PMID- 20112424
OWN - NLM
STAT- MEDLINE
DCOM- 20100426
LR  - 20140730
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 51
IP  - 3
DP  - 2010 Mar
TI  - 5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor 
      alpha-induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice.
PG  - 817-27
LID - 10.1002/hep.23463 [doi]
AB  - The actual risk factors that drive hepatic inflammation during the transition 
      from steatosis to steatohepatitis are unknown. We recently demonstrated that 
      hyperlipidemia-prone apolipoprotein E-deficient (ApoE(-/-)) mice exhibit hepatic 
      steatosis and increased susceptibility to hepatic inflammation and advanced 
      fibrosis. Because the proinflammatory 5-lipoxygenase (5-LO) pathway was found to 
      be up-regulated in these mice and given that 5-LO deficiency confers 
      cardiovascular protection to ApoE(-/-) mice, we determined the extent to which 
      the absence of 5-LO would alter liver injury in these mice. Compared with 
      ApoE(-/-) mice, which showed expected hepatic steatosis and inflammation, 
      ApoE/5-LO double-deficient (ApoE(-/-)/5-LO(-/-)) mice exhibited reduced hepatic 
      inflammation, macrophage infiltration, tumor necrosis factor alpha (TNF-alpha), 
      monocyte chemoattractant protein-1 (MCP-1) and interleukin (IL)-18 expression, 
      caspase-3 and nuclear factor-kappaB (NF-kappaB) activities, and serum alanine 
      aminotransferase levels in the absence of changes in hepatic steatosis. The lack 
      of 5-LO produced a remarkable insulin-sensitizing effect in the adipose tissue 
      because peroxisome proliferator-activated receptor gamma, insulin receptor 
      substrate-1, and adiponectin were up-regulated, whereas c-Jun amino-terminal 
      kinase phosphorylation and MCP-1 and IL-6 expression were down-regulated. On the 
      other hand, hepatocytes isolated from ApoE(-/-)/5-LO(-/-) mice were more 
      resistant to TNF-alpha-induced apoptosis. The 5-LO products leukotriene (LT) 
      B(4), LTD(4), and 5-HETE consistently triggered TNF-alpha-induced apoptosis and 
      compromised hepatocyte survival by suppressing NF-kappaB activity in the presence 
      of actinomycin D. Moreover, ApoE(-/-)/5-LO(-/-) mice were protected against 
      sustained high-fat diet (HFD)-induced liver injury and hepatic inflammation, 
      macrophage infiltration and insulin resistance were significantly milder than 
      those of ApoE(-/-) mice. Finally, pharmacological inhibition of 5-LO 
      significantly reduced hepatic inflammatory infiltrate in the HFD and ob/ob models 
      of fatty liver disease. CONCLUSION: These combined data indicate that 
      hyperlipidemic mice lacking 5-LO are protected against hepatic inflammatory 
      injury, suggesting that 5-LO is involved in mounting hepatic inflammation in 
      metabolic disease.
FAU - Martinez-Clemente, Marcos
AU  - Martinez-Clemente M
AD  - Department of Biochemistry and Molecular Genetics, Hospital Clinic, Centro de 
      Investigacion Biomedica Esther Koplowitz, Institut d'Investigacions Biomediques 
      August Pi i Sunyer, Barcelona, Spain.
FAU - Ferre, Natalia
AU  - Ferre N
FAU - Gonzalez-Periz, Ana
AU  - Gonzalez-Periz A
FAU - Lopez-Parra, Marta
AU  - Lopez-Parra M
FAU - Horrillo, Raquel
AU  - Horrillo R
FAU - Titos, Esther
AU  - Titos E
FAU - Moran-Salvador, Eva
AU  - Moran-Salvador E
FAU - Miquel, Rosa
AU  - Miquel R
FAU - Arroyo, Vicente
AU  - Arroyo V
FAU - Funk, Colin D
AU  - Funk CD
FAU - Claria, Joan
AU  - Claria J
LA  - eng
GR  - MOP-67146/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Apolipoproteins E)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 1.13.11.34 (Arachidonate 5-Lipoxygenase)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/genetics
MH  - Arachidonate 5-Lipoxygenase/*deficiency/*physiology
MH  - Hepatitis
MH  - Hepatocytes/*pathology
MH  - Hyperlipidemias/*enzymology/genetics/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - Tumor Necrosis Factor-alpha/*physiology
EDAT- 2010/01/30 06:00
MHDA- 2010/04/27 06:00
CRDT- 2010/01/30 06:00
PHST- 2010/01/30 06:00 [entrez]
PHST- 2010/01/30 06:00 [pubmed]
PHST- 2010/04/27 06:00 [medline]
AID - 10.1002/hep.23463 [doi]
PST - ppublish
SO  - Hepatology. 2010 Mar;51(3):817-27. doi: 10.1002/hep.23463.