Macrophage-specific FGF12 promotes liver fibrosis progression in mice.

BACKGROUND AND AIMS: Chronic liver diseases are associated with the development of liver fibrosis. Without treatment, liver fibrosis commonly leads to cirrhosis and HCC. FGF12 is an intracrine factor belonging to the FGF superfamily, but its role in liver homeostasis is largely unknown. This study aimed to investigate the role of FGF12 in the regulation of liver fibrosis. APPROACH AND RESULTS: FGF12 was up-regulated in bile duct ligation (BDL)-induced and CCL 4 -induced liver fibrosis mouse models. Expression of FGF12 was specifically up-regulated in nonparenchymal liver cells, especially in hepatic macrophages. By constructing myeloid-specific FGF12 knockout mice, we found that deletion of FGF12 in macrophages protected against BDL-induced and CCL 4 -induced liver fibrosis. Further results revealed that FGF12 deletion dramatically decreased the population of lymphocyte antigen 6 complex locus C high macrophages in mouse fibrotic liver tissue and reduced the expression of proinflammatory cytokines and chemokines. Meanwhile, loss-of-function and gain-of-function approaches revealed that FGF12 promoted the proinflammatory activation of macrophages, thus inducing HSC activation mainly through the monocyte chemoattractant protein-1/chemokine (C-C motif) receptor 2 axis. Further experiments indicated that the regulation of macrophage activation by FGF12 was mainly mediated through the Janus kinase-signal transducer of activators of transcription pathway. Finally, the results revealed that FGF12 expression correlates with the severity of fibrosis across the spectrum of fibrogenesis in human liver samples. CONCLUSIONS: FGF12 promotes liver fibrosis progression. Therapeutic approaches to inhibit macrophage FGF12 may be used to combat liver fibrosis in the future.

Fibroblast growth factor 18 attenuates liver fibrosis and HSCs activation via the SMO-LATS1-YAP pathway.

Liver fibrosis, which is characterized by excessive accumulation of extracellular matrix (ECM) primarily produced by hepatic stellate cells (HSCs), can eventually lead to cirrhosis. Fibroblast growth factor 18 (FGF18) mediates various biological activities. However, the precise role of FGF18 in the pathological process of liver fibrosis and the underlying mechanisms have not been elucidated. In this study, we found that FGF18 was markedly upregulated in carbon tetrachloride (CCl4)-induced fibrotic mouse liver tissues and transforming growth factor ß (TGF-ß) stimulated LX-2 cells. Furthermore, our studies demonstrated that overexpression of FGF18 in the liver significantly alleviated CCl4-induced fibrosis and inhibited the activation of HSCs, while exacerbated by HSC-specific deletion of FGF18. Mechanistically, FGF18 treatment dramatically activated Hippo signaling pathway by suppressing smoothened (SMO) both in vivo and in vitro. Moreover, the interaction between SMO and LATS1 was crucial for the FGF18 induced protective effects. In conclusion, these results indicated that FGF18 attenuates liver fibrosis at least partially via the SMO-LATS1-YAP signaling pathway and therefore may be a potential therapeutic target for liver fibrosis.

CK2 blockade alleviates liver fibrosis by suppressing activation of hepatic stellate cells via the Hedgehog pathway.

BACKGROUND AND PURPOSE: Liver fibrosis is a serious cause of morbidity and mortality worldwide characterized by accumulation of extracellular matrix produced by hepatic stellate cells (HSCs). The protein kinase CK2 is a pro-survival kinase overexpressed in human tumours. However, the biological role of CK2 in liver fibrosis is largely unknown. We aimed to investigate the mechanism by which CK2 promotes liver fibrosis. EXPERIMENTAL APPROACH: In vitro, LX-2 cells were stimulated with transforming growth factor-ß (TGF-ß). HSCs were also isolated for research. In vivo, the adeno-associated virus AAV-sh-csnk2a1 was used to knockdown CK2α specifically in HSCs, and CX-4945 was used to pharmacologically inhibit the enzymatic activity of CK2 in murine models of fibrosis induced by carbon tetrachloride (CCl4 ) and a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of CK2 in regulation of fibrogenic and fibrolytic factors as well as activation properties of HSCs. KEY RESULTS: HSC-specific genetic invalidation of CK2α or pharmacological inhibition of CK2 protected mice treated with CCl4 or fed a DDC diet against liver fibrosis and HSC accumulation. Mechanistically, CK2α, which bound to Smoothened (SMO), was a positive regulator of the Hedgehog signal transduction pathway. CK2 prevented ubiquitination and proteasomal degradation of SMO, which was abolished by knockdown of CK2α or pharmacological inhibition of CK2. CONCLUSIONS AND IMPLICATIONS: CK2 activation is critical to sustain the activated and fibrogenic phenotype of HSCs via SMO stabilization. Therefore, inactivation of CK2 by CX-4945 may be of therapeutic interest for liver fibrotic diseases.

FGF18 alleviates hepatic ischemia-reperfusion injury via the USP16-mediated KEAP1/Nrf2 signaling pathway in male mice.

Hepatic ischemia-reperfusion injury (IRI) is a common complication occurs during hepatic resection and transplantation. However, the mechanisms underlying hepatic IRI have not been fully elucidated. Here, we aim to explore the role of fibroblast growth factor 18 (FGF18) in hepatic IRI. In this work, we find that Hepatic stellate cells (HSCs) secrete FGF18 and alleviates hepatocytes injury. HSCs-specific FGF18 deletion largely aggravates hepatic IRI. Mechanistically, FGF18 treatment reduces the levels of ubiquitin carboxyl-terminal hydrolase 16 (USP16), leading to increased ubiquitination levels of Kelch Like ECH Associated Protein 1 (KEAP1) and the activation of nuclear factor erythroid 2-related factor 2 (Nrf2). Furthermore, USP16 interacts and deubiquitinates KEAP1. More importantly, Nrf2 directly binds to the promoter of USP16 and forms a negative feedback loop with USP16. Collectively, our results show FGF18 alleviates hepatic IRI by USP16/KEAP1/Nrf2 signaling pathway in male mice, suggesting that FGF18 represents a promising therapeutic approach for hepatic IRI.

FGF21 promotes migration and differentiation of epidermal cells during wound healing via SIRT1-dependent autophagy.

BACKGROUND AND PURPOSE: Migration and differentiation of epidermal cells are essential for epidermal regeneration during wound healing. Fibroblast growth factor 21 (FGF21) plays key roles in mediating a variety of biological activities. However, its role in skin wound healing remains unknown. EXPERIMENTAL APPROACH: Fgf21 knockout (Fgf21 KO) mice were used to determine the effect of FGF21 on wound healing. The source of FGF21 and its target cells were determined by immunohistochemistry, immunoblotting, and ELISA assay. Moreover, Sirt1flox/flox and Atg7flox/flox mice were constructed and injected with the epidermal-specific Cre virus to elucidate the underlying mechanisms. Migration and differentiation of keratinocytes were evaluated in vitro by cell scratch assays, immunofluorescence, and qRT-RCR. The effects were further assessed when SIRT1, ATG7, ATG5, BECN1, and P53 were silenced. Interactions between SIRT1 and autophagy-related genes were assessed using immunoprecipitation assays. KEY RESULTS: FGF21 was active in fibroblasts and promoted migration and differentiation of keratinocytes following injury. After wounding, SIRT1 expression and autophagosome synthesis were lower in Fgf21 KO mice. Depletion of ATG7 in keratinocytes counteracted the FGF21-induced increases in migration and differentiation, suggesting that autophagy is required for the FGF21-mediated pro-healing effects. Furthermore, epithelial-specific Sirt1 knockout abolished the FGF21-mediated improvements of autophagy and wound healing. Silencing of SIRT1 in keratinocytes, which decreased deacetylation of p53 and autophagy-related proteins, revealed that FGF21-induced autophagy during wound healing was SIRT1-dependent. CONCLUSIONS AND IMPLICATIONS: FGF21 is a key regulator of keratinocyte migration and differentiation during wound healing. FGF21 may be a novel therapeutic target to accelerate would healing.