KMID : 1141520210360010171
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Endocrinology and Metabolism 2021 Volume.36 No. 1 p.171 ~ p.184
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Mechanism of Lipid Accumulation through PAR2 Signaling in Diabetic Male Mice
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Kim Dae-Hyun
Kim Ye-Ra Bang Eun-Jin Ha Su-Gyeong Noh Sang-Gyun Kim Byeong-Moo Jeong Seong-Hoon Jung Hee-Jin Lee Ji-Young
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Abstract
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Background: Protease-activated protein-2 (PAR2) has been reported to regulate hepatic insulin resistance condition in type 2 diabetes mice. However, the mechanism of lipid metabolism through PAR2 in obesity mice have not yet been examined. In liver, Forkhead box O1 (FoxO1) activity induces peroxisome proliferator-activated receptor ¥ã (PPAR¥ã), leading to accumulation of lipids and hyperlipidemia. Hyperlipidemia significantly influence hepatic steatoses, but the mechanisms underlying PAR2 signaling are complex and have not yet been elucidated.
Methods: To examine the modulatory action of FoxO1 and its altered interaction with PPAR¥ã, we utilized db/db mice and PAR2-knockout (KO) mice administered with high-fat diet (HFD).
Results: Here, we demonstrated that PAR2 was overexpressed and regulated downstream gene expressions in db/db but not in db+ mice. The interaction between PAR2/¥â-arrestin and Akt was also greater in db/db mice. The Akt inhibition increased FoxO1 activity and subsequently PPAR¥ã gene in the livers that led to hepatic lipid accumulation. Our data showed that FoxO1 was negatively controlled by Akt signaling and consequently, the activity of a major lipogenesis-associated transcription factors such as PPAR¥ã increased, leading to hepatic lipid accumulation through the PAR2 pathway under hyperglycemic conditions in mice. Furthermore, the association between PPAR¥ã and FoxO1 was increased in hepatic steatosis condition in db/db mice. However, HFD-fed PAR2-KO mice showed suppressed FoxO1-induced hepatic lipid accumulation compared with HFD-fed control groups.
Conclusion: Collectively, our results provide evidence that the interaction of FoxO1 with PPAR¥ã promotes hepatic steatosis in mice. This might be due to defects in PAR2/¥â-arrestin-mediated Akt signaling in diabetic and HFD-fed mice.
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KEYWORD
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Forkhead box protein O1, PPAR gamma, Receptor, PAR-2, Obesity, Fatty liver, Hyperlipidemia
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