What has been described as a worldwide “pandemic” of obesity is often accompanied by a buildup of fatty tissue in the liver that can lead to liver failure and cancer, and which contributes to cardiovascular and kidney disease.
Currently, methods to detect early, obesity-related accumulation of fat in the liver other than a liver biopsy — the surgical removal of liver tissue for microscopic examination — are limited. But there is hope.
An international research team led by Vanderbilt University Medical Center, the Translational Genomics Research Institute (TGen) in Phoenix, Massachusetts General Hospital, and the University of Edinburgh has identified a “proteomic signature” of circulating proteins in the blood that reflect the progression of metabolic-associated steatotic (fatty) liver disease, or MASLD.
Their findings, reported Dec. 17 in the journal Cell Reports Medicine, open the door to the first noninvasive “liquid biopsy” of the liver, which, in turn, could lead to the discovery of diagnostic biomarkers and to new ways to stop and reverse MASLD before it causes irreversible damage.
“By looking at blood-based markers, we can detect changes that reflect the liver’s condition, potentially reducing the need for biopsies,” said the paper’s corresponding author, Ravi Shah, MD, professor of Medicine and director of Clinical and Translational Research in the Division of Cardiovascular Medicine at VUMC.
“This approach may open up new possibilities for screening for and tracking metabolic liver disease, particularly in large populations where invasive biopsies are clinically risky,” said Shah, who holds the Gottlieb C. Friesinger II Chair in Cardiovascular Medicine.
The study applied a translational approach, including multimodal imaging and broad proteomic profiling, to identify proteins largely encoded by genes in the liver that are expressed differentially during progressive stages of fat accumulation (steatosis).
“Our team used single-cell and spatial transcriptomics approaches to localize the steatosis-associated genes within primary liver tissue and examine how they differ between healthy and steatotic livers,” said Nicholas Banovich, PhD, director of TGen’s Bioinnovation and Genome Sciences Division, and with Shah, one of the paper’s four senior authors.
The researchers correlated proteomic data (levels of circulating proteins previously implicated in the development of MASLD) with noninvasive imaging studies to determine the extent of fat accumulation in three research cohorts totaling about 5,000 individuals.
They mapped the expression of implicated proteins across the liver at different stages of disease, then tested the accuracy of the resulting “proteomic signature” against the clinical outcomes of more than 26,000 individuals whose biological samples are stored in the UK Biobank
To validate the specificity of the biomarkers they had discovered, they created a “liver-on-a-chip” model and measured changes in gene expression in laboratory-grown liver cells following exposure to fatty acids.
“By contextualizing these changes, we are able to shift from predictors of disease to potential mechanisms,” said TGen’s Niran Hadad, PhD, a co-first author on the study. TGen is an affiliate of City of Hope, based in Duarte, California.
In addition to Hadad, the paper’s first authors were Andrew Perry, MD, Eric Farber-Eger and Rashedeh Roshani (VUMC/Vanderbilt University School of Medicine), Emeli Chatterjee, PhD (National Institute on Aging), and Maria Jimenez-Ramos (Harvard Medical School/Beth Israel Deaconess Medical Center).
The other senior authors were Jonathan Fallowfield, PhD, of the University of Edinburgh Institute for Regeneration and Repair, and Saumya Das, MD, PhD, of the MGH Cardiovascular Research Center.
Other VUMC co-authors were Lindsey Stolze, PhD, Michael Betti, Shilin Zhao, PhD, Shi Huang, PhD, Kaushik Amancherla, MD, Samuel Bailin, MD, MSCI, Curtis Gabriel, MD, PhD, John Koethe, MD, MSCI, Jeffrey Carr, MD, MSc, Nataraja Sarma Vaitinadin, MBBS, PhD, MPH, Jane Freedman, MD, Kahraman Tanriverdi, PhD, Jennifer Below, PhD, Quinn Wells, MD, PharmD, MSCI, and Eric Gamazon, PhD, MS.
The research was supported in part by National Institutes of Health grants R01HL122477, R35HL150807, UH3TR002878 and UL1TR000371, and by Innovate UK and the Medical Research Council Precision Medicine Doctoral Training Program.
TGen and VUMC researchers previously have collaborated to determine the genetic basis for pulmonary fibrosis, an incurable respiratory disorder characterized by scarring and loss of functional lung tissue. Shah and colleagues have used proteomic profiling to predict cardiovascular fitness.
