PMID- 34073834 OWN - NLM STAT- MEDLINE DCOM- 20210624 LR - 20210624 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 22 IP - 11 DP - 2021 May 24 TI - P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid beta-Oxidation through AMPK and PGC-1alpha Induction in High-Fat Diet-Fed Mice. LID - 10.3390/ijms22115528 [doi] LID - 5528 AB - 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 beta-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-1alpha (PGC-1alpha)-mediated mitochondrial biogenesis. Conclusively, P2Y2R deficiency ameliorated HFD-induced hepatic steatosis by enhancing FAO through AMPK signaling and PGC-1alpha pathway, suggesting P2Y2R as a promising therapeutic target for NAFLD. FAU - Dusabimana, Theodomir AU - Dusabimana T AUID- ORCID: 0000-0002-8337-4969 AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. AD - Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Korea. FAU - Park, Eun Jung AU - Park EJ AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. FAU - Je, Jihyun AU - Je J AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. FAU - Jeong, Kyuho AU - Jeong K AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. FAU - Yun, Seung Pil AU - Yun SP AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. AD - Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Korea. FAU - Kim, Hye Jung AU - Kim HJ AUID- ORCID: 0000-0002-7067-6810 AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. AD - Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Korea. FAU - Kim, Hwajin AU - Kim H AUID- ORCID: 0000-0002-7181-3696 AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. FAU - Park, Sang Won AU - Park SW AUID- ORCID: 0000-0002-6149-5284 AD - Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University College of Medicine, Jinju 52727, Korea. AD - Department of Convergence Medical Sciences, Institute of Health Sciences, Gyeongsang National University Graduate School, Jinju 52727, Korea. LA - eng GR - 2015R1A5A2008833/National Research Foundation of Korea/ GR - 2017R1A2B4009387/National Research Foundation of Korea/ PT - Journal Article DEP - 20210524 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (CD36 Antigens) RN - 0 (Fatty Acids) RN - 0 (Insulin) RN - 0 (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha) RN - 0 (Ppargc1a protein, mouse) RN - 0 (Receptors, Purinergic P2Y2) RN - EC 1.14.19.1 (Stearoyl-CoA Desaturase) RN - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase) RN - EC 2.3.1.85 (Fatty Acid Synthases) RN - EC 2.6.1.1 (Aspartate Aminotransferases) RN - EC 2.6.1.2 (Alanine Transaminase) RN - EC 2.7.11.31 (AMP-Activated Protein Kinases) RN - EC 3.1.1.3 (Lipase) RN - EC 3.1.1.3 (PNPLA2 protein, mouse) RN - EC 6.4.1.2 (Acetyl-CoA Carboxylase) SB - IM MH - AMP-Activated Protein Kinases/*metabolism MH - Acetyl-CoA Carboxylase/metabolism MH - Alanine Transaminase/metabolism MH - Animals MH - Aspartate Aminotransferases/metabolism MH - Body Weight MH - CD36 Antigens/metabolism MH - Carnitine O-Palmitoyltransferase/metabolism MH - Diet, High-Fat MH - Fatty Acid Synthases/metabolism MH - Fatty Acids/*metabolism MH - Insulin/blood MH - Insulin Resistance/physiology MH - Lipase/metabolism MH - Lipogenesis/*genetics MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Mice, Obese MH - Mitochondria/metabolism MH - Non-alcoholic Fatty Liver Disease/enzymology/*metabolism MH - Obesity/metabolism MH - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/*metabolism MH - Receptors, Purinergic P2Y2/deficiency/genetics/*metabolism MH - Stearoyl-CoA Desaturase/metabolism PMC - PMC8197197 OTO - NOTNLM OT - AMPK OT - NAFLD OT - P2Y2R OT - fatty acid beta-oxidation OT - hepatic steatosis COIS- The authors declare no conflict of interest. EDAT- 2021/06/03 06:00 MHDA- 2021/06/25 06:00 PMCR- 2021/05/24 CRDT- 2021/06/02 01:39 PHST- 2021/03/15 00:00 [received] PHST- 2021/05/10 00:00 [revised] PHST- 2021/05/18 00:00 [accepted] PHST- 2021/06/02 01:39 [entrez] PHST- 2021/06/03 06:00 [pubmed] PHST- 2021/06/25 06:00 [medline] PHST- 2021/05/24 00:00 [pmc-release] AID - ijms22115528 [pii] AID - ijms-22-05528 [pii] AID - 10.3390/ijms22115528 [doi] PST - epublish SO - Int J Mol Sci. 2021 May 24;22(11):5528. doi: 10.3390/ijms22115528.