5-lipoxygenase deficiency reduces hepatic inflammation and tumor necrosis factor alpha-induced hepatocyte damage in hyperlipidemia-prone ApoE-null mice.
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.


CONCLUSIONS
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.
Martínez-Clemente
Marcos
M
Department of Biochemistry and Molecular Genetics, Hospital Clínic, Centro de Investigación Biomédica Esther Koplowitz, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain.
Ferré
Natàlia
N
González-Périz
Ana
A
López-Parra
Marta
M
Horrillo
Raquel
R
Titos
Esther
E
Morán-Salvador
Eva
E
Miquel
Rosa
R
Arroyo
Vicente
V
Funk
Colin D
CD
Clària
Joan
J
D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D001094:Arachidonate 5-Lipoxygenase / Q000172:deficiency* / Q000502:physiology*; D006505:Hepatitis; D022781:Hepatocytes / Q000473:pathology*; D006949:Hyperlipidemias / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D001057:Apolipoproteins E; D014409:Tumor Necrosis Factor-alpha; D001094:Arachidonate 5-Lipoxygenase