PMID- 17925029
OWN - NLM
STAT- MEDLINE
DCOM- 20080115
LR  - 20211020
IS  - 1471-2164 (Electronic)
IS  - 1471-2164 (Linking)
VI  - 8
DP  - 2007 Oct 9
TI  - Identification of genes that regulate multiple cellular processes/responses in 
      the context of lipotoxicity to hepatoma cells.
PG  - 364
AB  - 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-alpha) 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-alpha. 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-alpha 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.
FAU - Srivastava, Shireesh
AU  - Srivastava S
AD  - Department of Chemical Engineering and Material Science, Michigan State 
      University, East Lansing, MI 48824, USA. srivas14@egr.msu.edu
FAU - Li, Zheng
AU  - Li Z
FAU - Yang, Xuerui
AU  - Yang X
FAU - Yedwabnick, Matthew
AU  - Yedwabnick M
FAU - Shaw, Stephen
AU  - Shaw S
FAU - Chan, Christina
AU  - Chan C
LA  - eng
GR  - R01 GM079688/GM/NIGMS NIH HHS/United States
GR  - R21 CA126136/CA/NCI NIH HHS/United States
GR  - 1R01GM079688-01/GM/NIGMS NIH HHS/United States
GR  - 1R21CA126136-01/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20071009
PL  - England
TA  - BMC Genomics
JT  - BMC genomics
JID - 100965258
RN  - 0 (Fatty Acids, Nonesterified)
RN  - 0 (Triglycerides)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.6.99.3 (NADH Dehydrogenase)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Algorithms
MH  - Fatty Acids, Nonesterified/*toxicity
MH  - *Gene Expression Profiling
MH  - Hepatoblastoma/genetics/*metabolism
MH  - Humans
MH  - Liver Neoplasms/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinases/genetics
MH  - NADH Dehydrogenase/genetics
MH  - Triglycerides/metabolism
MH  - Tumor Cells, Cultured
MH  - Tumor Necrosis Factor-alpha/metabolism/toxicity
PMC - PMC2110894
EDAT- 2007/10/11 09:00
MHDA- 2008/01/16 09:00
PMCR- 2007/10/09
CRDT- 2007/10/11 09:00
PHST- 2007/02/28 00:00 [received]
PHST- 2007/10/09 00:00 [accepted]
PHST- 2007/10/11 09:00 [pubmed]
PHST- 2008/01/16 09:00 [medline]
PHST- 2007/10/11 09:00 [entrez]
PHST- 2007/10/09 00:00 [pmc-release]
AID - 1471-2164-8-364 [pii]
AID - 10.1186/1471-2164-8-364 [doi]
PST - epublish
SO  - BMC Genomics. 2007 Oct 9;8:364. doi: 10.1186/1471-2164-8-364.