Advanced glycation end-products as mediators of the aberrant crosslinking of extracellular matrix in scarred liver tissue.
Cheng LyuWenyu KongZhiqiang LiuSihan WangPeng ZhaoKaini LiangYudi NiuWei YangCanhong XiangXiaoyu HuXueming LiYanan DuPublished in: Nature biomedical engineering (2023)
The extracellular matrix of cirrhotic liver tissue is highly crosslinked. Here we show that advanced glycation end-products (AGEs) mediate crosslinking in liver extracellular matrix and that high levels of crosslinking are a hallmark of cirrhosis. We used liquid chromatography-tandem mass spectrometry to quantify the degree of crosslinking of the matrix of decellularized cirrhotic liver samples from patients and from two mouse models of liver fibrosis and show that the structure, biomechanics and degree of AGE-mediated crosslinking of the matrices can be recapitulated in collagen matrix crosslinked by AGEs in vitro. Analyses via cryo-electron microscopy and optical tweezers revealed that crosslinked collagen fibrils form thick bundles with reduced stress relaxation rates; moreover, they resist remodelling by macrophages, leading to reductions in their levels of adhesion-associated proteins, altering HDAC3 expression and the organization of their cytoskeleton, and promoting a type II immune response of macrophages. We also show that rosmarinic acid inhibited AGE-mediated crosslinking and alleviated the progression of fibrosis in mice. Our findings support the development of therapeutics targeting crosslinked extracellular matrix in scarred liver tissue.
Keyphrases
- extracellular matrix
- liquid chromatography tandem mass spectrometry
- liver fibrosis
- electron microscopy
- immune response
- end stage renal disease
- type diabetes
- poor prognosis
- ejection fraction
- simultaneous determination
- chronic kidney disease
- insulin resistance
- wound healing
- inflammatory response
- metabolic syndrome
- high fat diet induced
- small molecule
- toll like receptor
- cell migration
- high speed
- stress induced
- heat stress
- histone deacetylase