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Publication
Epoxygenase Cyp2c44 Regulates Hepatic Lipid Metabolism and Insulin Signaling by
Controlling FATP2 Localization and Activation of the DAG/PKCd Axis.
Authors Ghoshal K, Luther JM, Pakala SB, Chetyrkin S, Falck JR, Zent R, Wasserman DH,
Pozzi A
Submitted By Submitted Externally on 10/15/2024
Status Published
Journal Diabetes
Year 2024
Date Published 8/1/2024
Volume : Pages 73 : 1229 - 1243
PubMed Reference 38743615
Abstract Cytochrome P450 epoxygenase Cyp2c44, a murine epoxyeicosatrienoic acid
(EET)-producing enzyme, promotes insulin sensitivity, and Cyp2c44-/- mice show
hepatic insulin resistance. Because insulin resistance leads to hepatic lipid
accumulation and hyperlipidemia, we hypothesized that Cyp2c44 regulates hepatic
lipid metabolism. Standard chow diet (SCD)-fed male Cyp2c44-/- mice had
significantly decreased EET levels and increased hepatic and plasma lipid levels
compared with wild-type mice. We showed increased hepatic plasma membrane
localization of the FA transporter 2 (FATP2) and total unsaturated fatty acids
and diacylglycerol (DAG) levels. Cyp2c44-/- mice had impaired glucose tolerance
and increased hepatic plasma membrane-associated PKCd and phosphorylated IRS-1,
two negative regulators of insulin signaling. Surprisingly, SCD and high-fat
diet (HFD)-fed Cyp2c44-/- mice had similar glucose tolerance and hepatic plasma
membrane PKCd levels, suggesting that SCD-fed Cyp2c44-/- mice have reached their
maximal glucose intolerance. Inhibition of PKCd resulted in decreased IRS-1
serine phosphorylation and improved insulin-mediated signaling in Cyp2c44-/-
hepatocytes. Finally, Cyp2c44-/- HFD-fed mice treated with the analog EET-A
showed decreased hepatic plasma membrane FATP2 and PCKd levels with improved
glucose tolerance and insulin signaling. In conclusion, loss of Cyp2c44 with
concomitant decreased EET levels leads to increased hepatic FATP2 plasma
membrane localization, DAG accumulation, and PKCd-mediated attenuation of
insulin signaling. Thus, Cyp2c44 acts as a regulator of lipid metabolism by
linking it to insulin signaling.




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