期刊
CELL METABOLISM
卷 4, 期 5, 页码 377-389出版社
CELL PRESS
DOI: 10.1016/j.cmet.2006.10.002
关键词
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资金
- NCI NIH HHS [CA71387, CA21765] Funding Source: Medline
- NHLBI NIH HHS [HL57278, P50 HL083762] Funding Source: Medline
- NIA NIH HHS [AG20091] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056341-06, P30 DK056341, P30 DK056341-05S2, DK56341, DK20579] Funding Source: Medline
- NIEHS NIH HHS [ES05777] Funding Source: Medline
Metabolic syndrome is associated with insulin resistance and atherosclerosis. Here, we show that deficiency of one or two alleles of ATM, the protein mutated in the cancer-prone disease ataxia telangiectasia, worsens features of the metabolic syndrome, increases insulin resistance, and accelerates atherosclerosis in apoE(-/-) mice. Transplantation with ATM(-/-) as compared to ATM(+/+) bone marrow increased vascular disease. Jun N-terminal kinase (JNK) activity was increased in ATM-deficient cells. Treatment of ATM(+/+)apoE(-/-) mice with low-dose chloroquine, an ATM activator, decreased atherosclerosis. In an ATM-dependent manner, chloroquine decreased macrophage JNK activity, decreased macrophage lipoprotein lipase activity (a proatherogenic consequence of JNK activation), decreased blood pressure, and improved glucose tolerance. Chloroquine also improved metabolic abnormalities in ob/ob and db/db mice. These results suggest that ATMdependent stress pathways mediate susceptibility to the metabolic syndrome and that chloroquine or related agents promoting ATM activity could modulate insulin resistance and decrease vascular disease.
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