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Abstract Details
Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles
Hepatology. 2022 Oct;76(4):1121-1134. doi: 10.1002/hep.32427. Epub 2022 Mar 17.
2CIC bioGUNE, BRTA, CIBERehd, Derio, Bizkaia, Spain.
3Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California, USA.
4Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.
5Center for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri, USA.
6Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute, Donostia University Hospital, Donostia, Spain.
7First Faculty of Medicine, Charles University, Prague, Czech Republic.
8Departamento de Gastroenterologia, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago de Chile, Chile.
9Marqués de Valdecilla University Hospital, Cantabria University, Santander, Spain.
10Department of Digestive System, Osakidetza Basque Health Service, Donostia University Hospital, San Sebastian, Spain.
11Department of Medicine II, Saarland University Medical Center, Homburg, Germany.
12Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland.
13Department of Metabolic Health Research, Netherlands Organization for Applied Scientific Research, Leiden, The Netherlands.
14Alcalá University School of Medicine and Health Sciences, University Hospital Principe de Asturias, Madrid, Spain.
15Galmed Pharmaceuticals, Tel Aviv, Israel.
16Department of Digestive Disease, Clinic University Hospital, University Hospital of Valladolid, Valladolid, Spain.
17Valme University Hospital, CiBERehd, Sevilla, Spain.
18University of the Basque Country, CIBERehd, IKERBASQUE, Donostia, Spain.
19Centro de Envejecimiento y Regeneración, Santiago, Chile.
20Division of Endocrinology, Diabetes and Metabolism, University of Florida and Malcom Randall VAMC, Gainesville, Florida, USA.
21Gastroenterology Department, University of Turin, Turin, Italy.
22Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle Upon Tyne, UK.
23Newcastle NIHR Biomedical Research Center, Newcastle Upon Tyne Hospitals NHS Trust, Newcastle Upon Tyne, UK.
Abstract
Background and aims: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors.
Approach and results: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A.
Conclusions: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.