Long-Term Administration of Fibroblast Growth Factor 21 Prevents Chemically-Induced Hepatocarcinogenesis in Mice

Xu, Pengfei; Zhang, Yingjie; Wang, Wenfei; Yuan, Qingyan; Liu, Zhihang; Rasoul, Lubna Muhi; Wu, Qiang; Liu, Mingyao; Ye, Xianlong; Li, Deshan; Ren, Guangxin

doi:10.1007/s10620-015-3711-z

Cited by 17 publications

(13 citation statements)

References 51 publications

(62 reference statements)

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“…In agreement with these findings, no signs of pathological proliferation were detected in the liver of two different transgenic mouse models overexpressing FGF21 from birth (Kharitonenkov et al , ; Huang et al , ) or in mice treated with recombinant native FGF21 (Adams et al , ,b). Moreover, overexpression of FGF21 specifically in the liver in transgenic mice or treatment with native FGF21 delayed the appearance of chemically induced tumors (Huang et al , ; Xu et al , ).…”

Section: Discussionmentioning

confidence: 99%

FGF21 gene therapy as treatment for obesity and insulin resistance

et al. 2018

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Prevalence of type 2 diabetes (T2D) and obesity is increasing worldwide. Currently available therapies are not suited for all patients in the heterogeneous obese/T2D population, hence the need for novel treatments. Fibroblast growth factor 21 (FGF21) is considered a promising therapeutic agent for T2D/obesity. Native FGF21 has, however, poor pharmacokinetic properties, making gene therapy an attractive strategy to achieve sustained circulating levels of this protein. Here, adeno‐associated viral vectors (AAV) were used to genetically engineer liver, adipose tissue, or skeletal muscle to secrete FGF21. Treatment of animals under long‐term high‐fat diet feeding or of ob/ob mice resulted in marked reductions in body weight, adipose tissue hypertrophy and inflammation, hepatic steatosis, inflammation and fibrosis, and insulin resistance for > 1 year. This therapeutic effect was achieved in the absence of side effects despite continuously elevated serum FGF21. Furthermore, FGF21 overproduction in healthy animals fed a standard diet prevented the increase in weight and insulin resistance associated with aging. Our study underscores the potential of FGF21 gene therapy to treat obesity, insulin resistance, and T2D.

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Section: Discussionmentioning

confidence: 99%

FGF21 gene therapy as treatment for obesity and insulin resistance

et al. 2018

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“…Deficiency of FGF-21 is reported to promote HCC in mice receiving a long-term obesogenic diet [36]. Long-term administration of FGF-21 prevents chemically induced hepatocarcinogenesis in mice [37]. However, FGF-21 is known to be expressed in several tissues, including those of the liver, fat, and pancreas [38].…”

Section: Discussionmentioning

confidence: 99%

Impact of Decorin on the Physical Function and Prognosis of Patients with Hepatocellular Carcinoma

Kawaguchi

Yoshio

Sakamoto

et al. 2020

JCM

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The outcome of patients with hepatocellular carcinoma (HCC) is still poor. Decorin is a small leucine-rich proteoglycan, which exerts antiproliferative and antiangiogenic properties in vitro. We aimed to investigate the associations of decorin with physical function and prognosis in patients with HCC. We enrolled 65 patients with HCC treated with transcatheter arterial chemoembolization (median age, 75 years; female/male, 25/40). Serum decorin levels were measured using enzyme-linked immunosorbent assays; patients were classified into the High or Low decorin groups by median levels. Associations of decorin with physical function and prognosis were evaluated by multivariate correlation and Cox regression analyses, respectively. Age and skeletal muscle indices were not significantly different between the High and Low decorin groups. In the High decorin group, the 6-min walking distance was significantly longer than the Low decorin group and was significantly correlated with serum decorin levels (r = 0.2927, p = 0.0353). In multivariate analysis, the High decorin group was independently associated with overall survival (hazard ratio 2.808, 95% confidence interval 1.016–8.018, p = 0.0498). In the High decorin group, overall survival rate was significantly higher than in the Low decorin group (median 732 days vs. 463 days, p = 0.010). In conclusion, decorin may be associated with physical function and prognosis in patients with HCC.

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“…It has been reported that the serum level and hepatocyte expression of FGF21 are elevated in patients with liver cancer, and the induction of FGF21 may involve P53 (14). Moreover, long‐term administration or overexpression of FGF21 was shown to prevent chemically induced hepatocarcinogenesis in mice models (39, 40). Thus, FGF21 may not be suitable for kidney protection in patients with cancer during cisplatin chemotherapy because it may suppress the chemotherapy effect.…”

Section: Discussionmentioning

confidence: 99%

FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury

Liu

Tang

et al. 2018

FASEB j.

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Cisplatin, a widely used cancer therapy drug, induces nephrotoxicity or acute kidney injury (AKI), but the underlying mechanism remains unclear, and renal protective approaches are not available. Fibroblast growth factor (FGF)21 is an endocrine factor that regulates glucose uptake, metabolism, and energy expenditure. However, recent work has also implicated FGF21 in cellular stress response under pathogenic conditions. The role and regulation of FGF21 in AKI are unclear. Here, we show that FGF21 was dramatically induced during cisplatin treatment of renal tubular cells in vitro and mouse kidneys in vivo. The inductive response was suppressed by pifithrin (a pharmacological inhibitor of P53), suggesting a role of P53 in FGF21 induction. In cultured renal tubular cells, knockdown of FGF21 aggravated cisplatin-induced apoptosis, whereas supplementation of recombinant FGF21 was protective. Consistently, recombinant FGF21 alleviated cisplatin-induced kidney dysfunction, tissue damage, and tubular apoptosis in mice. Mechanistically, FGF21 suppressed P53 induction and activation during cisplatin treatment. Together, these results indicate that FGF21 is induced during cisplatin nephrotoxicity to protect renal tubules, and recombinant FGF21 may have therapeutic potential.-Li, F., Liu, Z., Tang, C., Cai, J., Dong, Z. FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury.

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Long-Term Administration of Fibroblast Growth Factor 21 Prevents Chemically-Induced Hepatocarcinogenesis in Mice

Abstract: Systemic administration of FGF-21 can prevent DEN-induced hepatocarcinogenesis via suppressing oxidative stress and increasing the expression of KLB.

Cited by 17 publications

References 51 publications

FGF21 gene therapy as treatment for obesity and insulin resistance

FGF21 gene therapy as treatment for obesity and insulin resistance

Impact of Decorin on the Physical Function and Prognosis of Patients with Hepatocellular Carcinoma

FGF21 is induced in cisplatin nephrotoxicity to protect against kidney tubular cell injury

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