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| 1 | Hierarchical activation of compartmentalized pools of AMPK depends on severity of nutrient or energy stress显示文摘AMPK, a master regulator of metabolic homeostasis, is activated by both AMP-dependent and AMP-independent mechanisms. The conditions under which these different mechanisms operate, and their biological implications are unclear. Here, we show that, depending on the degree of elevation of cellular AMP, distinct compartmentalized pools of AMPK are activated, phosphorylating different sets of targets. Low glucose activates AMPK exclusively through the AMP-independent, AXIN-based pathway in lysosomes to phosphorylate targets such as ACC1 and SREBP1c, exerting early anti-anabolic and pro-catabolic roles. Moderate increases in AMP expand this to activate cytosolic AMPK also in an AXIN-dependent manner. In contrast, high concentrations of AMP, arising from severe nutrient stress, activate all pools of AMPK independently of AXIN. Surprisingly, mitochondrion-localized AMPK is activated to phosphorylate ACC2 and mitochondrial fission factor (MFF) only during severe nutrient stress. Our findings reveal a spatiotemporal basis for hierarchical activation of different pools of AMPK during differing degrees of stress severity. | Yue Zong Chen-Song Zhang Mengqi Li Wen Wang Zhichao Wang Simon A. Hawley Teng Ma Jin-Wei Feng Xiao Tian Qu Qi Yu-Qing Wu Cixiong Zhang Zhiyun Ye Shu-Yong Lin Hai-Long Piao D. Grahame Hardie Sheng-Cai Lin | 2019 | Cell Research2019，29，6： | 8 |
| 2 | Meta-analysis of dose-response relationships for hydrochlorothiazide, chlorthali- done, and bendroflumethiazide on blood pressure, serum potassi- um, and urata显示文摘 | Peterzan MA Hardy R Chaturvedi N | 2012 | Hypertension2012，59，6： | 1 |
| 3 | Principles of metacarpal and phalangeal fracture manage- ment:a review of rehabilitation concepts 显示文摘 | Hardy MA | 2004 | J Orthop Sports Phys Ther2004，34，： | 1 |
| 4 | Noninvasive measurement of glucose and pyruvate uptake by individual human oocytes and premplantation embryos 显示文摘 | Hardy K Hooper MA Handyside AH | 1989 | Hum Reprod1989，4，： | 1 |
| 5 | Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival显示文摘 | DePaz HA Oluwole OO Adeyert AO Witkowski P Jin MX Hardy MA et ol | 2003 | Transplantation2003，75，4： | 1 |
| 6 | Negative impact of neutro- phil-lymphocyte ratio on outcome after liver transplantation for hepato- cellular careinomaa显示文摘 | Halazun K J Hardy MA Rana AA | 2009 | Ann Surg2009，250，1： | 1 |
| 7 | Henri Albert Hartmann: labor and disci- pline 显示文摘 | Ronel DN Hardy MA | 2002 | Curr Surg2002，59，1： | 1 |
| 8 | Protein kinase C-mediated phosphorylation of the human multidrug resistance P-glycoprotein regulates cell volume-activated chloride channels显示文摘 | Hardy SP Goodfellow HR Valverde MA | 1995 | EMBO J1995，14，： | 1 |
| 9 | Principles of metacarpal and phalangeal fracture management: a review of rehabilitation concepts 显示文摘 | Hardy MA | 2004 | J Orthop Sports Phys Ther2004，34，12： | 1 |
| 10 | The fetal origins of the metabolic syndrome: can we intervene显示文摘 | MA N HARDY DB | 2012 | J Pregnancy2012，2012，： | 1 |
| 11 | Negative impact of neutrophil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma显示文摘 | Halazun KI Hardy MA Rana AA | 2009 | Ann Surg2009，250，： | 1 |
| 12 | Noninvasive measurement of glucose and pyruvate uptake by individual hu- man oocytes and preimplantation embryos 显示文摘 | Hardy K Hooper MA Handyside AH | 1989 | Hum Re- prod1989，4，2： | 1 |
| 13 | Principles of metacarpal and phalangeal fracture management:areview of rehabilitation concepts显示文摘 | Hardy MA | 2004 | J Orthop Sports Phys Ther2004，34，12： | 1 |
| 14 | Negative impactof neut rophi l - lymphocyt e r a t io on out come a f t e r l ive rtransplantation for hepatocellular carcinoma显示文摘 | Halazun KJ Hardy MA Rana AA | 2009 | Ann Surg2009，250，1： | 1 |
| 15 | Dependence of acquired systemic tolerance to rat isolet allografts induced by intrathymic solubleallo antigens on host responsiveness,MHC differences and transient immunosuppression in the high responder recipient显示文摘 | Fiedor P Jin MX Hardy MA | 1997 | Transplantation1997，63，： | 1 |
| 16 | Pancreatic islet trnsplantation: induction of graft acceptance by ultraviolet irradiation of donor tissue 显示文摘 | Hardy MA Lau H Weber C | 1984 | Ann Surg1984，200，4： | 1 |
| 17 | Evaluation of the LIAISON chemiluminescence immunoassay for diagnosis of syphilis显示文摘 | Knight CS Crum MA Hardy RW | 2007 | Clin Vaccine Immunol2007，14，6： | 1 |
| 18 | Multicenter, randomized study of the use of everolimus with tacrolimus after renal transplantation demonstrates its effectiveness 显示文摘 | Chan L Greenstein S Hardy MA | 2008 | Transplantation2008，85，6： | 1 |
| 19 | Genomic profile of matrix and vasculature remodeling in TGF-alpha induced pulmohary fibrosis显示文摘 | Hardie WD Korfhagen TR Sartor MA | 2007 | Am J Respir Cell Mol Biol2007，37，3： | 1 |
| 20 | Negative impact of neutro- phil-lymphocyte ratio on outcome after liver transplantation for hepatocellular carcinoma显示文摘 | Halazun KJ Hardy MA Rana AA | 2009 | Ann Surg2009，250，1： | 1 |
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