PMID- 29605541
OWN - NLM
STAT- MEDLINE
DCOM- 20190130
LR  - 20190130
IS  - 1098-8823 (Print)
IS  - 1098-8823 (Linking)
VI  - 136
DP  - 2018 May
TI  - Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in 
      db/db pre-diabetic mice.
PG  - 23-32
LID - S1098-8823(17)30103-X [pii]
LID - 10.1016/j.prostaglandins.2018.03.003 [doi]
AB  - The 12-lipoxygenase (12LO) pathway is a promising target to reduce islet 
      dysfunction, adipose tissue (AT) inflammation and insulin resistance. Optimal 
      pre-clinical models for the investigation of selective12LO inhibitors in this 
      context have not yet been identified. The objective of this study was to 
      characterize the time course of 12LO isoform expression and metabolite production 
      in pancreatic islets and AT of C57BLKS/J-db/db obese diabetic mouse in a 
      pre-diabetic state in order to establish a suitable therapeutic window for 
      intervention with selective lipoxygenase inhibitors. Mice have 2 major 12LO 
      isoforms -the leukocyte type (12/15LO) and the platelet type (p12LO) and both are 
      expressed in islets and AT. We found a sharp increase in protein expression of 
      12/15LO in the pancreatic islets of 10-week old db-/- mice compared to 8- week 
      old counterparts. Immunohistochemistry showed that the increase in islet 12/15LO 
      parallels a decline in islet number. Analysis of 12- and 
      15-hydroperoxytetraeicosanoid acids (HETE)s showed a 2-3 fold increase especially 
      in 12(S)-HETE that mirrored the increase in 12/15LO expression in islets. 
      Analysis of AT and stromal vascular fraction (SVF) showed a significant increase 
      of platelet 12LO gene expression along with 12- and 15- HETEs. The data 
      demonstrate that the db/db mouse is a suitable model for investigation of 12/15LO 
      inhibitors in the development of inflammatory mediated type 2 diabetes, with a 
      narrow window of therapeutic intervention prior to 8 weeks of age.
CI  - Copyright (c) 2018. Published by Elsevier Inc.
FAU - Dobrian, Anca D
AU  - Dobrian AD
AD  - Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, 
      VA, United States. Electronic address: dobriaad@evms.edu.
FAU - Huyck, Ryan W
AU  - Huyck RW
AD  - Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, 
      VA, United States.
FAU - Glenn, Lindsey
AU  - Glenn L
AD  - Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 
      United States.
FAU - Gottipati, Vijay
AU  - Gottipati V
AD  - Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, 
      VA, United States.
FAU - Haynes, Bronson A
AU  - Haynes BA
AD  - Department of Physiological Sciences, Eastern Virginia Medical School, Norfolk, 
      VA, United States.
FAU - Hansson, Goran I
AU  - Hansson GI
AD  - Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development 
      Biotech Unit, AstraZeneca, Pepparedsleden 1, Molndal, 431 83, Sweden.
FAU - Marley, Anna
AU  - Marley A
AD  - Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, 
      AstraZeneca,Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK.
FAU - McPheat, William L
AU  - McPheat WL
AD  - Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development 
      Biotech Unit, AstraZeneca, Pepparedsleden 1, Molndal, 431 83, Sweden.
FAU - Nadler, Jerry L
AU  - Nadler JL
AD  - Department of Internal Medicine, Eastern Virginia Medical School, Norfolk, VA, 
      United States.
LA  - eng
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180329
PL  - United States
TA  - Prostaglandins Other Lipid Mediat
JT  - Prostaglandins & other lipid mediators
JID - 9808648
RN  - 0 (12-15-lipoxygenase)
RN  - 0 (Isoenzymes)
RN  - 0 (Lipoxygenase Inhibitors)
RN  - EC 1.13.11.31 (Arachidonate 12-Lipoxygenase)
RN  - EC 1.13.11.33 (Arachidonate 15-Lipoxygenase)
SB  - IM
MH  - Animals
MH  - Arachidonate 12-Lipoxygenase/*metabolism
MH  - Arachidonate 15-Lipoxygenase/*metabolism
MH  - Diabetes Mellitus, Type 2/drug therapy/*enzymology/pathology
MH  - Enzyme Activation/drug effects
MH  - Insulin-Secreting Cells/*enzymology/pathology
MH  - Isoenzymes/antagonists & inhibitors/metabolism
MH  - Lipoxygenase Inhibitors/*pharmacology
MH  - Male
MH  - Mice
MH  - Mice, Obese
MH  - Prediabetic State/drug therapy/*enzymology/pathology
OTO - NOTNLM
OT  - Adipocytes
OT  - Adipose tissue
OT  - Crown-like structures
OT  - Eicosanoids
OT  - HETEs
OT  - Hyperglycemia
OT  - Lipoxygenases
OT  - Macrophages
OT  - Obesity
OT  - Panceratic islets
OT  - Pre-diabetes
OT  - Resolvins
OT  - Stromal vascular fraction
OT  - db/db
EDAT- 2018/04/02 06:00
MHDA- 2019/01/31 06:00
CRDT- 2018/04/02 06:00
PHST- 2017/08/15 00:00 [received]
PHST- 2018/02/06 00:00 [revised]
PHST- 2018/03/15 00:00 [accepted]
PHST- 2018/04/02 06:00 [pubmed]
PHST- 2019/01/31 06:00 [medline]
PHST- 2018/04/02 06:00 [entrez]
AID - S1098-8823(17)30103-X [pii]
AID - 10.1016/j.prostaglandins.2018.03.003 [doi]
PST - ppublish
SO  - Prostaglandins Other Lipid Mediat. 2018 May;136:23-32. doi: 
      10.1016/j.prostaglandins.2018.03.003. Epub 2018 Mar 29.