Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells

Shireesh Srivastava, Zheng Li, Xuerui Yang, Matthew Yedwabnick, Stephen Shaw, Christina Chan

Research output: Contribution to journalArticle

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Abstract

Background: In order to devise efficient treatments for complex, multi-factorial diseases, it is important to identify the genes which regulate multiple cellular processes. Exposure to elevated levels of free fatty acids (FFAs) and tumor necrosis factor alpha (TNF-α) alters multiple cellular processes, causing lipotoxicity. Intracellular lipid accumulation has been shown to reduce the lipotoxicity of saturated FFA. We hypothesized that the genes which simultaneously regulate lipid accumulation as well as cytotoxicity may provide better targets to counter lipotoxicity of saturated FFA. Results: As a model system to test this hypothesis, human hepatoblastoma cells (HepG2) were exposed to elevated physiological levels of FFAs and TNF-α. Triglyceride (TG) accumulation, toxicity and the genomic responses to the treatments were measured. Here, we present a framework to identify such genes in the context of lipotoxicity. The aim of the current study is to identify the genes that could be altered to treat or ameliorate the cellular responses affected by a complex disease rather than to identify the causal genes. Genes that regulate the TG accumulation, cytotoxicity or both were identified by a modified genetic algorithm partial least squares (GA/PLS) analysis. The analyses identified NADH dehydrogenase and mitogen activated protein kinases (MAPKs) as important regulators of both cytotoxicity and lipid accumulation in response to FFA and TNF-α exposure. In agreement with the predictions, inhibiting NADH dehydrogenase and c-Jun N-terminal kinase (JNK) reduced cytotoxicity significantly and increased intracellular TG accumulation. Inhibiting another MAPK pathway, the extracellular signal regulated kinase (ERK), on the other hand, improved the cytotoxicity without changing TG accumulation. Much greater reduction in the toxicity was observed upon inhibiting the NADH dehydrogenase and MAPK (which were identified by the dual-response analysis), than for the stearoyl-CoA desaturase (SCD) activation (which was identified for the TG-alone analysis). Conclusion: These results demonstrate the applicability of GA/PLS in identifying the genes that regulate multiple cellular responses of interest and that genes regulating multiple cellular responses may be better candidates for countering complex diseases.

LanguageEnglish (US)
Article number364
JournalBMC Genomics
Volume8
DOIs
StatePublished - Oct 9 2007

Profile

Hepatocellular Carcinoma
Nonesterified Fatty Acids
Triglycerides
NADH Dehydrogenase
Genes
Tumor Necrosis Factor-alpha
Mitogen-Activated Protein Kinases
Least-Squares Analysis
Lipids
Fatty Acids
Stearoyl-CoA Desaturase
Hepatoblastoma
JNK Mitogen-Activated Protein Kinases
Lipoma
Extracellular Signal-Regulated MAP Kinases
Hep G2 Cells

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells. / Srivastava, Shireesh; Li, Zheng; Yang, Xuerui; Yedwabnick, Matthew; Shaw, Stephen; Chan, Christina.

In: BMC Genomics, Vol. 8, 364, 09.10.2007.

Research output: Contribution to journalArticle

Srivastava, Shireesh ; Li, Zheng ; Yang, Xuerui ; Yedwabnick, Matthew ; Shaw, Stephen ; Chan, Christina. / Identification of genes that regulate multiple cellular processes/ responses in the context of lipotoxicity to hepatoma cells. In: BMC Genomics. 2007 ; Vol. 8.
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abstract = "Background: In order to devise efficient treatments for complex, multi-factorial diseases, it is important to identify the genes which regulate multiple cellular processes. Exposure to elevated levels of free fatty acids (FFAs) and tumor necrosis factor alpha (TNF-α) alters multiple cellular processes, causing lipotoxicity. Intracellular lipid accumulation has been shown to reduce the lipotoxicity of saturated FFA. We hypothesized that the genes which simultaneously regulate lipid accumulation as well as cytotoxicity may provide better targets to counter lipotoxicity of saturated FFA. Results: As a model system to test this hypothesis, human hepatoblastoma cells (HepG2) were exposed to elevated physiological levels of FFAs and TNF-α. Triglyceride (TG) accumulation, toxicity and the genomic responses to the treatments were measured. Here, we present a framework to identify such genes in the context of lipotoxicity. The aim of the current study is to identify the genes that could be altered to treat or ameliorate the cellular responses affected by a complex disease rather than to identify the causal genes. Genes that regulate the TG accumulation, cytotoxicity or both were identified by a modified genetic algorithm partial least squares (GA/PLS) analysis. The analyses identified NADH dehydrogenase and mitogen activated protein kinases (MAPKs) as important regulators of both cytotoxicity and lipid accumulation in response to FFA and TNF-α exposure. In agreement with the predictions, inhibiting NADH dehydrogenase and c-Jun N-terminal kinase (JNK) reduced cytotoxicity significantly and increased intracellular TG accumulation. Inhibiting another MAPK pathway, the extracellular signal regulated kinase (ERK), on the other hand, improved the cytotoxicity without changing TG accumulation. Much greater reduction in the toxicity was observed upon inhibiting the NADH dehydrogenase and MAPK (which were identified by the dual-response analysis), than for the stearoyl-CoA desaturase (SCD) activation (which was identified for the TG-alone analysis). Conclusion: These results demonstrate the applicability of GA/PLS in identifying the genes that regulate multiple cellular responses of interest and that genes regulating multiple cellular responses may be better candidates for countering complex diseases.",
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