Titre
Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Hu, K.
Auteure/Auteur
Perez-Matos, M.C.
Auteure/Auteur
Argemi, J.
Auteure/Auteur
Vilar-Gomez, E.
Auteure/Auteur
Shalaurova, I.
Auteure/Auteur
Bullitt, E.
Auteure/Auteur
Landeen, L.
Auteure/Auteur
Sugahara, G.
Auteure/Auteur
Deng, H.
Auteure/Auteur
Mathur, K.
Auteure/Auteur
Tran, S.
Auteure/Auteur
Cai, H.
Auteure/Auteur
He, H.
Auteure/Auteur
Yalcin, Y.
Auteure/Auteur
Vieira Barbosa, J.
Auteure/Auteur
Ventura-Cots, M.
Auteure/Auteur
Marx, K.
Auteure/Auteur
Gad, A.P.
Auteure/Auteur
Niezen, S.
Auteure/Auteur
Izunza Barba, S.
Auteure/Auteur
Ang, L.H.
Auteure/Auteur
Popov, Y.V.
Auteure/Auteur
Fricker, Z.
Auteure/Auteur
Lai, M.
Auteure/Auteur
Curry, M.
Auteure/Auteur
Afdhal, N.
Auteure/Auteur
Szabo, G.
Auteure/Auteur
Mukamal, K.J.
Auteure/Auteur
Sanyal, A.J.
Auteure/Auteur
Otvos, J.D.
Auteure/Auteur
Malik, R.
Auteure/Auteur
Saito, T.
Auteure/Auteur
Connelly, M.A.
Auteure/Auteur
Chalasani, N.P.
Auteure/Auteur
Bataller, R.
Auteure/Auteur
Jiang, Z.G.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1527-3350
Statut éditorial
Publié
Date de publication
2022-04
Volume
75
Numéro
4
Première page
968
Dernière page/numéro d’article
982
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Publication Status: ppublish
Résumé
Lipoprotein Z (LP-Z) is an abnormal free cholesterol (FC)-enriched LDL-like particle discovered from patients with cholestatic liver disease. This study aims to define the diagnostic value of LP-Z in alcohol-associated hepatitis (AH) and interrogate the biology behind its formation.
We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z.
Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
We measured serum levels of LP-Z using nuclear magnetic resonance spectroscopy, a well-established clinical assay. Serum levels of LP-Z were significantly elevated in four AH cohorts compared with control groups, including heavy drinkers and patients with cirrhosis. We defined a Z-index, calculated by the ratio of LP-Z to total apolipoprotein B-containing lipoproteins, representing the degree of deviation from normal VLDL metabolism. A high Z-index was associated with 90-day mortality independent from the Model for End-Stage Liver Disease (MELD) and provided added prognosticative value. Both a Z-index ≤ 0.6 and a decline of Z-index by ≥0.1 in 2 weeks predicted 90-day survival. RNA-sequencing analyses of liver tissues demonstrated an inverse association in the expression of enzymes responsible for the extrahepatic conversion of VLDL to LDL and AH disease severity, which was further confirmed by the measurement of serum enzyme activity. To evaluate whether the FC in LP-Z could contribute to the pathogenesis of AH, we found significantly altered FC levels in liver explant of patients with AH. Furthermore, FC in reconstituted LP-Z particles caused direct toxicity to human hepatocytes in a concentration-dependent manner, supporting a pathogenic role of FC in LP-Z.
Impaired lipoprotein metabolism in AH leads to the accumulation of LP-Z in the circulation, which is hepatotoxic from excessive FC. A Z-index ≤ 0.6 predicts 90-day survival independent from conventional biomarkers for disease prognostication.
PID Serval
serval:BIB_821F00F0B361
PMID
Open Access
Oui
Date de création
2021-10-25T07:31:14.059Z
Date de création dans IRIS
2025-05-21T03:13:43Z
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Nom
34662439_BIB_821F00F0B361.pdf
Version du manuscrit
published
Licence
https://creativecommons.org/licenses/by-nc/4.0
Taille
1.43 MB
Format
Adobe PDF
PID Serval
serval:BIB_821F00F0B361.P001
URN
urn:nbn:ch:serval-BIB_821F00F0B3615
Somme de contrôle
(MD5):cd0c02b13d2c848e54188a9a41a2bda3