Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction

Nepal, Saroj; Kim, Mi Jin; Subedi, Amit; Lee, Eung-Seok; Yong, Chul Soon; Kim, Jung-Ae; Kang, Wonku; Kwak, Mi-Kyung; Arya, Dharamvir Singh; Park, Pil-Hoon

doi:10.1016/j.bcp.2012.07.019

Cited by 41 publications

(27 citation statements)

References 52 publications

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“…HO-1 is induced as a protective mechanism in response to various stimuli. HO-1 overexpression has been demonstrated to protect against ethanolinduced apoptosis (28). By contrast, suppression of HO-1 activity results in increased hepatocellular injury, apoptosis, and death from infection/sepsis in mice (29).…”

Section: Discussionmentioning

confidence: 97%

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

Lin

Zhai

Wang

et al. 2015

Journal of Pharmacological Sciences

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Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.

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Section: Discussionmentioning

confidence: 97%

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

Lin

Zhai

Wang

et al. 2015

Journal of Pharmacological Sciences

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“…Possible mechanisms that could explain our results include a possible angiogenic role and/or an anti-apoptotic effect of adiponectin, particularly in the setting of high levels of glucose [39–41]. In a study of 609 patients with type II diabetes, higher adiponectin levels were also associated with worsened overall survival.…”

Section: Discussionmentioning

confidence: 98%

Serum Adiponectin Is Associated with Worsened Overall Survival in a Prospective Cohort of Hepatocellular Carcinoma Patients

et al. 2014

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Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide. The rise in metabolic syndrome has contributed to this trend. Adipokines, such as adiponectin, are associated with prognosis in several cancers, but have not been well studied in HCC. Methods: We prospectively enrolled 140 patients with newly diagnosed or recurrent HCC with Child-Pugh (CP) class A or B cirrhosis. We examined associations between serum adipokines, clinicopathological features of HCC, and time to death. We also examined a subset of tumors with available pathology for tissue adiponectin receptor (AR) expression by immunohistochemistry. Results: The median age of subjects was 62 years; 79% were men, 59% had underlying hepatitis C, and 36% were diabetic. Adiponectin remained a significant predictor of time to death (hazard ratio 1.90; 95% confidence interval 1.05-3.45; p = 0.03) in a multivariable adjusted model that included age, alcohol history, CP class, stage, and serum E-fetoprotein level. Cytoplasmic AR expression (AR1 and AR2) in tumors trended higher in those with higher serum adiponectin levels and in those with diabetes mellitus, but the association was not statistically significant. Conclusions: In this hypothesis-generating study, we found the serum adiponectin level to be an independent predictor of overall survival in a diverse cohort of HCC patients. Impact: Understanding how adipokines affect the HCC outcome may help develop novel treatment and prevention strategies. i 2014 S. Karger AG, Basel

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“…HO-1 is also critical for hepatocyte proliferation; mice treated with CO exhibit a more robust proliferative response after partial hepatectomy [28]. HO-1 mediates the effects of several agents, including globular adiponectin and quercetin, in protecting HepG2 cells and rat hepatocytes from ethanol-induced cell death [9,29]. …”

Section: Discussionmentioning

confidence: 99%

“…Surprisingly, chronic ethanol exposure induces HO-1 expression in some, but not all, pre-clinical models [5], in part dependent on the animal’s age [6,7]. However, pharmacological induction of HO-1 prevents ethanol-induced inflammation in intestine [8], as well as oxidative damage and apoptosis in cultured hepatocytes [9,10]. Further, HO-1- mediated pathways can be activated in Kupffer cells after chronic ethanol feeding to suppress TLR4-dependent signaling in primary cultures of Kupffer cells, as well as an in vivo mouse model of LPS challenge [5,11].…”

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confidence: 99%

Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice

Bakhautdin

Das

Mandal

et al. 2014

Journal of Hepatology

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Background and Aims Alcoholic liver disease is associated with inflammation and cell death. Heme oxygenase-1 (HO-1) is a stress-inducible enzyme with anti-apoptotic and anti-inflammatory properties. Here we tested the hypothesis that induction of HO-1 or treatment with a carbon monoxide releasing molecule (CORM) during chronic ethanol exposure protects and/or reverses ethanol-induced liver injury. Methods Female C57BL/6J mice were allowed free access to a complete liquid diet containing ethanol or pair-fed control diets for 25 days. Mice were treated with cobalt protoporphyrin (CoPP) to induce HO-1 expression during ethanol feeding or once injury had been established. Mice were also treated with CORM-A1, a CO-releasing molecule (CORM), after ethanol-induced liver injury was established. The impact of HO-1 induction on ethanol-induced cell death was investigated in primary cultures of hepatocytes. Results Induction of HO-1 during or after ethanol feeding, as well as treatment with CORM-A1, ameliorated ethanol-induced increases in AST and expression of mRNA for inflammatory cytokines. Treatment with CoPP or CORM-A1 also reduced hepatocyte cell death, indicated by decreased accumulation of CK18 cleavage products and reduced RIP3 expression in hepatocytes. Exposure of primary hepatocyte cultures to ethanol increased their sensitivity to TNFα-induced cell death; this response was attenuated by necrostatin-1, an inhibitor of necroptosis, but not by caspase inhibitors. Induction of HO-1 with CoPP or CORM-3 treatment normalized the sensitivity of hepatocytes to TNFα-induced cell death after ethanol exposure. Conclusions Therapeutic strategies to increase HO-1 and/or modulate CO availability ameliorated chronic ethanol-induced liver injury in mice, at least in part by decreasing hepatocellular death.

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Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction

Cited by 41 publications

References 52 publications

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

Serum Adiponectin Is Associated with Worsened Overall Survival in a Prospective Cohort of Hepatocellular Carcinoma Patients

Protective role of HO-1 and carbon monoxide in ethanol-induced hepatocyte cell death and liver injury in mice

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