The P72R Polymorphism of p53 Predisposes to Obesity and Metabolic Dysfunction

被引:92
作者
Kung, Che-Pei [1 ]
Leu, Julia I-Ju [2 ]
Basu, Subhasree [1 ]
Khaku, Sakina [1 ]
Anokye-Danso, Frederick [3 ]
Liu, Qin [1 ,4 ]
George, Donna L. [2 ]
Ahima, Rexford S. [3 ]
Murphy, Maureen E. [1 ]
机构
[1] Wistar Inst Anat & Biol, Mol & Cellular Oncogenesis Program, 3601 Spruce St, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Perelman Sch, Dept Genet, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Perelman Sch, Inst Diabet Obes & Metab, Philadelphia, PA 19104 USA
[4] Wistar Inst Anat & Biol, Biostat Unit, 3601 Spruce St, Philadelphia, PA 19104 USA
关键词
TUMOR-SUPPRESSOR P53; FATTY LIVER-DISEASE; DIABETES-MELLITUS; PROGRESSION; ASSOCIATION; VARIANTS; INFLAMMATION; INHIBITION; RS1042522; APOPTOSIS;
D O I
10.1016/j.celrep.2016.02.037
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
p53 is well known for its tumor suppressor role, but this protein also has a poorly understood role in the regulation of metabolism. Human studies have implicated a common polymorphism at codon 72 of p53 in diabetic and pre-diabetic phenotypes. To understand this role, we utilized a humanized mouse model of the p53 codon 72 variants and monitored these mice following challenge with a high-fat diet (HFD). Mice with the arginine 72 (R72) variant of p53 developed more-severe obesity and glucose intolerance on a HFD, compared tomice with the proline 72 variant (P72). R72 mice developed insulin resistance, islet hypertrophy, increased infiltration of immune cells, and fatty liver disease. Gene expression analyses and studies with small-molecule inhibitors indicate that the p53 target genes Tnf and Npc1l1 underlie this phenotype. These results shed light on the role of p53 in obesity, metabolism, and inflammation.
引用
收藏
页码:2413 / 2425
页数:13
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