AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells

Lv, Qiong; Zhen, Qianna; Liu, Lulu; Gao, Rufei; Yang, Sen; Huang, Zhou; Goswami, Richa; Li, Qifu

doi:10.1016/j.lfs.2015.03.003

Cited by 32 publications

(23 citation statements)

References 28 publications

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“…AICAR inhibited hepatic steatosis, reducing HFD-induced hepatic triacylglycerol accumulation in both wild-type and Adipoq −/− mice. This is in agreement with earlier studies demonstrating that AICAR reduces diet-induced hepatic triacylglycerol content in rats [9] and TNF-α-induced intracellular triacylglycerol accumulation in human hepatic HepG2 cell lines [11]. AICAR also attenuated HFD-induced hepatic cholesterol accumulation in Adipoq −/− mice, an interesting finding since AICAR-induced activation of AMPK inhibits the hepatic thyroid stimulating hormone (TSH)/sterol regulatory element-binding protein-2 (SREBP-2)/3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) pathway necessary for cholesterol biosynthesis [10].…”

Section: Discussionsupporting

confidence: 94%

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AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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Aims/hypothesis In this study, we aimed to evaluate the therapeutic potential of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), an activator of AMP-activated protein kinase, for ameliorating high-fat diet (HFD)-induced pathophysiology in mice. We also aimed to determine whether the beneficial effects of AICAR were dependent on adiponectin. Furthermore, human adipose tissue was used to examine the effect of AICAR ex vivo. Methods Six-week-old male C57BL/6J wild-type and Adipoq −/− mice were fed a standard-fat diet (10% fat) or an HFD (60% fat) for 12 weeks and given vehicle or AICAR (500 μg/g) three times/week from weeks 4-12. Diet-induced pathophysiology was examined in mice after 11 weeks by IPGTT and after 12 weeks by flow cytometry and western blotting. Human adipose tissue biopsies from obese (BMI 35-50 kg/m 2 ) individuals were incubated with vehicle or AICAR (1 mmol/l) for 6 h at 37°C, after which inflammation was characterised by ELISA (TNF-α) and flow cytometry. Results AICAR attenuated adipose inflammation in mice fed an HFD, promoting an M1-to-M2 macrophage phenotype switch, while reducing infiltration of CD8 + T cells. AICAR treatment of mice fed an HFD partially restored glucose tolerance and attenuated hepatic steatosis and kidney disease, as evidenced by reduced albuminuria (p < 0.05), urinary H 2 O 2 (p < 0.05) and renal superoxide levels (p < 0.01) in both wild-type and Adipoq −/− mice. AICAR-mediated protection occurred independently of adiponectin, as similar protection was observed in wild-type and Adipoq −/− mice. In addition, AICAR promoted an M1-to-M2 macrophage phenotype switch and reduced TNF-α production in tissue explants from obese human patients. Conclusions/interpretation AICAR may promote metabolic health and protect against obesity-induced systemic diseases Catherine Godson and Kumar Sharma are joint senior authors.Electronic supplementary material The online version of this article

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Section: Discussionsupporting

confidence: 94%

“…Evidence from experimental models has shown that AICAR may attenuate metabolic [6][7][8], hepatic [9][10][11] and renal pathophysiology [12][13][14][15]. However, the use of AICAR could be compromised as some reports indicate that AICAR increases adiponectin production [13].…”

Section: Introductionmentioning

confidence: 99%

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

et al. 2017

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“…AMPK is known to function as an intracellular energy sensor, being activated in response to an increased AMP⁄ATP ratio, a condition of energetic stress, to promote the catabolic pathway, thereby inhibiting cell proliferation (18,19). Growing evidence suggests that AMPK is dysregulated in most cancer tissues, including HCC, when compared to normal tissues (26)(27)(28), and several studies have shown that AMPK activators exhibit inhibitory effects on HCC growth (21,26,27,(29)(30)(31)36). Scientific interest continues to grow in the search for molecular pathways and novel compounds that target AMPK signaling as new potential therapeutic options for HCC.…”

Section: Discussionmentioning

confidence: 99%

“…Once activated, AMPK suppresses cell proliferation in tumor as well as non-tumor cells, through regulation of the cell cycle, apoptosis, autophagy, and inhibition of protein synthesis (20)(21)(22)(23)(24)(25). Current evidence supports the alteration of AMPK levels in various cancers, implicating AMPK as a potential target for prevention and/or treatment of cancer, specifically HCC (26)(27)(28). Several studies have also demonstrated that activation of AMPK induces apoptosis in many human cancer cells, including HCC cells (29)(30)(31).…”

Section: Introductionmentioning

confidence: 98%

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

Park

Jeong

Jeong³

et al. 2015

International Journal of Oncology

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Abstract. The Kalopanax septemlobus leaf (Thunb.) Koidz. has been used as a traditional medicine herb for the treatment of various human diseases for hundreds of years. In this study, we investigated the mechanism underlying the inhibitory effects of an ethanol extract of K. septemlobus leaf (EEKS) on proliferation of HepG2 hepatocellular carcinoma cells. For this study, cell viability and apoptosis were evaluated using the MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay, DAPI (4,6-diamidino-2-phenylindole) staining, agarose gel electrophoresis, and flow cytometry. Measurements of the mitochondrial membrane potential (MMP), caspase activity assays and western blots were conducted to determine whether HepG2 cell death occurred by apoptosis. Treatment of HepG2 cells with EEKS concentration-dependently reduced cell survival while significantly increasing the ratio of apoptotic cells. EEKS treatment increased the levels of the death receptors (DRs), DR4 and DR5, and activated caspases, as well as promoting proteolytic degradation of poly(ADP-ribose)-polymerase associated with the downregulation of protein expression of members of the inhibitor of apoptosis protein family. Treatment with EEKS also caused truncation of Bid, translocation of pro-apoptotic Bax to the mitochondria, and loss of mitochondrial membrane permeabilization, thereby inducing the release of cytochrome c into the cytosol. However, treatment of HepG2 cells with a pan-caspase inhibitor reversed EEKS-induced apoptosis and growth suppression, indicating that EEKS appears to induce apoptosis though a caspase-dependent mechanism involving both intrinsic and extrinsic apoptotic pathways. In addition, the phosphorylation level of AMP-activated protein kinase (AMPK) was elevated when cells were exposed to EEKS. A specific inhibitor for AMPK attenuated the EEKS-induced activation of caspases, and consequently prevented the EEKS-induced apoptosis and reduction in cell viability. Overall, our findings suggest that EEKS inhibits the growth of HepG2 cells by inducing AMPK-mediated caspase-dependent apoptosis, suggesting the potential therapeutic application of EEKS in the treatment or prevention of cancers.

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“…TNF- could induce c-Jun N-terminal kinase (JNK) activation, which is associated with the induction of hepatocyte death (31,32). On the other hand, Lv and his colleagues (33) found that TNF- could directly induce lipid accumulation through the AMP-activated protein kinase (AMPK) pathway, which is known as an important factor in the process of energy homeostasis. In addition, lipopolysaccharides (LPS) could induce activation of mitogen-activated protein kinases (MAPKs) and liver injury (28).…”

Section: Ppar Agonists and Inflammation In Nafldmentioning

confidence: 99%

The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease

2017

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Non-alcoholic fatty liver disease (NAFLD) has been defined as a spectrum of histological abnormalities and is characterized by significant and excessive accumulation of triglycerides in the hepatocytes in patients without alcohol consumption or other diseases. Current studies are targeting new molecular mechanisms that underlie NAFLD and associated metabolic disorders. Many therapeutic targets have been found and used in clinical studies. Peroxisome proliferator-activated receptors (PPARs) are among the potential targets and have been demonstrated to exert a pivotal role in modulation of NAFLD. Many drugs developed so far are targeted at PPARs. Thus, the aim of this paper is to summarize the roles of PPARs in the treatment of NAFLD.

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AMP-kinase pathway is involved in tumor necrosis factor alpha-induced lipid accumulation in human hepatoma cells

Cited by 32 publications

References 28 publications

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

AICAR ameliorates high-fat diet-associated pathophysiology in mouse and ex vivo models, independent of adiponectin

Ethanol extract of Kalopanax septemlobus leaf induces caspase-dependent apoptosis associated with activation of AMPK in human hepatocellular carcinoma cells

The role of peroxisome proliferator-activated receptor in the treatment of non-alcoholic fatty liver disease

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