학술논문
LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes.
Document Type
Article
Author
Jingzhong Ding; Anh Tram Nguyen; Lohman, Kurt; Hensley, Michael T.; Parker, Daniel; Li Hou; Taylor, Jackson; Voora, Deepak; Sawyer, Janet K.; Boudyguina, Elena; Bancks, Michael P.; Bertoni, Alain; Pankow, James S.; Rotter, Jerome I.; Goodarzi, Mark O.; Tracy, Russell P.; Murdoch, David M.; Rich, Stephen S.; Psaty, Bruce M.; Siscovick, David
Source
Subject
*CHOLESTEROL metabolism
*CD14 antigen
*CELLULAR signal transduction
*GENE regulatory networks
*GENE expression
*PREDIABETIC state
*EFFLUX (Microbiology)
*COMPULSIVE eating
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Language
ISSN
0021-9738
Abstract
BACKGROUND. Preclinical studies suggest that cholesterol accumulation leads to insulin resistance. We previously reported that alterations in a monocyte cholesterol metabolism transcriptional network (CMTN) -- suggestive of cellular cholesterol accumulation -- were cross-sectionally associated with obesity and type 2 diabetes (T2D). Here, we sought to determine whether the CMTN alterations independently predict incident prediabetes/T2D risk, and correlate with cellular cholesterol accumulation. METHODS. Monocyte mRNA expression of 11 CMTN genes was quantified among 934 Multi-Ethnic Study of Atherosclerosis (MESA) participants free of prediabetes/T2D; cellular cholesterol was measured in a subset of 24 monocyte samples. RESULTS. During a median 6-year follow-up, lower expression of 3 highly correlated LXR target genes -- ABCG1 and ABCA1 (cholesterol efflux) and MYLIP (cholesterol uptake suppression) -- and not other CMTN genes, was significantly associated with higher risk of incident prediabetes/T2D. Lower expression of the LXR target genes correlated with higher cellular cholesterol levels (e.g., 47% of variance in cellular total cholesterol explained by ABCG1 expression). Further, adding the LXR target genes to overweight/obesity and other known predictors significantly improved prediction of incident prediabetes/T2D. CONCLUSION. These data suggest that the aberrant LXR/ABCG1-ABCA1-MYLIP pathway (LAAMP) is a major T2D risk factor and support a potential role for aberrant LAAMP and cellular cholesterol accumulation in diabetogenesis. FUNDING. The MESA Epigenomics and Transcriptomics Studies were funded by NIH grants 1R01HL101250, 1RF1AG054474, R01HL126477, R01DK101921, and R01HL135009. This work was supported by funding from NIDDK R01DK103531 and NHLBI R01HL119962. [ABSTRACT FROM AUTHOR]