Endotrophin, a Key Marker and Driver for Fibroinflammatory Disease

Abstract

Our overview covers several key areas related to recent results obtained for collagen type VI and endotrophin (ETP). (1) An introduction to the history of ETP, including how it was identified, how it is released, and its function and potential receptors. (2) An introduction to the collagen family, with a focus on what differentiates collagen type VI from an evolutionary standpoint. (3) An overview of collagen type VI, the 6 individual chains (COL6A1, A2, A3, A4, A5, and A6), their differences and similarities, as well as their expression profiles and function. (4) A detailed analysis of COL6A3, including the cleaved product endotrophin, and what separates it from the other 5 collagen 6 molecules, including its suggested function based on insights gained from knockout and gain of function mouse models. (5) The pathology of ETP. What leads to its presence and release and what are the consequences thereof? (6) Functional implications of circulating ETP. Here we review the data with the functional roles of ETP in mind. (7) We propose that ETP is a mediator for fibrotic (or fibroinflammatory) disorders. Based on what we know about ETP, we have to consider it as a target for the treatment of fibrotic (or fibroinflammatory) disorders. What segment(s) of the patient population would most dramatically respond to an ETP-targeted intervention? How can we find the population that would profit most from an intervention? We aim to present a broad overview over the ETP field at large, providing an assessment of where the future research efforts need to be placed to tap into the vast potential of ETP, both as a marker and as a target in different diseases.

Keywords: ColVIα3; endotrophin; extracellular matrix; fibroinflammatory diseases.

Graphical abstract

Figure 1.

Phylogenetic tree of the 28 different collagen chains. The phylogenetic tree was generated by finding reviewed, human, collagen sequences (no isoforms were included) on the UniProt website (www.uniprot.org). The sequences were downloaded in the Fasta format and uploaded to the Clustal Omega website (https://www.ebi.ac.UK/Tools/msa/clustalo/, version 1.2.4) to generate a multiple sequence alignment file. The generated phylogenetic tree data was downloaded, and the phylogenetic tree was displayed by using FigTree software version 1.4.3 (http://tree.bio.ed.ac.UK/software/figtree/). The tree is presented as a midpoint rooted tree and proportionally transformed branches. The classic basement membrane collagens are dark green, while the newer basement membrane collagens are light green. Likewise, the classic fibrillar collagens are dark blue, and the newer fibrillar collagens light blue.

Figure 2.

Assembly of the type VI collagen beaded microfilaments. The process includes the release of the C5/ETP domain upon formation of the microfibrils. Inspired by (73).

Figure 3.

Diverse functions of ETP across various cell types. In this illustration, the multifaceted roles of ETP are depicted within different cellular environments. Obese adipocytes act as sources of EPT, influencing multiple cell types in various metabolic tissues/organs as well as tumor tissues. ETP exerts its effects through autocrine, paracrine, and endocrine pathways, triggering a range of responses including fibrosis, inflammation, lipid accumulation, angiogenesis, and proliferation of cancer cells.