 30 outpatient COVID negative children.ResultsDecreasing HDL cholesterol (HDL-c), apolipoprotein AI (ApoA-I), total, large and small HDL particles and HDL CEC showed a strong and direct linear dose-response relationship with increasing severity of COVID-19 symptoms. Youth with mild or no symptoms closely resembled the uninfected. An atypical lipoprotein that arises in the presence of severe hepatic inflammation, lipoprotein Z (LP-Z), was absent in COVID-19 negative controls but identified more often in youth with the most severe infections and the lowest HDL parameters. The relationship between HDL CEC and symptom severity and ApoA-I remained significant in a multiply adjusted model that also incorporated age, race/ethnicity, the presence of LP-Z and of GlycA, a composite biomarker reflecting multiple acute phase proteins.ConclusionHDL parameters, especially HDL function, may help identify youth at risk of more severe consequences of COVID-19 and other novel infectious pathogens.

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“…Lipoprotein particles were measured in EDTA plasma using nuclear magnetic resonance (NMR) spectroscopy with a Vantera ® Clinical Analyzer (Labcorp, Morrisville, NC, USA) [ 34 , 35 ]. Further details regarding this analysis have been published elsewhere [ 36 ]. Small, medium and large HDL particles were quantified using the amplitudes of their spectroscopically distinct methyl group NMR signals [ 35 ].…”

Section: Methodsmentioning

confidence: 99%

High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients

Jonker,

Doorenbos,

Kremer

et al. 2024

Viruses

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Torque teno virus (TTV) is emerging as a potential marker for monitoring immune status. In transplant recipients who are immunosuppressed, higher TTV DNA loads are observed than in healthy individuals. TTV load measurement may aid in optimizing immunosuppressive medication dosing in solid organ transplant recipients. Additionally, there is a growing interest in the role of HDL particles in immune function; therefore, assessment of both HDL concentrations and TTV load may be of interest in transplant recipients. The objective of this study was to analyze TTV loads and HDL parameters in serum samples collected at least one year post-transplantation from 656 stable outpatient kidney transplant recipients (KTRs), enrolled in the TransplantLines Food and Nutrition Cohort (Groningen, the Netherlands). Plasma HDL particles and subfractions were measured using nuclear magnetic resonance spectroscopy. Serum TTV load was measured using a quantitative real-time polymerase chain reaction. Associations between HDL parameters and TTV load were examined using univariable and multivariable linear regression. The median age was 54.6 [IQR: 44.6 to 63.1] years, 43.3% were female, the mean eGFR was 52.5 (±20.6) mL/min/1.73 m2 and the median allograft vintage was 5.4 [IQR: 2.0 to 12.0] years. A total of 539 participants (82.2%) had a detectable TTV load with a mean TTV load of 3.04 (±1.53) log10 copies/mL, the mean total HDL particle concentration was 19.7 (±3.4) μmol/L, and the mean HDL size was 9.1 (±0.5) nm. The univariable linear regression revealed a negative association between total HDL particle concentration and TTV load (st.β = −0.17, 95% CI st.β: −0.26 to −0.09, p < 0.001). An effect modification of smoking behavior influencing the association between HDL particle concentration and TTV load was observed (Pinteraction = 0.024). After adjustment for age, sex, alcohol intake, hemoglobin, eGFR, donor age, allograft vintage and the use of calcineurin inhibitors, the negative association between HDL particle concentration and TTV load remained statistically significant in the non-smoking population (st.β = −0.14, 95% CI st.β: −0.23 to −0.04, p = 0.006). Furthermore, an association between small HDL particle concentration and TTV load was found (st.β = −0.12, 95% CI st.β: −0.22 to −0.02, p = 0.017). Higher HDL particle concentrations were associated with a lower TTV load in kidney transplant recipients, potentially indicative of a higher immune function. Interventional studies are needed to provide causal evidence on the effects of HDL on the immune system.

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Profoundly Disturbed Lipoproteins in Cirrhotic Patients: Role of Lipoprotein-Z, a Hepatotoxic LDL-like Lipoprotein

Cited by 6 publications

References 61 publications

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients

Circulating Trimethylamine-N-Oxide Is Elevated in Liver Transplant Recipients

Changes in HDL cholesterol, particles, and function associate with pediatric COVID-19 severity

High-Density Lipoprotein Particles and Torque Teno Virus in Stable Outpatient Kidney Transplant Recipients

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