P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice
Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P...
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MDPI AG
2021-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/11/5528 |
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| author | Theodomir Dusabimana Eun Jung Park Jihyun Je Kyuho Jeong Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park |
| author_facet | Theodomir Dusabimana Eun Jung Park Jihyun Je Kyuho Jeong Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park |
| author_sort | Theodomir Dusabimana |
| collection | DOAJ |
| description | Non-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD. |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T11:06:34Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-9d0185334f6443ab9bebdce6968729022023-11-21T21:07:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-05-012211552810.3390/ijms22115528P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed MiceTheodomir Dusabimana0Eun Jung Park1Jihyun Je2Kyuho Jeong3Seung Pil Yun4Hye Jung Kim5Hwajin Kim6Sang Won Park7Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaDepartment of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, KoreaNon-alcoholic fatty liver disease (NAFLD) is a chronic metabolic liver disease associated with obesity and insulin resistance. Activation of the purinergic receptor P2Y2R has been reported to promote adipogenesis, inflammation and dyslipidemia in adipose tissues in obese mice. However, the role of P2Y2R and its mechanisms in NAFLD remain unknown. We hypothesized that P2Y2R deficiency may play a protective role in NAFLD by modulating lipid metabolism in the liver. In this study, we fed wild type and P2Y2R knockout mice with a high-fat diet (HFD) for 12 weeks and analyzed metabolic phenotypes. First, P2Y2R deficiency effectively improved insulin resistance with a reduction in body weight and plasma insulin. Second, P2Y2R deficiency attenuated hepatic lipid accumulation and injury with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Third, P2Y2R deficiency decreased the expression of fatty acid synthesis mediators (cluster of differentiation (CD36), fatty acid synthase (FAS), and stearoyl-CoA desaturase 1 (SCD1)); and increased the expression of adipose triglyceride lipase (ATGL), a lipolytic enzyme. Mechanistically, P2Y2R deficiency increased the AMP-activated protein kinase (AMPK) activity to improve mitochondrial fatty acid β-oxidation (FAO) by regulating acetyl-CoA carboxylase (ACC) and carnitine palmitoyltransferase 1A (CPT1A)-mediated FAO pathway. In addition, P2Y2R deficiency increased peroxisome proliferator-activated gamma co-activator-1α (PGC-1α)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1α pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD.https://www.mdpi.com/1422-0067/22/11/5528P2Y2RAMPKfatty acid β-oxidationhepatic steatosisNAFLD |
| spellingShingle | Theodomir Dusabimana Eun Jung Park Jihyun Je Kyuho Jeong Seung Pil Yun Hye Jung Kim Hwajin Kim Sang Won Park P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice International Journal of Molecular Sciences P2Y2R AMPK fatty acid β-oxidation hepatic steatosis NAFLD |
| title | P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice |
| title_full | P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice |
| title_fullStr | P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice |
| title_full_unstemmed | P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice |
| title_short | P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice |
| title_sort | p2y2r deficiency ameliorates hepatic steatosis by reducing lipogenesis and enhancing fatty acid β oxidation through ampk and pgc 1α induction in high fat diet fed mice |
| topic | P2Y2R AMPK fatty acid β-oxidation hepatic steatosis NAFLD |
| url | https://www.mdpi.com/1422-0067/22/11/5528 |
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