CCN6 improves hepatic steatosis, inflammation, and fibrosis in non‐alcoholic steatohepatitis

The cellular (centralized) communication network (CCN) factor protein family contains six small secreted cysteine-rich proteins sharing high structural similarity. These matricellular proteins have vital biological functions in cell adhesion, migration, cell cycle progression, and control of production and degradation of extracellular matrix. However, in liver the biological functions of CCN proteins become most visible during hepatic injury, disease, and remodeling. In particular, most of the hepatic functions of CCN proteins were derived from CCN2/CTGF, which becomes highly expressed in damaged hepatocytes and acts as a profibrogenic molecule. On the contrary, CCN1/CYR61 seems to have opposite effects, while the biological activity during hepatic fibrosis is somewhat controversially discussed for other CCN family members. In the present study, we analyzed the expression of CCN5/WISP2 in cultures of different types of primary liver cells and in an experimental model of hepatic fibrosis. We found that CCN5 is expressed in hepatic stellate cells, myofibroblasts and portal myofibroblasts, while CCN5 expression is virtually absent in hepatocytes. During hepatic fibrogenesis, CCN5 is significantly upregulated. Overexpression of CCN5 in portal myofibroblasts reduced expression of transforming growth factor-β receptor I (ALK5) and concomitant Smad2 activation, whereas JunB expression is upregulated. Moreover, elevated expression of CCN5 induces endoplasmic reticulum stress, unfolded protein response and apoptosis in portal myofibroblasts. We suggest that upregulated expression of CCN5 might be an intrinsic control mechanism that counteracts overshooting fibrotic responses in profibrogenic liver cells. Graphical abstract

Section: Discussionmentioning

confidence: 99%

Expression and biological function of the cellular communication network factor 5 (CCN5) in primary liver cells

Borkham-Kamphorst

Meurer

Weiskirchen

2023

“…It has been reported that CCN6–IGF‐1 interaction regulates chondrocyte hypertrophy (Repudi et al 2013). Unlike CCN3 and − 4, CCN6 expression is downregulated in the liver of experimental fatty liver disease and in patients suffering from NASH; while the overexpression of CCN6 attenuated hepatic steatosis, inflammation, and fibrosis in NASH mice suggesting that CCN6 is also anti‐fibrotic (Song et al 2023). CCN6 is a secretory protein involved in mitochondrial homeostasis and oxidative stress; a new report further studied whether it is involved in the pathogenesis of NASH (Song et al 2023).…”

Section: Ccn6/wisp3 Protects Against Hepatic Steatosis Inflammation A...mentioning

confidence: 99%

“…Unlike CCN3 and − 4, CCN6 expression is downregulated in the liver of experimental fatty liver disease and in patients suffering from NASH; while the overexpression of CCN6 attenuated hepatic steatosis, inflammation, and fibrosis in NASH mice suggesting that CCN6 is also anti‐fibrotic (Song et al 2023). CCN6 is a secretory protein involved in mitochondrial homeostasis and oxidative stress; a new report further studied whether it is involved in the pathogenesis of NASH (Song et al 2023). In human NASH patients and two murine models, wherein NASH is induced either by high‐fat‐high‐cholesterol (HFHC) or by methionine choline‐deficient (MCD) diet, hepatic CCN6 level was significantly down regulated by ≥ 25%.…”

Section: Ccn6/wisp3 Protects Against Hepatic Steatosis Inflammation A...mentioning

confidence: 99%

“…However, this last part of the Results, especially concerning Fig. 7E in Song et al (2023), was problematic. ( 1) Together with the changes in AST, the text also quoted ALT without reporting it in Anti- (Song et al 2023) Signaling mechanism Integrins, MRTF, cytoskeleton (Xi et al 2022) MAPK (Song et al 2023)…”

Section: Ccn6/wisp3 Protects Against Hepatic Steatosis Inflammation A...mentioning

confidence: 99%

“…, heart, liver, kidney, lung Pro-liver, kidney, lung (Mirr and Owecki 2021; Pivovarova-Ramich et al 2021; Xi et al 2022) (Zhong et al 2017) (Klee et al 2016; Kulkarni et al 2020) (Li et al 2015)Anti-heart, lung(Sun et al 2021) Anti-(Repudi et al 2013;Song et al 2023) …”

mentioning

confidence: 99%

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Recent progress on the role of cellular communication network factors (CCN) 3, 4 and 6 in regulating adiposity, liver fibrosis and pancreatic islets

Xega

Alami

Liu

2023

CCN/WISP (cellular communication network factors, or Wnt-inducted secreted proteins) family of proteins consists of six extracellular matrix (ECM)-associated proteins that regulate development, cell adhesion and proliferation, ECM remodeling, inflammation, and tumorigenesis. In the last two decades, metabolic regulation by these matricellular proteins has been studied extensively, several excellent reviews have covered the roles of CCN1, -2 and − 5. In this brief review, we will focus on those lesser-known members and more recent discoveries, together with other recent articles presenting a more complete picture of the current state of knowledge. We have found that CCN2, -4, and − 5 promote pancreatic islet function, while CCN3 plays a unique and negative role. CCN3 and − 4 are pro-adiposity leading to insulin resistance, but CCN5 and − 6 are anti-adiposity. While CCN2 and − 4 promote tissue fibrosis and inflammation, all other four members are clearly anti-fibrotic. As for cellular signaling, they are known to interact with integrins, other cell membrane proteins and ECM thereby regulate Akt/protein kinase B, myocardin-related transcription factor (MRTF), and focal adhesion kinase. Yet, a cohesive mechanism of action to comprehensively explain those major functions is still lacking.

Significance of CCNs in liver regeneration

Barkin

Jin-Smith

Török

et al. 2023

The liver has an inherent regenerative capacity via hepatocyte proliferation after mild‐to‐modest damage. When hepatocytes exhaust their replicative ability during chronic or severe liver damage, liver progenitor cells (LPC), also termed oval cells (OC) in rodents, are activated in the form of ductular reaction (DR) as an alternative pathway. LPC is often intimately associated with hepatic stellate cells (HSC) activation to promote liver fibrosis. The Cyr61/CTGF/Nov (CCN) protein family consists of six extracellular signaling modulators (CCN1–CCN6) with affinity to a repertoire of receptors, growth factors, and extracellular matrix proteins. Through these interactions, CCN proteins organize microenvironments and modulate cell signalings in a diverse variety of physiopathological processes. In particular, their binding to subtypes of integrin (αvβ5, αvβ3, α6β1, αvβ6, etc.) influences the motility and mobility of macrophages, hepatocytes, HSC, and LPC/OC during liver injury. This paper summarizes the current understanding of the significance of CCN genes in liver regeneration in relation to hepatocyte‐driven or LPC/OC‐mediated pathways. Publicly available datasets were also searched to compare dynamic levels of CCNs in developing and regenerating livers. These insights not only add to our understanding of the regenerative capability of the liver but also provide potential targets for the pharmacological management of liver repair in the clinical setting.