Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention
Background Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacki...
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Wiley
2025-05-01
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| Series: | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
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| Online Access: | https://www.ahajournals.org/doi/10.1161/JAHA.124.037100 |
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| author | Bassim El‐Sabawi Kahraman Tanriverdi Priya Gajjar Matthew Nayor Joshua M. Landman Jennifer E. Below Madeleine Haff Michelle Long Mark Ezpeleta Jane E. Freedman Krista Varady Ravi Shah Andrew S. Perry |
| author_facet | Bassim El‐Sabawi Kahraman Tanriverdi Priya Gajjar Matthew Nayor Joshua M. Landman Jennifer E. Below Madeleine Haff Michelle Long Mark Ezpeleta Jane E. Freedman Krista Varady Ravi Shah Andrew S. Perry |
| author_sort | Bassim El‐Sabawi |
| collection | DOAJ |
| description | Background Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort. Methods and Results We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3‐month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross‐sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, P<0.001) and insulin resistance (homeostatic model assessment for insulin resistance, Spearman rho=0.39, P=0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, P<0.001). Moreover, cross‐sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis. Conclusions These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study. |
| format | Article |
| id | doaj-art-d7ac467f371c48cf980948998d6b445d |
| institution | OA Journals |
| issn | 2047-9980 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease |
| spelling | doaj-art-d7ac467f371c48cf980948998d6b445d2025-08-20T01:54:08ZengWileyJournal of the American Heart Association: Cardiovascular and Cerebrovascular Disease2047-99802025-05-01141010.1161/JAHA.124.037100Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic InterventionBassim El‐Sabawi0Kahraman Tanriverdi1Priya Gajjar2Matthew Nayor3Joshua M. Landman4Jennifer E. Below5Madeleine Haff6Michelle Long7Mark Ezpeleta8Jane E. Freedman9Krista Varady10Ravi Shah11Andrew S. Perry12Vanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USAVanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USASections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USASections of Cardiovascular Medicine and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USAVanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USAVanderbilt Genetics Institute Vanderbilt University Medical Center Nashville TN USASections of Gastroenterology and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USASections of Gastroenterology and Preventive Medicine and Epidemiology, Department of Medicine Boston University School of Medicine Boston MA USAUniversity of Illinois at Chicago Chicago IL USAVanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USAUniversity of Illinois at Chicago Chicago IL USAVanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USAVanderbilt Translational and Clinical Cardiovascular Research Center Vanderbilt University School of Medicine Nashville TN USABackground Weight reduction through lifestyle, activity, and dietary interventions are the mainstay of initial therapy for metabolic dysfunction associated steatotic liver disease. Data on the relative effectiveness and metabolic pathways linking weight loss and decreased hepatic steatosis are lacking. We sought to identify coordinated changes between the circulating proteome and hepatic steatosis within a randomized clinical trial of alternate day fasting and exercise and prioritize proteins relevant to hepatic steatosis within a broader context using a community cohort. Methods and Results We quantified a broad cardiometabolic proteome (>300 proteins) in 67 individuals randomized in a 2×2 factorial design to alternate day fasting and exercise before and after the 3‐month intervention to identify proteomic signatures of hepatic steatosis (measured by magnetic resonance imaging proton density fat fraction). Then, we analyzed the cross‐sectional relationship of overlapping proteins (≈170) with hepatic attenuation (a computed tomographic technique linked to steatosis) in 707 participants from a community cohort. Principal component analysis demonstrated a proteomic signature associated with intrahepatic triglyceride content (Spearman rho=0.55, P<0.001) and insulin resistance (homeostatic model assessment for insulin resistance, Spearman rho=0.39, P=0.001). Changes in this proteomic signature were associated with changes in intrahepatic triglyceride content over the intervention period (beta=0.12, P<0.001). Moreover, cross‐sectional analysis of overlapping proteins with hepatic attenuation in the community cohort showed generally, directionally consistent associations with hepatic steatosis. Conclusions These findings highlight the potential for broad proteomic profiling in small nutritional interventional studies with serial phenotyping alongside confirmatory large cohort epidemiology to prioritize targets of hepatic steatosis and cardiometabolic risk for mechanistic study.https://www.ahajournals.org/doi/10.1161/JAHA.124.037100caloric restrictionmedical weight lossmetabolic dysfunction associated steatotic liver diseasenonalcoholic fatty liver diseaseproteomics |
| spellingShingle | Bassim El‐Sabawi Kahraman Tanriverdi Priya Gajjar Matthew Nayor Joshua M. Landman Jennifer E. Below Madeleine Haff Michelle Long Mark Ezpeleta Jane E. Freedman Krista Varady Ravi Shah Andrew S. Perry Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease caloric restriction medical weight loss metabolic dysfunction associated steatotic liver disease nonalcoholic fatty liver disease proteomics |
| title | Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention |
| title_full | Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention |
| title_fullStr | Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention |
| title_full_unstemmed | Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention |
| title_short | Circulating Proteomics Identifies a Dynamic Profile of Hepatic Steatosis During Metabolic Intervention |
| title_sort | circulating proteomics identifies a dynamic profile of hepatic steatosis during metabolic intervention |
| topic | caloric restriction medical weight loss metabolic dysfunction associated steatotic liver disease nonalcoholic fatty liver disease proteomics |
| url | https://www.ahajournals.org/doi/10.1161/JAHA.124.037100 |
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