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Hu K, Perez-Matos MC, Argemi J, et al. Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis. Hepatology. 2021;doi: 10.1002/hep.32203.
Hu, K., Perez-Matos, M. C., Argemi, J., Vilar-Gomez, E., Shalaurova, I., Bullitt, E., Landeen, L., Sugahara, G., Deng, H., Mathur, K., Tran, S., Cai, H., He, H., Yalcin, Y., Vieira Barbosa, J., Ventura-Cots, M., Marx, K., Gad, A. P., Niezen, S., Izunza Barba, S., Ang, L. H., Popov, Y. V., Fricker, Z., Lai, M., Curry, M., Afdhal, N., Szabo, G., Mukamal, K. J., Sanyal, A. J., Otvos, J. D., Malik, R., Saito, T., Connelly, M. A., Chalasani, N. P., Bataller, R., & Jiang, Z. G. (2021). Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis. Hepatology (Baltimore, Md.), . https://doi.org/10.1002/hep.32203
Hu, Kunpeng, et al. "Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis." Hepatology (Baltimore, Md.) vol. (2021). doi: https://doi.org/10.1002/hep.32203
Hu K, Perez-Matos MC, Argemi J, Vilar-Gomez E, Shalaurova I, Bullitt E, Landeen L, Sugahara G, Deng H, Mathur K, Tran S, Cai H, He H, Yalcin Y, Vieira Barbosa J, Ventura-Cots M, Marx K, Gad AP, Niezen S, Izunza Barba S, Ang LH, Popov YV, Fricker Z, Lai M, Curry M, Afdhal N, Szabo G, Mukamal KJ, Sanyal AJ, Otvos JD, Malik R, Saito T, Connelly MA, Chalasani NP, Bataller R, Jiang ZG. Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis. Hepatology. 2021 Oct 18; doi: 10.1002/hep.32203. Epub 2021 Oct 18. PMID: 34662439.
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Hepatology. 2021 Oct 18; doi: 10.1002/hep.32203. Epub 2021 Oct 18.

Lipoprotein Z, a hepatotoxic lipoprotein, predicts outcome in alcohol-associated hepatitis.

Hepatology (Baltimore, Md.)

Kunpeng Hu, Maria C Perez-Matos, Josepmaria Argemi, Eduardo Vilar-Gomez, Irina Shalaurova, Esther Bullitt, Lee Landeen, Go Sugahara, Huiyan Deng, Karan Mathur, Stephanie Tran, Huimei Cai, Hanchang He, Yusuf Yalcin, Joana Vieira Barbosa, Meritxell Ventura-Cots, Katherine Marx, Aniket P Gad, Sebastian Niezen, Sofia Izunza Barba, Lay-Hong Ang, Yury V Popov, Zachary Fricker, Michelle Lai, Michael Curry, Nezam Afdhal, Gyongyi Szabo, Kenneth J Mukamal, Arun J Sanyal, James D Otvos, Raza Malik, Takeshi Saito, Margery A Connelly, Naga P Chalasani, Ramon Bataller, Z Gordon Jiang

Affiliations

  1. Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  2. Division of General Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China.
  3. Division of Gastroenterology, Hepatology, and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
  4. Hepatology Program, Centro de Investigacion Medica Aplicada, Liver Unit, Clinica Universidad de Navarra, Instituto de Investigacion de Navarra, University of Navarra, Pamplona, Spain.
  5. Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA.
  6. Laboratory Corporation of America Holdings, Morrisville, North Carolina, USA.
  7. Department of Physiology and Biophysics, Boston University School of Medicine, Boston, Massachusetts, USA.
  8. Vital Therapies, San Diego, California, USA.
  9. Division of Gastrointestinal and Liver Diseases, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  10. Research and Development Department, PhoenixBio, Co., Ltd, Higashi-Hiroshima, Hiroshima, Japan.
  11. Division of Gastroenterology and Hepatology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
  12. Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  13. Confocal Imaging Core facility, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  14. Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
  15. Division of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA.
  16. Liver Center, Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts, USA.

PMID: 34662439 DOI: 10.1002/hep.32203

Abstract

BACKGROUND AND AIMS: 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.

APPROACH AND RESULTS: 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.

CONCLUSIONS: 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.

© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.

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