Plasma proteomic signatures of liver steatosis and fibrosis in people living with HIV: a cross-sectional study.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL EBioMedicine Pub Date : 2024-10-18 DOI:10.1016/j.ebiom.2024.105407

Louise E van Eekeren, Quirijn de Mast, Elise M G Meeder, Adriana Navas, Albert L Groenendijk, Marc J T Blaauw, Wilhelm A J W Vos, Nadira Vadaq, Jéssica C Dos Santos, Joost Rutten, Niels P Riksen, Jan van Lunzen, Gert Weijers, Mihai G Netea, André J A M van der Ven, Eric T T L Tjwa, Leo A B Joosten

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Abstract

Background: Insights into the mechanisms driving metabolic dysfunction-associated steatotic liver disease (MASLD) in people living with HIV (PLHIV) remain limited. Plasma proteomics holds promise for biomarker discovery and the elucidation of biological mechanisms.

Methods: We performed cross-sectional analyses on data from 1036 virally suppressed PLHIV using antiretroviral treatment (ART) from the Dutch multi-centre 2000HIV cohort. Participants underwent transient elastography to assess liver steatosis (controlled attenuation parameter (CAP) ≥263 dB/m) and -fibrosis (liver stiffness measurement (LSM) ≥7.0 kPa). Plasma protein concentrations (n = 2367) (Olink® Explore Panel) were compared between PLHIV with vs. without liver steatosis and PLHIV with vs. without fibrosis. Enriched pathways (using GO, KEGG and Reactome libraries) and correlations with clinical characteristics were assessed, and analyses were stratified by BMI category. In addition, concentrations of 242 proteins were compared between individuals ("controls") with and without liver steatosis (ratio of methylene:methylene and water >5.6% on magnetic resonance spectroscopy) from a separate cohort (300-OB), all having a BMI >26 kg/m².

Findings: Steatosis and fibrosis were associated with 67/2367 (2.2%) and 17/2367 (0.7%) differentially expressed proteins (DEP), respectively, enriched in mostly metabolic pathways. Immunoglobulin superfamily member 9 (IGSF9) was amongst the top DEP associated with both steatosis and fibrosis. Stratifying by BMI revealed 8/2367 DEP associated with steatosis in lean- and 12/2367 DEP in overweight/obese individuals, with two shared DEP (IGSF9 and GHR). Conversely, protein signatures of overweight/obese PLHIV (32/242 DEP) and overweight/obese HIV-uninfected individuals (32/242 DEP) exhibited substantial overlap with 16 shared DEP. Notably, DEP correlated with HIV characteristics in lean individuals but not in overweight/obese PLHIV.

Interpretation: Lean and overweight/obese PLHIV exhibit distinct proteomic signatures associated with liver steatosis, with the former being more strongly correlated with HIV-specific factors and ART. In addition, we identified a protein, IGSF9, strongly related to liver fibrosis and steatosis across BMI categories.

Funding: The 2000HIV study is funded by ViiV Healthcare.

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艾滋病病毒感染者肝脏脂肪变性和纤维化的血浆蛋白质组特征：一项横断面研究。

背景：对艾滋病病毒感染者（PLHIV）代谢功能障碍相关性脂肪性肝病（MASLD）发病机制的了解仍然有限。血浆蛋白质组学有望发现生物标志物并阐明生物机制：我们对荷兰多中心 2000HIV 队列中 1036 名使用抗逆转录病毒疗法（ART）的病毒已被抑制的 PLHIV 的数据进行了横断面分析。参与者接受了瞬态弹性成像检查，以评估肝脏脂肪变性（控制衰减参数 (CAP) ≥ 263 dB/m）和肝纤维化（肝脏硬度测量 (LSM) ≥ 7.0 kPa）。比较了有肝脂肪变性和无肝脂肪变性的 PLHIV 和有肝纤维化和无肝纤维化的 PLHIV 之间的血浆蛋白质浓度（n = 2367）（Olink® Explore Panel）。评估了丰富的通路（使用 GO、KEGG 和 Reactome 库）以及与临床特征的相关性，并按体重指数类别进行了分层分析。此外，还比较了来自一个独立队列（300-OB）的有肝脏脂肪变性（磁共振波谱显示亚甲基：亚甲基和水的比率大于 5.6%）和无肝脏脂肪变性（磁共振波谱显示亚甲基：亚甲基和水的比率大于 5.6%）的个体（"对照组"）之间 242 种蛋白质的浓度，所有个体的体重指数均大于 26 kg/m2：脂肪变性和纤维化分别与 67/2367 个（2.2%）和 17/2367 个（0.7%）差异表达蛋白（DEP）有关，这些蛋白主要富集在代谢途径中。免疫球蛋白超家族成员 9 (IGSF9) 是与脂肪变性和纤维化相关的最大差异表达蛋白之一。按体重指数（BMI）分层后发现，瘦人中有8/2367个DEP与脂肪变性相关，而超重/肥胖者中有12/2367个DEP与脂肪变性相关，其中有两个DEP是共用的（IGSF9和GHR）。相反，超重/肥胖 PLHIV（32/242 DEP）和超重/肥胖 HIV 未感染者（32/242 DEP）的蛋白质特征与 16 个共有 DEP 有很大的重叠。值得注意的是，瘦人的 DEP 与 HIV 特征相关，而超重/肥胖 PLHIV 的 DEP 与 HIV 特征无关：瘦弱和超重/肥胖的艾滋病毒感染者表现出与肝脏脂肪变性相关的不同蛋白质组特征，前者与艾滋病毒特异性因素和抗逆转录病毒疗法的相关性更强。此外，我们还发现了一种与肝纤维化和脂肪变性密切相关的蛋白质--IGSF9，它跨越了体重指数的类别：2000HIV 研究由 ViiV Healthcare 资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.