OR02-1 Differences in HDL Particle Composition in Patients with Nonalcoholic Fatty Liver Disease (NAFLD) and Advanced Liver Fibrosis May Explain Higher Cardiovascular Risk
Authors: Collier Timothy , Cusi Kenneth , Kalavalapalli Srilaxmi , McPhaul Michael , Pearce Ryan , Bril Fernando 
Published: November 2022

Abstract

The severity of liver fibrosis in patients with NAFLD is a strong predictor of cardiovascular mortality, independently of other well-known cardiovascular risk factors. However, the exact mechanisms leading to cardiovascular disease in patients with advanced liver fibrosis remain incompletely understood. As many of the apolipoproteins are synthesized in the liver, we hypothesized that lipoprotein composition may explain the association between liver disease and cardiovascular disease. Patients (n=185) underwent a liver proton magnetic resonance spectroscopy (1H-MRS) to measure intrahepatic triglyceride accumulation and a percutaneous liver biopsy if they had NAFLD. Advanced lipid testing and lipoprotein subfractions were measured by ion mobility. ApoA-I containing particles (i.e., HDL) were isolated and a novel targeted proteomic approach utilizing multiple reaction monitoring (MRM) by liquid chromatography and tandem mass spectrometry (LC-MS/MS) was undertaken to measure HDL-bound proteins that are associated with lipid metabolism. Forty-five patients did not have NAFLD by 1H-MRS and were used as controls for comparisons. One-hundred and forty patients had a liver biopsy, and 26 were diagnosed with advanced fibrosis. Patients with vs. without advanced fibrosis had similar clinical characteristics (Age: 54±9 vs. 52±11 years; sex: 77% vs. 76% males; BMI: 34.2±4.3 vs. 34.5±4.6 kg/m2). Patients with advanced fibrosis had lower HDL-C (34±8 vs. 38±9 mg/dl, p=0.024) and higher A1c (7.3±1.3% vs. 6.5±1.0%, p&lt;0.001). No differences were observed in LDL or VLDL particle number or size between the groups. Patients with advanced fibrosis showed a mild reduction in HDL particle number, mainly driven by a reduction of small HDL particles (17269±3705 vs. 19057±4052 nmol/L, p=0.042). Despite this small difference in HDL particle number, a significant difference was observed in the proteomic signature of these particles. A panel of twenty-eight HDL-bound proteins were targeted and quantified by MRM LC-MS/MS. After adjustment for multiple comparisons based on a false discovery rate set at 10% (method of Benjamini-Krieger-Yekutieli), five proteins were found to be decreased in patients with advanced fibrosis (ApoC-I, ApoC-IV, ApoM, LCAT, and SAA4; all p&lt;0.017). No differences were observed in these proteins in patients with vs. without NAFLD or steatohepatitis (NASH). The pCAD index [range from 0-100] is a well-validated model based on measurement of 5 HDL-associated apolipoproteins (Apolipoproteins A-I, C-I, C-II, C-III, and C-IV) that is associated with presence of coronary artery disease and cardiovascular mortality. We observed a stepwise increase in pCAD index with every stage of fibrosis among patients with NAFLD (F0: 84±3; F1: 88±3; F2: 90±6; F3-4: 97±1, p=0.037).

Conclusion
Patients with NAFLD with advanced fibrosis showed significant differences in the apolipoproteomic composition of HDL particles, and this translated into increased cardiovascular risk based on pCAD index. Different lipoprotein composition and function may explain the link between liver disease and increased cardiovascular mortality in these patients.
Presentation: Saturday, June 11, 2022 11:30 a.m. - 11:45 a.m.