期刊
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
卷 297, 期 2, 页码 E474-E482出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.90369.2008
关键词
leptin receptor; acyl-coenzyme A:cholesterol acyltransferase-1; acyl-coenzyme A:cholesterol acyltransferase inhibitor; atherosclerosis
资金
- Japan Society for the Promotion of Science [18590824, 20591084]
- Grants-in-Aid for Scientific Research [18590824, 20591084] Funding Source: KAKEN
Hongo S, Watanabe T, Arita S, Kanome T, Kageyama H, Shioda S, Miyazaki A. Leptin modulates ACAT1 expression and cholesterol efflux from human macrophages. Am J Physiol Endocrinol Metab 297: E474-E482, 2009; doi: 10.1152/ajpendo.90369.2008.-Leptin is an adipose tissue-derived hormone implicated in atherosclerosis and macrophage foam cell formation. The current study was conducted to examine the effect of leptin on cholesteryl ester accumulation in human monocytes/macrophages. Exogenously added leptin at 5 nM during differentiation of monocytes into macrophages for 7 days accelerated acetylated LDL (acetyl-LDL)-induced cholesteryl ester accumulation by 30-50%. Leptin did not affect endocytic uptake of acetyl-LDL; however, it increased ACAT activity 1.8-fold and ACAT-1 protein expression 1.9-fold. Among the four ACAT-1 mRNA transcripts, two shorter transcripts (2.8 and 3.6 kb) were upregulated similar to 1.7-fold upon leptin treatment. The enhanced expression of ACAT-1 protein by leptin was suppressed by inhibitors of Janus-activated kinase2 (JAK2) and phosphatidylinositol 3-kinase (PI3K). HDL-mediated cholesterol efflux was suppressed by leptin, which was canceled by K-604, an ACAT-1 inhibitor. Expression of long form of leptin receptor was upregulated during monocytic differentiation into macrophages and sustained after differentiation. Thus, the results suggest that leptin accelerates cholesteryl ester accumulation in human monocyte-derived macrophages by increasing ACAT-1 expression via JAK2 and PI3K, thereby suppressing cholesterol efflux.
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