LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes

Jingzhong Ding; Anh Tram Nguyen; Kurt Lohman; Michael T Hensley; Daniel Parker; Li Hou; Jackson Taylor; Deepak Voora; Janet K Sawyer; Elena Boudyguina; Michael P Bancks; Alain Bertoni; James S Pankow; Jerome I Rotter; Mark O Goodarzi; Russell P Tracy; David M Murdoch; Stephen S Rich; Bruce M Psaty; David Siscovick; Christopher Newgard; David Herrington; Ina Hoeschele; Steven Shea; James H Stein; Manesh Patel; Wendy Post; David Jacobs Jr; John S Parks; Yongmei Liu

doi:10.1172/JCI173278

LXR signaling pathways link cholesterol metabolism with risk for prediabetes and diabetes

J Clin Invest. 2024 May 15;134(10):e173278. doi: 10.1172/JCI173278.

Authors

Jingzhong Ding¹, Anh Tram Nguyen², Kurt Lohman², Michael T Hensley², Daniel Parker³, Li Hou², Jackson Taylor⁴, Deepak Voora², Janet K Sawyer¹, Elena Boudyguina¹, Michael P Bancks⁵, Alain Bertoni¹, James S Pankow⁶, Jerome I Rotter⁷, Mark O Goodarzi⁸, Russell P Tracy⁹, David M Murdoch¹⁰, Stephen S Rich¹¹, Bruce M Psaty¹², David Siscovick¹³, Christopher Newgard¹⁴, David Herrington¹, Ina Hoeschele¹⁵, Steven Shea¹⁶, James H Stein¹⁷, Manesh Patel², Wendy Post¹⁸, David Jacobs Jr⁶, John S Parks¹, Yongmei Liu²

Affiliations

¹ Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
² Department of Medicine, Division of Cardiology, and.
³ Department of Medicine, Division of Geriatrics, Duke University, Durham, North Carolina, USA.
⁴ Department of Biological, Geological, and Environmental Sciences, Cleveland State University, Cleveland, Ohio, USA.
⁵ Department of Epidemiology and Prevention, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
⁶ Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.
⁷ The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California, USA.
⁸ Division of Endocrinology, Diabetes and Metabolism, Cedars-Sinai Medical Center, Los Angeles, California, USA.
⁹ Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, Vermont, USA.
¹⁰ Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Durham, North Carolina, USA.
¹¹ Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia, USA.
¹² Cardiovascular Health Research Unit, Departments of Medicine, Epidemiology, and Health Systems and Population Health, University of Washington, Seattle, Washington, USA.
¹³ New York Academy of Medicine, New York, New York, USA.
¹⁴ Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina, USA.
¹⁵ Fralin Life Sciences Institute, Virginia Tech, Blacksburg, Virginia, USA.
¹⁶ Department of Medicine, Columbia University, New York, New York, USA.
¹⁷ School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
¹⁸ Division of Cardiology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.

Abstract

BACKGROUNDPreclinical 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.METHODSMonocyte 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.RESULTSDuring 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.CONCLUSIONThese 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.FUNDINGThe 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.

Keywords: Cholesterol; Diabetes; Expression profiling; Metabolism.

Publication types

Clinical Trial
Multicenter Study

MeSH terms

ATP Binding Cassette Transporter 1 / genetics
ATP Binding Cassette Transporter 1 / metabolism
ATP Binding Cassette Transporter, Subfamily G, Member 1 / genetics
ATP Binding Cassette Transporter, Subfamily G, Member 1 / metabolism
Aged
Aged, 80 and over
Cholesterol* / metabolism
Diabetes Mellitus, Type 2* / epidemiology
Diabetes Mellitus, Type 2* / genetics
Diabetes Mellitus, Type 2* / metabolism
Female
Humans
Liver X Receptors* / genetics
Liver X Receptors* / metabolism
Male
Middle Aged
Monocytes / metabolism
Prediabetic State* / genetics
Prediabetic State* / metabolism
Risk Factors
Signal Transduction*

Grants and funding

R01 HL119962/HL/NHLBI NIH HHS/United States