Trovafloxacin-induced replication stress sensitizes HepG2 cells to tumor necrosis factor-alpha-induced cytotoxicity mediated by extracellular signal-regulated kinase and ataxia telangiectasia and Rad3-related

ABSTRACT Among the large family of intermediate filament proteins, the keratin 8 and 18 (K8/K18) pair constitutes a hallmark for all simple epithelial cells, such as hepatocytes and mammary cells. Functional studies with different cell models have suggested that K8/K18 are involved in simple epithelial cell resistance to several forms of stress that may lead to cell death. We have reported recently that K8/K18-deprived hepatocytes from K8-null mice are more sensitive to Fas-mediated apoptosis. Here we show that upon Fas, tumor necrosis factor alpha receptor, or tumor necrosis factor alpha-related apoptosis-inducing ligand receptor stimulation, an inhibition of extracellular signal-regulated kinase 1 and 2 (ERK1/2) activation sensitizes wild-type but not K8-null mouse hepatocytes to apoptosis and that a much weaker ERK1/2 activation occurs in K8-null hepatocytes. In turn, this impaired ERK1/2 activation in K8-null hepatocytes is associated with a drastic reduction in c-Flip protein, an event that also holds in a K8-null mouse mammary cell line. c-Flip, along with Raf-1, is part of a K8/K18-immunoisolated complex from wild-type hepatocytes, and Fas stimulation leads to further c-Flip and Raf-1 recruitment in the complex. This points to a new regulatory role of simple epithelium keratins in the c-Flip/ERK1/2 antiapoptotic signaling pathway.

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434 Induction of tumor necrosis factor alpha by hepatitis C virus (HCV) nonstructural protein 3 (NS3) in HepG2 cells is both AP-1 and NF-κB-dependent activation

Journal of Hepatology ◽

10.1016/s0168-8278(05)81846-x ◽

2005 ◽

Vol 42 ◽

pp. 158

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Hepg2 Cells ◽

Tumor Necrosis ◽

Nonstructural Protein ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

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Eicosapentaenoic Acid Improves Hepatic Metabolism and Reduces Inflammation Independent of Obesity in High-Fat-Fed Mice and in HepG2 Cells

Nutrients ◽

10.3390/nu11030599 ◽

2019 ◽

Vol 11 (3) ◽

pp. 599 ◽

Cited By ~ 10

Author(s):

Kembra Albracht-Schulte ◽

Samantha Gonzalez ◽

Abigail Jackson ◽

Savanna Wilson ◽

Latha Ramalingam ◽

...

Keyword(s):

Lipid Metabolism ◽

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Hepg2 Cells ◽

Tumor Necrosis ◽

Mrna Levels ◽

High Fat ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, concurrent with increased obesity. Thus, there is urgent need for research that can lead to effective NAFLD prevention/treatment strategies. Omega-3 polyunsaturated fatty acids (n-3 PUFAs), including eicosapentaenoic acid (EPA), improve inflammation- and dyslipidemia-related metabolic disorders; however, mechanisms mediating the benefits of n-3 PUFAs in NAFLD treatment are less understood. We previously reported that EPA reversed obesity-induced hepatic steatosis in high-fat (HF)-fed B6 mice. Utilizing a combination of biochemical analyses of liver tissues from HF and HF-EPA-fed mice and a series of in vitro studies in tumor necrosis factor-alpha (TNF-α)-stimulated HepG2 cells, we dissect the mechanistic effects of EPA in reducing hepatic steatosis, including the role of EPA-targeted microRNAs (miRNA). With EPA, hepatic lipid metabolism was improved in HF-EPA mice, as indicated by decreased protein and messenger RNA (mRNA) levels of fatty acid synthase (FASN) and acetyl-CoA carboxylase (Acaca) gene, and increased mRNA levels for the peroxisome proliferator activated receptor-α (Pparα), and carnitine palmitoyltransferase (Cpt) 1a and 2 genes in the HF-EPA mice. Additionally, inflammation was reduced, as shown by decreased tumor necrosis factor-alpha (Tnfα) gene expression. Accordingly, EPA also significantly reduced FASN and ACACA mRNAs in human HepG2 cells. Glycolysis, estimated by extracellular acidification rate, was significantly reduced in HepG2 cells treated with EPA vs. vehicle. Furthermore, we identified several miRNAs that are regulated by EPA in mouse liver, including miR-19b-3p, miR-21a-5p, and others, which target lipid metabolism and inflammatory pathways. In conclusion, our findings provide novel mechanistic evidence for beneficial effects of EPA in NAFLD, through the identification of specific genes and miRNAs, which may be further exploited as future NAFLD therapies.

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