Abstract
The extracellular matrix (ECM) is a highly dynamic structural network and plays an essential role in cell behavior and regulation during metabolic homeostasis and obesity progression. Abnormal ECM remodeling impairs adipocyte plasticity required for diverse cellular functions. Collagen XV (ColXV) is a proteoglycan localized to the outermost layer of basement membranes (BMs) and forms a bridge between the BMs and the fibrillar collagen matrix. Nevertheless, how ColXV affects ECM composition and the reason for subsequent adipocyte apoptosis is still unclear. This report found, through RNA-seq data, that ColXV is linked to cell growth and ECM remodeling. Findings show that, in response to excessive expression of extracellular ColXV, the AMPK/mTORC1 pathway is strongly activated and triggers a cascade of mitochondrial apoptosis. This is the first study to make use of ECM three-dimensional reconstruction, based on decellularization in the adipose tissues and the study reveals that ColXV is an activation factor that alters ECM remodeling in adipose tissues. It was also demonstrated that the fibroblast growth factor 2 (FGF2)/fibroblast growth factor receptor 1 (FGFR1) axis involved in ECM remodeling is suppressed by ColXV due to reduction of FGF2 translocation to FGFR1. Furthermore, ColXV induced remodeling of ECM preceding apoptosis and continued to induce apoptosis in adipocytes. Collectively, our findings establish ColXV as a basement membrane collagen with homology to ColXVIII, indicating that it is one of the positive regulators for inducing ECM remodeling and further promoting adipocyte apoptosis.
Highlights
The extracellular matrix (ECM) is a highly dynamic three-dimensional structure, continuously undergoing remodeling processes wherein ECM components are degraded, deposited, or otherwise modified
Further analyses revealed that alteration of the expression of signature genes by Collagen XV (ColXV) was associated with B-cell lymphoma family and ECM remodeling, especially Bcl-2, Col1a1, Col6a1, MMP-2 and MMP-9 (Figure 1A,B)
MMP-2 and MMP-9, which are activators of ECM dynamic changes, were decreased by forced Col15a1 (Figure 1C). These findings showed that ColXV was closely linked to apoptosis and ECM remodeling
Summary
The extracellular matrix (ECM) is a highly dynamic three-dimensional structure, continuously undergoing remodeling processes wherein ECM components are degraded, deposited, or otherwise modified. The ECM undergoes remodeling by cells in response to a variety of external and internal stimuli in adipocytes. It especially undergoes a strong structural remodeling when fat mass increases, as seen in obesity [1]. It has been reported that over the course of obesity development, increased interstitial and peripheral ECM deposition in adipose tissues decreases matrix flexibility and reduces tissue plasticity, leading to dysfunction in adipocytes. Lack of collagen VI (Col6a1) exhibited reduced cell apoptosis accompanied by enlarged adipocytes in ob/ob mice. The volume and number of adipocytes in adipose tissues, which highly depend on the ECM remodeling and apoptosis processes, determine obesity. The intrinsic interaction between ECM remodeling and apoptosis still needs to be further investigated
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