Increased CYP2J3 expression reduces insulin resistance in fructose-treated rats and db/db mice.
OBJECTIVE
Accumulating evidence suggests that cytochrome P450 (CYP) epoxygenases metabolize arachidonic acid into epoxyeicosatrienoic acids (EETs), which play crucial and diverse roles in cardiovascular homeostasis. The anti-inflammatory, antihypertensive, and pro-proliferative effects of EETs suggest a possible beneficial role for EETs on insulin resistance and diabetes.


METHODS
This study investigated the effects of CYP2J3 epoxygenase gene therapy on insulin resistance and blood pressure in diabetic db/db mice and in a model of fructose-induced hypertension and insulin resistance in rats.


RESULTS
CYP2J3 gene delivery in vivo increased EET generation, reduced blood pressure, and reversed insulin resistance as determined by plasma glucose levels, homeostasis model assessment insulin resistance index, and glucose tolerance test. Furthermore, CYP2J3 treatment prevented fructose-induced decreases in insulin receptor signaling and phosphorylation of AMP-activated protein kinases (AMPKs) in liver, muscle, heart, kidney, and aorta. Thus, overexpression of CYP2J3 protected against diabetes and insulin resistance in peripheral tissues through activation of insulin receptor and AMPK pathways.


CONCLUSIONS
These results highlight the beneficial roles of the CYP epoxygenase-EET system in diabetes and insulin resistance.
Xu
Xizhen
X
Department of Internal Medicine and The Institute of Hypertension, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, People's Republic of China.
Zhao
Chun Xia
CX
Wang
Luyun
L
Tu
Ling
L
Fang
Xiaosai
X
Zheng
Changlong
C
Edin
Matthew L
ML
Zeldin
Darryl C
DC
Wang
Dao Wen
DW
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000652:urine; D000818:Animals; D001794:Blood Pressure; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D017931:DNA Primers; D019332:Endothelin-1 / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005632:Fructose / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000235:genetics / Q000517:prevention & control; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology; D024821:Metabolic Syndrome / Q000235:genetics / Q000517:prevention & control*; D051379:Mice; D052250:Nitric Oxide Synthase Type III / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D044022:Receptor, Endothelin A / Q000235:genetics
C107016:14,15-dihydroxyeicosatrienoic acid; D017931:DNA Primers; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D005632:Fructose; D003577:Cytochrome P-450 Enzyme System; D052250:Nitric Oxide Synthase Type III; C106098:Cyp2j3 protein, rat; D015126:8,11,14-Eicosatrienoic Acid