Lipidomic and Multi-Omics Profiling of Fatty Liver Disease in People With and Without HIV (MASLD)

Multi-Omics Characterization of Lipid Metabolic Reprogramming in People With HIV Versus HIV-Negative Metabolic Dysfunction-Associated Steatotic Liver Disease

Metabolic dysfunction-associated steatotic liver disease (MASLD), commonly known as fatty liver disease, is increasingly prevalent worldwide. People living with HIV (PWH) face a higher risk of developing MASLD due to chronic immune activation and long-term antiretroviral therapy, yet whether the underlying biological changes differ from those in HIV-negative individuals with MASLD remains unknown.

This prospective observational study will enroll three groups: PWH with MASLD, HIV-negative individuals with MASLD, and healthy controls without liver disease. A single fasting blood sample will be collected from each participant. Using targeted lipidomics, proteomics, and transcriptomics platforms, researchers will compare plasma molecular profiles across the three groups to identify MASLD-specific lipid signatures, characterize metabolic pathway dysregulation, and discover potential blood-based biomarkers for non-invasive diagnosis of MASLD.

Findings from this study may help explain how HIV infection alters lipid metabolism in the context of MASLD and support the development of HIV-specific diagnostic tools for fatty liver disease.

Study Overview

• Status: Not yet recruiting
• Conditions: HIV (Human Immunodeficiency Virus); MASLD

Detailed Description

MASLD is characterized by hepatic lipid accumulation driven by metabolic dysfunction, and its pathophysiology involves extensive lipid metabolic reprogramming - including dysregulation of triglycerides, diacylglycerols, ceramides, and phosphatidylcholines. In people living with HIV (PWH), the metabolic burden imposed by chronic immune activation and long-term antiretroviral therapy (ART) further disrupts circulating lipid homeostasis, potentially creating a distinct pathophysiological profile compared to HIV-negative individuals with MASLD. However, the molecular differences between HIV-associated and HIV-negative MASLD have not been systematically characterized.

This prospective, observational, cross-sectional study enrolls three groups: (1) PWH with MASLD, (2) HIV-negative individuals with MASLD, and (3) healthy controls matched for age, sex, and BMI. All participants are recruited from Shanghai Public Health Clinical Center and affiliated health examination centers. A single fasting peripheral blood sample (10 mL) is collected from each participant, from which plasma is isolated and stored at -80°C until analysis.

Plasma samples will undergo multi-omics profiling including:

Targeted lipidomics: quantitative analysis of core lipid classes (free fatty acids, ceramides, sphingomyelins, triglycerides, diacylglycerols, phosphatidylcholines) using UPLC-MS/MS in multiple reaction monitoring (MRM) mode Proteomics: plasma protein profiling to identify disease-associated protein expression changes Transcriptomics: gene expression analysis to characterize transcriptional alterations associated with MASLD in the context of HIV infection Differential lipid features will be identified using multivariate analysis (PCA, OPLS-DA) and univariate filtering (VIP > 1, |FC| > 1.5, FDR < 0.05). KEGG and LipidMaps pathway enrichment analyses will reveal key metabolic pathways involved in lipid reprogramming. Correlations between lipid signatures and clinical parameters will be examined using Spearman correlation analysis. ROC curve analysis and logistic regression will be used to evaluate the diagnostic performance of candidate biomarkers.

This study aims to: (1) establish a comprehensive plasma lipidomic and multi-omics atlas of MASLD in PWH versus HIV-negative individuals; (2) identify HIV-specific lipid dysregulation patterns; and (3) discover novel, non-invasive biomarkers for MASLD diagnosis applicable to the HIV-infected population.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Yinzhong Shen, PhD; Phone Number: +8618916113951; Email: shenyinzhong@shphc.org.cn
• Study Contact Backup: Name: Wei Xu, PhD; Phone Number: +8613660308971; Email: 24111300008@m.fudan.edu.cn

Study Locations

• China
  • Shanghai Municipality
    • Shanghai, Shanghai Municipality, China, 201508
      • Shanghai Public Health Clinical Center
      • Contact: Yinzhong Shen, PhD; Phone Number: +86 18916113951; Email: shenyinzhong@shphc.org.cn
      • Contact: Wei Xu, PhD; Phone Number: +86 13660308971; Email: 24111300008@m.fudan.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Participants are recruited from a single tertiary hospital (Shanghai Public Health Clinical Center): (1) treatment-naive people with HIV and MASLD from the outpatient Department of Infection and Immunity; (2) HIV-negative individuals with MASLD identified through the hospital's Health Management Center; and (3) healthy controls without liver disease from the same Health Management Center, matched to MASLD groups by age, sex, and BMI.

Description

Inclusion Criteria:

• Age 18-80 years
• Able to provide written informed consent and cooperate with blood sample collection and clinical data recording

For Group 1 (Treatment-naive people with HIV and MASLD):

• Confirmed HIV infection with no prior antiretroviral therapy (treatment-naive)
• Diagnosis of MASLD per the 2024 Chinese Guidelines: hepatic steatosis confirmed by imaging or histology (≥5% macrovesicular steatosis), exclusion of excessive alcohol consumption (>210 g/week for men, >140 g/week for women), and at least one metabolic cardiovascular risk factor

For Group 2 (HIV-negative individuals with MASLD):

• HIV-negative
• Diagnosis of MASLD as defined above

For Group 3 (Healthy Controls):

• HIV-negative
• Normal liver morphology on abdominal ultrasonography within the past year, with no evidence of hepatic steatosis
• Matched to MASLD groups by age (within 5 years), sex, and BMI (within 3 kg/m²)

Exclusion Criteria:

• Chronic liver disease with decompensated cirrhosis, hepatic malignancy, or history of liver transplantation
• Pregnancy or lactation
• Active severe infectious disease (other than HIV for Group 1)
• Severe critical illness or major organ failure

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
PWH with MASLD; People with HIV diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD), enrolled from the outpatient clinic of Shanghai Public Health Clinical Center.
HIV negative with MASLD; HIV-negative individuals diagnosed with MASLD, enrolled from Shanghai Public Health Clinical Center and affiliated health examination centers.
healthy controls; HIV-negative individuals without liver disease, matched to MASLD groups by age, sex, and BMI, enrolled from affiliated health examination centers.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of differentially abundant plasma lipid species identified by targeted lipidomics (UPLC-MS/MS)	Number of plasma lipid species showing statistically significant differential abundance among the three groups (treatment-naïve people with HIV and MASLD, HIV-negative people with MASLD, and healthy controls). Lipid species across core lipid classes (free fatty acids, ceramides, sphingomyelins, triglycerides, diacylglycerols, and phosphatidylcholines) are quantified by targeted lipidomics using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) in multiple reaction monitoring (MRM) mode, with quality-control samples and internal standards (e.g., TAG 17:0, Cer d18:1/17:0; RSD <15%). A lipid species is counted as differentially abundant if it meets fold change ≥1.5 or ≤0.67, and FDR <0.05.	At enrollment (single time point, cross-sectional)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of differentially abundant plasma proteins identified by quantitative proteomics	Number of plasma proteins showing statistically significant differential abundance among the three groups (treatment-naïve people with HIV and MASLD, HIV-negative people with MASLD, and healthy controls), quantified by mass spectrometry-based (DIA) proteomics. A protein is counted as differentially abundant if it meets |log2 fold change| >1 and adjusted p <0.05.	At enrollment
Number of differentially expressed genes in PBMCs identified by RNA sequencing	Number of genes showing statistically significant differential expression in peripheral blood mononuclear cells (PBMCs) among the three groups (treatment-naïve people with HIV and MASLD, HIV-negative people with MASLD, and healthy controls), quantified by RNA sequencing. A gene is counted as differentially expressed if it meets |log2 fold change| >1 and FDR <0.05.	At enrollment

Collaborators and Investigators

• Sponsor: Yinzhong Shen
• Investigators: Principal Investigator: Yinzhong Shen, Shanghai Public Health Clinical Center, Shanghai, Shanghai 201508

Publications and helpful links

General Publications

• Bo T, Gao L, Yao Z, Shao S, Wang X, Proud CG, Zhao J. Hepatic selective insulin resistance at the intersection of insulin signaling and metabolic dysfunction-associated steatotic liver disease. Cell Metab. 2024 May 7;36(5):947-968. doi: 10.1016/j.cmet.2024.04.006.
• Rui L, Lin JD. Reprogramming of Hepatic Metabolism and Microenvironment in Nonalcoholic Steatohepatitis. Annu Rev Nutr. 2022 Aug 22;42:91-113. doi: 10.1146/annurev-nutr-062220-105200. Epub 2022 May 18.
• Waters DD, Hsue PY. Lipid Abnormalities in Persons Living With HIV Infection. Can J Cardiol. 2019 Mar;35(3):249-259. doi: 10.1016/j.cjca.2018.11.005. Epub 2018 Nov 15.
• Horn P, Tacke F. Metabolic reprogramming in liver fibrosis. Cell Metab. 2024 Jul 2;36(7):1439-1455. doi: 10.1016/j.cmet.2024.05.003. Epub 2024 May 31.

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2026
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): September 1, 2026

Study Registration Dates

• First Submitted: May 31, 2026
• First Submitted That Met QC Criteria: June 5, 2026
• First Posted (Actual): June 11, 2026

Study Record Updates

• Last Update Posted (Actual): June 11, 2026
• Last Update Submitted That Met QC Criteria: June 5, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: HIV; lipidomics; MASLD
• Additional Relevant MeSH Terms: Blood-Borne Infections; Urogenital Diseases; Genital Diseases; Immune System Diseases; Infections; RNA Virus Infections; Virus Diseases; Communicable Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; Immunologic Deficiency Syndromes; Slow Virus Diseases; HIV Infections; Acquired Immunodeficiency Syndrome
• Other Study ID Numbers: GKT1341

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be shared publicly to protect the privacy and confidentiality of people living with HIV, given the sensitive nature of HIV status and the potential risk of participant re-identification in this population. De-identified data may be made available from the corresponding author upon reasonable request and with appropriate ethical approval.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No