Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice

Zeng, Lin; Wu, Fan; Lin, Shaoqiang; Pan, Xuebo; Jin, Libo; Lü, Tingting; Shi, Lei; Wang, Yudong; Xu, Aimin; Li, Xiaokun

doi:10.1016/j.jhep.2014.05.033

Cited by 112 publications

(75 citation statements)

References 39 publications

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“…bFGF is another member of the FGF family, whose efficacy in promoting fibroblast-cell migration has been previously described (7). The functions of FGF21 in glucose homeostasis as well as in hepato-and cardioprotection have been reported (9)(10)(11). While it has been reported that FGF21 is highly expressed in the liver (8), the present study revealed that its expression was even higher in the injured skin of mice.…”

Section: Discussionsupporting

confidence: 45%

“…Initially, 1, a member of the FGF family, was reported to be preferentially expressed in the liver (8). However, recent studies have identified that FGF21 is inducible by starvation or certain drugs, and have reported on its diverse functions in glucose homeostasis as well as hepatoand cardioprotection (9)(10)(11). FGF19, FGF21 and FGF23 belong to the FGF19 sub-family.…”

Section: Introductionmentioning

confidence: 99%

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Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration

Song

Ding

Jin

et al. 2016

Molecular Medicine Reports

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Abstract. Fibroblast growth factor (FGF)21 functions in the maintenance of glucose homeostasis and exerts protective effects on the liver, heat and kidneys. However, the roles of FGF21 in other tissue types are yet to be fully elucidated. The present study detected elevated expression levels of FGF21 in skin tissue. Furthermore, it was revealed that FGF21 expression in the skin was induced upon wounding. In addition, β-klotho expression was detected in the skin tissue. To examine the role of FGF21 in the wound healing process, recombinant human (h)FGF21 was expressed in a the yeast strain Pichia (P.) pastoris, a well-known system for recombinant protein production. Based on the sequence of hFGF21 and the optimal codon of P. pastoris, codon-optimized FGF21 open reading frame sequences were obtained using seven pairs of 55-59-nt primers with seven rounds of PCR. The recombinant FGF21 was purified and its function was examined in human fibroblast cells using a wound healing cell migration assay. Treatment with FGF21 promoted cell migration, which is an important step in wound healing. Furthermore, FGF21 treatment enhanced the activity of c-Jun N-terminal kinase, a key regulator in fibroblast-cell migration. In conclusion, FGF21 is induced after wounding and FGF21 expressed and purified from yeast markedly accelerates wound healing. The present study was the first to elucidate the function of FGF21 in skin tissues and provided a theoretical basis for the use of FGF21 in the treatment of skin wounds. IntroductionThe mammalian genome contains 23 fibroblast growth factors (FGFs) (1), which have essential roles in metabolism and development. FGFs have been identified to be involved in processes of embryogenesis, including gastrulation, somitogenesis, body plan formation and organogenesis, as well as in skin wound healing (2-7). Initially, 1, a member of the FGF family, was reported to be preferentially expressed in the liver (8). However, recent studies have identified that FGF21 is inducible by starvation or certain drugs, and have reported on its diverse functions in glucose homeostasis as well as hepatoand cardioprotection (9-11). FGF19, FGF21 and FGF23 belong to the FGF19 sub-family. Among them, FGF21 primarily activates FGF receptor (FGFR)1c, for which co-receptor β-klotho is required (12,13).Previous efforts to produce recombinant human FGF21 (rhFGF21) using an Escherichia (E.) coli system resulted in low expression of soluble protein, indicating that the majority of recombinant protein localized in inclusion bodies. Although the small ubiquitin-like modifier (SUMO) fusion system has been shown to facilitate the soluble expression and enhance the production of bioactive rhFGF21 (14), additional steps are required for the removal of tags from the protein expressed in vitro. At present, Pichia (P.) pastoris (yeast) is among the most successful eukaryotic protein expression systems. Compared with mammalian cells, culture of P. pastoris requires simple and cheap growth media and conditions, and P. pastoris is known to...

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Section: Discussionsupporting

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration

Song

Ding

Jin

et al. 2016

Molecular Medicine Reports

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“…Cultured cardiomyocytes in specific experiments were also collected for mitochondria isolation using the same methods. Measurement of mitochondrial respiratory chain (MRC) complex activities was performed using the same previously described methods [28].…”

Section: Isolation Of Mitochondria and Measurement Of Mitochondrial Rmentioning

confidence: 99%

“…Intracellular ROS levels in mouse primary cardiomyocytes were determined using CM-H2DCFDA or a fluorescent probe as described in [28]. The fluorescence intensity (relative fluorescence units) was measured at an excitation and emission wavelength of 485 and 530 nm, respectively.…”

Section: Measurement Of Intracellular Rosmentioning

confidence: 99%

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

Wang

Zhang

et al. 2017

Clinical Science

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The aim of the present study is to explore the molecular mechanism of fibroblast growth factor 21 (FGF21) in protecting against diabetic cardiomyopathy (DCM). Streptozotocin/high-fat diet (STZ/HFD) was used to induced diabetes in FGF21-deficient mice and their wild-type littermates, followed by evaluation of the difference in DCM between the two genotypes. Primary cultured cardiomyocytes were also used to explore the potential molecular mechanism of FGF21 in the protection of high glucose (HG)-induced cardiomyocyte injury. STZ/HFD-induced cardiomyopathy was exacerbated in FGF21 knockout mice, which was accompanied by a significant reduction in cardiac AMP-activated protein kinase (AMPK) activity and paraoxonase 1 (PON1) expression. By contrast, adeno-associated virus (AAV)-mediated overexpression of FGF21 in STZ/HFD-induced diabetic mice significantly enhanced cardiac AMPK activity, PON1 expression and its biological activity, resulting in alleviated DCM. In cultured cardiomyocytes, treatment with recombinant mouse FGF21 (rmFGF21) counteracted HG-induced oxidative stress, mitochondrial dysfunction, and inflammatory responses, leading to increased AMPK activity and PON1 expression. However, these beneficial effects of FGF21 were markedly weakened by genetic blockage of AMPK or PON1. Furthermore, inactivation of AMPK also markedly blunted FGF21-induced PON1 expression but significantly increased HG-induced cytotoxicity in cardiomyocytes, the latter of which was largely reversed by adenovirus-mediated PON1 overexpression. These findings suggest that FGF21 ameliorates DCM in part by activation of the AMPK-PON1 axis.

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“…This autophagy induction contributes to restoration of ethanol-induced apoptosis in rat hepatocytes and HepG2 cells. 6,14) In addition, autophagy induction plays a crucial role in liver protection from acetaminophen-induced hepatocyte damage, 15) which occurs through mitochondria dysfunction, necrosis, and oxidative stress. However, the role of autophagy in cell death and survival is controversial.…”

Section: Anti-apoptotic and Pro-survival Effects Of Adiponectin In LImentioning

confidence: 99%

Modulation of Cell Death and Survival by Adipokines in the Liver

Nepal

Park

2015

Biological & Pharmaceutical Bulletin

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Adipokines, hormones predominantly produced from adipose tissue, have been shown to impart dynamic functions in the liver. Emerging evidence has shown that adipokines are also involved in modulating liver cell survival and/or death. Among the various adipokines, adiponectin and leptin directly regulate proliferation of hepatocytes, Kupffer cells, and hepatic stellate cells. Moreover, these adipokines control apoptosis and cell cycle of hepatic cancer cells in a complex manner. Adiponectin possesses both pro-and anti-proliferative properties, whereas leptin appears to play roles as a pro-survival hormone. Recent studies have revealed that regulation of cell death and proliferation is one of the critical factors regulating liver physiology by adipokines. In this review, we summarize the effects of adipokines on apoptosis and survival of liver cells and also demonstrate their implications in regulating various liver functions and decipher the underlying molecular mechanisms.

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Adiponectin protects against acetaminophen-induced mitochondrial dysfunction and acute liver injury by promoting autophagy in mice

Cited by 112 publications

References 39 publications

Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration

Expression and purification of FGF21 in Pichia pastoris and its effect on fibroblast-cell migration

FGF21 ameliorates diabetic cardiomyopathy by activating the AMPK-paraoxonase 1 signaling axis in mice

Modulation of Cell Death and Survival by Adipokines in the Liver

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