Mechanism of Lipid Accumulation through PAR2 Signaling in Diabetic Male Mice
| Autor: | Ji Young Lee, Hee Jin Jung, EunJin Bang, Hae Young Chung, Byeong Moo Kim, Sang Gyun Noh, Ye Ra Kim, Dae Hyun Kim, Sugyeong Ha, Seong Ho Jeong |
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| Rok vydání: | 2021 |
| Předmět: |
Male
medicine.medical_specialty Endocrinology Diabetes and Metabolism Peroxisome proliferator-activated receptor PAR-2 030209 endocrinology & metabolism FOXO1 lcsh:Diseases of the endocrine glands. Clinical endocrinology Mice 03 medical and health sciences 0302 clinical medicine Endocrinology Insulin resistance Internal medicine medicine Animals Obesity Receptor Forkhead box protein O1 Protein kinase B chemistry.chemical_classification lcsh:RC648-665 Lipogenesis Fatty liver nutritional and metabolic diseases Lipid metabolism medicine.disease Lipids Fatty Liver Mice Inbred C57BL PPAR gamma Hyperlipidemia Diabetes Mellitus Type 2 chemistry 030220 oncology & carcinogenesis Original Article lipids (amino acids peptides and proteins) Steatosis |
| Zdroj: | Endocrinology and Metabolism Endocrinology and Metabolism, Vol 36, Iss 1, Pp 171-184 (2021) |
| ISSN: | 2093-5978 2093-596X |
| Popis: | Background: Protease-activated protein-2 (PAR2) has been reported to regulate hepatic insulin resistance condition in type 2 diabe tes mice. However, the mechanism of lipid metabolism through PAR2 in obesity mice have not yet been examined. In liver, Fork head box O1 (FoxO1) activity induces peroxisome proliferator-activated receptor γ (PPARγ), leading to accumulation of lipids and hyperlipidemia. Hyperlipidemia significantly influence hepatic steatoses, but the mechanisms underlying PAR2 signaling are com plex and have not yet been elucidated. Methods: To examine the modulatory action of FoxO1 and its altered interaction with PPARγ, 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/β-arrestin and Akt was also greater in db/db mice. The Akt inhibition increased FoxO1 activity and subsequently PPARγ gene in the livers that led to hepatic lipid accumulation. Our data showed that FoxO1 was negatively con trolled by Akt signaling and consequently, the activity of a major lipogenesis-associated transcription factors such as PPARγ in creased, leading to hepatic lipid accumulation through the PAR2 pathway under hyperglycemic conditions in mice. Furthermore, the association between PPARγ 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 PPARγ promotes hepatic steatosis in mice. This might be due to defects in PAR2/β-arrestin-mediated Akt signaling in diabetic and HFD-fed mice. |
| Databáze: | OpenAIRE |
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