PMID- 20967760
OWN - NLM
STAT- MEDLINE
DCOM- 20110110
LR  - 20140730
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 52
IP  - 6
DP  - 2010 Dec
TI  - Disruption of the 12/15-lipoxygenase gene (Alox15) protects hyperlipidemic mice 
      from nonalcoholic fatty liver disease.
PG  - 1980-91
LID - 10.1002/hep.23928 [doi]
AB  - We have shown that Alox15, the gene encoding for 12/15-lipoxygenase (12/15-LO), 
      is markedly up-regulated in livers from apolipoprotein E-deficient (ApoE(-/-)) 
      mice, which spontaneously develop nonalcoholic fatty liver disease secondary to 
      hyperlipidemia. In the current study, we used ApoE(-/-) mice with a targeted 
      disruption of the Alox15 gene to assess the role of 12/15-LO in the development 
      and progression of hepatic steatosis and inflammation. Compared with ApoE(-/-) 
      mice, which exhibited extensive hepatic lipid accumulation and exacerbated 
      inflammatory injury, ApoE/12/15-LO double-knockout (ApoE(-/-)/12/15-LO(-/-)) mice 
      showed reduced serum alanine aminotransferase levels; decreased hepatic 
      steatosis, inflammation, and macrophage infiltration; and decreased fatty acid 
      synthase, tumor necrosis factor alpha (TNFalpha), monocyte chemoattractant protein-1 
      (MCP-1), interleukin (IL)-18, and IL-6 expression. Remarkably, disruption of 
      Alox15 attenuated glucose intolerance and high-fat diet-induced insulin 
      resistance, up-regulated insulin receptor substrate-2, and exerted opposite 
      effects on hepatic c-Jun amino-terminal kinase and adenosine 
      monophosphate-activated protein kinase phosphorylation, known negative and 
      positive regulators of insulin signaling, respectively. In adipose tissue, the 
      absence of Alox15 induced significant reductions in the expression of the 
      proinflammatory and insulin-resistant adipokines MCP-1, TNFalpha, and resistin while 
      increasing the expression of glucose transporter-4. Interestingly, compared with 
      ApoE(-/-) mice, which exhibited increased hepatic caspase-3 staining, 
      ApoE(-/-)/12/15-LO(-/-) mice showed attenuated hepatocellular injury. Consistent 
      with this finding, hepatocytes isolated from ApoE(-/-) mice were more vulnerable 
      to TNFalpha-induced programmed cell death, an effect that was not observed in 
      hepatocytes carrying a targeted disruption of the Alox15 gene. CONCLUSION: 
      Collectively, our data suggest a potentially relevant mechanism linking 12/15-LO 
      to the promotion of hepatic steatosis, insulin resistance, and inflammation in 
      experimental liver disease of metabolic origin.
CI  - Copyright (c) 2010 American Association for the Study of Liver Diseases.
FAU - Martinez-Clemente, Marcos
AU  - Martinez-Clemente M
AD  - Department of Biochemistry and Molecular Genetics, Hospital Clinic, Centro de 
      Investigaciones Biomedicas Esther Koplowitz, Institut d'Investigacions 
      Biomediques August Pi i Sunyer, University of Barcelona, Spain.
FAU - Ferre, Natalia
AU  - Ferre N
FAU - Titos, Esther
AU  - Titos E
FAU - Horrillo, Raquel
AU  - Horrillo R
FAU - Gonzalez-Periz, Ana
AU  - Gonzalez-Periz A
FAU - Moran-Salvador, Eva
AU  - Moran-Salvador E
FAU - Lopez-Vicario, Cristina
AU  - Lopez-Vicario C
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
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101021
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (12-15-lipoxygenase)
RN  - 0 (Antigens, Differentiation)
RN  - 0 (Apolipoproteins E)
RN  - 0 (monocyte-macrophage differentiation antigen)
RN  - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase)
RN  - EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
RN  - EC 2.6.1.2 (Alanine Transaminase)
SB  - IM
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - Antigens, Differentiation/immunology
MH  - Apolipoproteins E/*deficiency
MH  - Apoptosis
MH  - Arachidonate 12-Lipoxygenase/*genetics/physiology
MH  - Arachidonate 15-Lipoxygenase/*genetics/physiology
MH  - Fatty Liver/genetics/*prevention & control
MH  - Glucose Tolerance Test
MH  - Insulin Resistance
MH  - Liver/pathology
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Up-Regulation
EDAT- 2010/10/23 06:00
MHDA- 2011/01/11 06:00
CRDT- 2010/10/23 06:00
PHST- 2010/05/21 00:00 [received]
PHST- 2010/08/10 00:00 [accepted]
PHST- 2010/10/23 06:00 [entrez]
PHST- 2010/10/23 06:00 [pubmed]
PHST- 2011/01/11 06:00 [medline]
AID - 10.1002/hep.23928 [doi]
PST - ppublish
SO  - Hepatology. 2010 Dec;52(6):1980-91. doi: 10.1002/hep.23928. Epub 2010 Oct 21.