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Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice.

Mao Y, Wang J, Yu F, Cheng J, Li H, Guo C, Fan X - Drug Des Devel Ther (2015)

Bottom Line: Inflammatory cytokines were significantly reduced by ghrelin pretreatment.However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2.These effects could be interrupted by an Akt kinase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background and aims: Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.

Methods: Balb/C mice were divided into four groups: normal control (NC) (mice injected with vehicle [saline]); Con A (25 mg/kg); Con A + 10 μg/kg ghrelin; and Con A + 50 μg/kg ghrelin (1 hour before Con A injection). Pro-inflammatory cytokine levels were detected. Protein levels of phosphoinositide 3-kinase (PI3K); phosphorylated Akt (p-Akt); caspase 3, 8, and 9; and microtubule-associated protein 1 light chain 3 (LC3) were also detected. Perifosine (25 mM) (an Akt inhibitor) was used to investigate whether the protective effect of ghrelin was interrupted by an Akt inhibitor. Protein levels of p-AKT; Bcl-2; Bax; and caspase 3, 8, and 9 were also detected.

Results: Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by ghrelin pretreatment in Con A-induced hepatitis. Inflammatory cytokines were significantly reduced by ghrelin pretreatment. Bcl-2; Bax; and caspase 3, 8, and 9 expression were also clearly affected by ghrelin pretreatment, compared with the Con A-treated group. However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2. Ghrelin activated the PI3K/Akt/Bcl-2 pathway and inhibited activation of autophagy.

Conclusion: Our results demonstrate that ghrelin attenuates Con A-induced acute immune hepatitis by activating the PI3K/Akt pathway and inhibiting the process of autophagy, which might be related to inhibition of inflammatory cytokine release, and prevention of hepatocyte apoptosis. These effects could be interrupted by an Akt kinase inhibitor.

No MeSH data available.


Related in: MedlinePlus

Mechanism of the protective effect of ghrelin on Con A-induced hepatitis.Notes: Ghrelin activates PI3K and promotes the phosphorylation of its downstream Akt, leading to the proliferation of injured hepatocytes and the inhibition of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Phosphorylated Akt promotes the expression of Bcl-2, which inhibits Bax and downregulates caspase 3, 8, and 9. PI3K/Akt may lead to the inhibition of the process of autophagy, which is activated by Con A treatment in uncertain mechanisms.Abbreviations: Con, concanavalin; IL, interleukin; PI3K, phosphoinositide 3-kinase; TNF, tumor necrosis factor.
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f1-dddt-9-5385: Mechanism of the protective effect of ghrelin on Con A-induced hepatitis.Notes: Ghrelin activates PI3K and promotes the phosphorylation of its downstream Akt, leading to the proliferation of injured hepatocytes and the inhibition of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Phosphorylated Akt promotes the expression of Bcl-2, which inhibits Bax and downregulates caspase 3, 8, and 9. PI3K/Akt may lead to the inhibition of the process of autophagy, which is activated by Con A treatment in uncertain mechanisms.Abbreviations: Con, concanavalin; IL, interleukin; PI3K, phosphoinositide 3-kinase; TNF, tumor necrosis factor.

Mentions: Concanavalin A (Con A) is a plant lectin and T-cell mitogen, which rapidly induces T-helper (Th) cell activation, mostly CD4+ T-cells, leading to inflammatory liver injury in mice.1–3 Natural killer (NK) T-cells and macrophages are also considered to play key roles in the development of liver damage induced by Con A.4 Pro-inflammatory cytokines – including interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-α, and interferon-γ – are significantly increased in Con A-induced liver injury (Figure 1).5–7 Therefore, Con A-induced liver injury is an ideal model of T-cell-induced hepatitis, especially immune hepatitis.


Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice.

Mao Y, Wang J, Yu F, Cheng J, Li H, Guo C, Fan X - Drug Des Devel Ther (2015)

Mechanism of the protective effect of ghrelin on Con A-induced hepatitis.Notes: Ghrelin activates PI3K and promotes the phosphorylation of its downstream Akt, leading to the proliferation of injured hepatocytes and the inhibition of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Phosphorylated Akt promotes the expression of Bcl-2, which inhibits Bax and downregulates caspase 3, 8, and 9. PI3K/Akt may lead to the inhibition of the process of autophagy, which is activated by Con A treatment in uncertain mechanisms.Abbreviations: Con, concanavalin; IL, interleukin; PI3K, phosphoinositide 3-kinase; TNF, tumor necrosis factor.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4592035&req=5

f1-dddt-9-5385: Mechanism of the protective effect of ghrelin on Con A-induced hepatitis.Notes: Ghrelin activates PI3K and promotes the phosphorylation of its downstream Akt, leading to the proliferation of injured hepatocytes and the inhibition of pro-inflammatory cytokines such as IL-1β, IL-6, and TNF-α. Phosphorylated Akt promotes the expression of Bcl-2, which inhibits Bax and downregulates caspase 3, 8, and 9. PI3K/Akt may lead to the inhibition of the process of autophagy, which is activated by Con A treatment in uncertain mechanisms.Abbreviations: Con, concanavalin; IL, interleukin; PI3K, phosphoinositide 3-kinase; TNF, tumor necrosis factor.
Mentions: Concanavalin A (Con A) is a plant lectin and T-cell mitogen, which rapidly induces T-helper (Th) cell activation, mostly CD4+ T-cells, leading to inflammatory liver injury in mice.1–3 Natural killer (NK) T-cells and macrophages are also considered to play key roles in the development of liver damage induced by Con A.4 Pro-inflammatory cytokines – including interleukin (IL)-1, IL-2, IL-6, tumor necrosis factor (TNF)-α, and interferon-γ – are significantly increased in Con A-induced liver injury (Figure 1).5–7 Therefore, Con A-induced liver injury is an ideal model of T-cell-induced hepatitis, especially immune hepatitis.

Bottom Line: Inflammatory cytokines were significantly reduced by ghrelin pretreatment.However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2.These effects could be interrupted by an Akt kinase inhibitor.

View Article: PubMed Central - PubMed

Affiliation: Department of Gastroenterology and Hepatology, Jinshan Hospital of Fudan University, Shanghai, People's Republic of China.

ABSTRACT

Background and aims: Ghrelin is a 28-amino-acid gut hormone that was first discovered as a potent growth hormone secretagogue. Recently, it has been shown to exert a strong anti-inflammatory effect. The purpose of the study reported here was to explore the effect and mechanism of ghrelin on concanavalin (Con) A-induced acute hepatitis.

Methods: Balb/C mice were divided into four groups: normal control (NC) (mice injected with vehicle [saline]); Con A (25 mg/kg); Con A + 10 μg/kg ghrelin; and Con A + 50 μg/kg ghrelin (1 hour before Con A injection). Pro-inflammatory cytokine levels were detected. Protein levels of phosphoinositide 3-kinase (PI3K); phosphorylated Akt (p-Akt); caspase 3, 8, and 9; and microtubule-associated protein 1 light chain 3 (LC3) were also detected. Perifosine (25 mM) (an Akt inhibitor) was used to investigate whether the protective effect of ghrelin was interrupted by an Akt inhibitor. Protein levels of p-AKT; Bcl-2; Bax; and caspase 3, 8, and 9 were also detected.

Results: Aspartate aminotransferase, alanine aminotransferase, and pathological damage were significantly ameliorated by ghrelin pretreatment in Con A-induced hepatitis. Inflammatory cytokines were significantly reduced by ghrelin pretreatment. Bcl-2; Bax; and caspase 3, 8, and 9 expression were also clearly affected by ghrelin pretreatment, compared with the Con A-treated group. However, the Akt kinase inhibitor reversed the decrease of Bax and caspase 3, 8, 9, and reduced the protein level of p-Akt and Bcl-2. Ghrelin activated the PI3K/Akt/Bcl-2 pathway and inhibited activation of autophagy.

Conclusion: Our results demonstrate that ghrelin attenuates Con A-induced acute immune hepatitis by activating the PI3K/Akt pathway and inhibiting the process of autophagy, which might be related to inhibition of inflammatory cytokine release, and prevention of hepatocyte apoptosis. These effects could be interrupted by an Akt kinase inhibitor.

No MeSH data available.


Related in: MedlinePlus