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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins B
  • Cardiovascular Diseases* / epidemiology
  • Cardiovascular Diseases* / etiology
  • Cholesterol, VLDL / metabolism
  • Heart Disease Risk Factors
  • Lipoproteins, VLDL
  • Liver / pathology
  • Mice
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Phospholipases / metabolism
  • Risk Factors
  • Triglycerides / metabolism


  • Apolipoproteins B
  • Cholesterol, VLDL
  • Lipoproteins, VLDL
  • Triglycerides
  • Phospholipases