Cardiovascular

Enhydrin from yacon attenuates atherosclerosis by modulating the FABP5/PPARγ/ABCA1 axis: An integrated multi-omics and in vivo validation.

TL;DR

Integrative multi-omics analysis pinpointed FABP5 as a promising novel target for yacon-derived Enhydrin in atherosclerosis, with in vivo validation showing Enhydrin markedly downregulated FABP5 and upregulated PPARγ and ABCA1, suggesting this axis mediates its anti-atherosclerotic activity.

Key Findings

Network pharmacology analysis of yacon identified 12 active constituents, 384 targets, and seven core targets relevant to atherosclerosis, with FABP5 ranked highest.

  • Active constituents and targets were curated from literature, TCMSP, and SwissTargetPrediction databases.
  • Lipid/AS genes were sourced from GeneCards, OMIM, and GEO datasets.
  • Filtering was performed via limma, WGCNA, LASSO, randomForest, and SVM-RFE machine learning methods.
  • Seven core targets were identified including AURKA, MMP9, and FABP5, with FABP5 top-ranked.
  • Immune infiltration and external validation were used to confirm hub gene relevance.

Single-cell RNA sequencing analysis prioritized FABP5 as the primary target for yacon's anti-atherosclerotic effects.

  • scRNA-seq data was used to refine and prioritize targets identified through network pharmacology.
  • FABP5 emerged as the top candidate target from the scRNA-seq analysis.
  • This finding was corroborated by the machine learning-based ranking of hub genes.

Molecular docking and dynamics simulations identified Enhydrin as the strongest FABP5 binder among yacon's active constituents.

  • Docking and molecular dynamics simulations were used to quantify compound-FABP5 interactions.
  • Enhydrin, a sesquiterpene lactone constituent of yacon, showed the highest binding affinity to FABP5.
  • These computational findings guided selection of Enhydrin for in vivo validation.

Enhydrin administration in HFD-fed ApoE-/- mice reduced hepatic lipid accumulation and improved serum lipid profiles.

  • In vivo efficacy was tested in high-fat diet (HFD)-fed ApoE-/- mice.
  • Enhydrin treatment was associated with decreased serum triacylglycerol (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels.
  • Enhydrin treatment was associated with increased high-density lipoprotein cholesterol (HDL-C) levels.
  • Reduced hepatic lipid accumulation was observed, assessed by Oil Red O, H&E, and Masson histological staining.

Histopathological analysis of arterial tissues from Enhydrin-treated mice showed attenuated vascular lipid deposition and delayed atherosclerotic lesion progression.

  • Arterial tissue analysis was performed using Oil Red O, H&E, and Masson staining.
  • Enhydrin treatment was associated with markedly reduced vascular lipid deposition.
  • Atherosclerotic lesion progression was delayed in Enhydrin-treated animals compared to controls.

Enhydrin downregulated FABP5, reduced abnormal fatty acid trafficking, and upregulated PPARγ and ABCA1, consistent with enhanced cholesterol efflux.

  • Molecular assays included RT-qPCR, Western blot, and immunofluorescence.
  • FABP5 downregulation was observed across multiple assay types.
  • Upregulation of PPARγ and ABCA1 was detected, suggesting activation of the FABP5/PPARγ/ABCA1 axis.
  • These molecular changes were interpreted as reflecting enhanced cholesterol efflux from vascular tissues.
  • Reduced abnormal fatty acid trafficking was also observed in association with FABP5 downregulation.

What This Means

This research suggests that Enhydrin, a natural compound found in yacon (an Andean root vegetable), may help slow the development of atherosclerosis — the buildup of fatty plaques in blood vessel walls that underlies heart attacks and strokes. The researchers used a combination of computer-based analysis (including machine learning and analysis of gene activity in individual cells) to identify a protein called FABP5 as a key molecular target involved in both atherosclerosis and the effects of yacon's active ingredients. They then confirmed computationally that Enhydrin binds strongly to FABP5, and tested its effects in mice prone to atherosclerosis fed a high-fat diet. In the animal experiments, mice treated with Enhydrin showed lower levels of harmful blood fats (triglycerides, total cholesterol, and LDL cholesterol), higher levels of protective HDL cholesterol, less fat buildup in the liver, and reduced fatty plaque formation in their arteries. At the molecular level, Enhydrin reduced the activity of FABP5, which is involved in transporting fatty acids inside cells, and increased the activity of two other proteins — PPARγ and ABCA1 — that help move cholesterol out of cells, a process called cholesterol efflux. Together, these changes suggest Enhydrin works through a specific biological pathway (FABP5/PPARγ/ABCA1) to improve fat metabolism and reduce arterial plaque buildup. This research suggests that Enhydrin from yacon could be a candidate for further development as a treatment for atherosclerosis, and that FABP5 may be a useful drug target. However, these findings are based on animal and computational studies, and further research — including clinical trials in humans — would be needed before any clinical applications could be established.

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Citation

Tian C, He G, Zu L, Bi C, Wu Z, Sun J. (2026). Enhydrin from yacon attenuates atherosclerosis by modulating the FABP5/PPARγ/ABCA1 axis: An integrated multi-omics and in vivo validation.. Biochimica et biophysica acta. Molecular and cell biology of lipids. https://doi.org/10.1016/j.bbalip.2026.159751