Dissertation/Thesis Abstract

Modulation of Liver X Receptor Signaling by a Novel Cofactor PARP-1 and LXRα S196 phosphorylation in Atherosclerosis and Diabetes
by Shrestha, Elina, Ph.D., New York University, 2017, 215; 10260780
Abstract (Summary)

Atherosclerosis is an inflammatory disease characterized by accumulation of cholesterol-laden macrophages in arterial walls. LXRs are transcription factors that impart anti-atherogenic effects by upregulating expression of genes crucial in maintaining cholesterol homeostasis and repressing inflammatory gene expression. LXR activation reduces atherosclerosis and enhances regression of established plaques in mice. However, regulation of LXR dependent gene expression in macrophages by coregulatory factors and posttranslational modifications on LXR remain to be elucidated. To identify novel regulators of LXR that modulate its activity, I used affinity purification and mass spectrometry to analyze nuclear LXRα complexes, and identified poly(ADP-ribose) polymerase-1 (PARP-1) as an LXR-associated factor. Both depletion of PARP-1 and inhibition of PARP-1 activity augmented LXR ligand-induced expression of ABCA1, an important cholesterol efflux transporter. Notably, inhibition of PARP1 enhanced macrophage ABCA1-mediated cholesterol efflux to the lipid acceptor ApoAI. I found that LXR is poly(ADP-ribosyl)ated by PARP-1, a potential mechanism by which PARP-1 influences LXR function. These findings highlight the importance of PARP-1 in LXR-regulated lipid homeostasis and suggest that inhibition of PARP1 activity could be atheroprotective. Importantly, diabetes impairs regression of atherosclerotic plaques in mice likely through changes in the expression of genes involved in macrophage retention in the plaque. I hypothesized that LXR function is dysregulated under hyperglycemia through LXRα phosphorylation at serine 198 (pS196), which inhibits LXRα activity at select target genes. To investigate the effects of pS196 during regression, I used Reversa mice reconstituted with bone marrow cells capable of switching LXRα WT expression to phosphorylation deficient S196A. Surprisingly, S196A increased circulating leukocytes, which potentially contributed to increased monocyte recruitment and macrophage content in the plaque under normoglycemia, and showed less regression compared to controls. Under hyperglycemia however, S196A did not increase macrophage content in the plaque despite increased blood leukocytes and monocyte recruitment profiles, and thus regression was similar between S196A and controls. Consistent with these findings, I found that diabetes is associated with enhanced LXRα pS196 and increased macrophage retention in the plaque, which is reversed in the LXRα pS196 deficient mice. RNA-seq analysis of plaque macrophages showed increased expression of genes important in chemotaxis and reduced expression of genes important in cell adhesion in diabetic mice deficient in LXRα pS196, elucidating a potential role of diabetes-associated LXRα pS196 in preventing macrophage emigration. Therefore, inhibiting LXRα phosphorylation at S196 could be beneficial in diabetic atherosclerosis to reverse the accumulation of macrophages in the plaque.

Indexing (document details)
Advisor: Garabedian, Michael J.
Commitee: Fisher, Edward A., Loke, P'ng, Rogatsky, Inez, Wilson, Angus C.
School: New York University
Department: Basic Medical Science
School Location: United States -- New York
Source: DAI-B 79/01(E), Dissertation Abstracts International
Source Type: DISSERTATION
Subjects: Biology, Molecular biology, Cellular biology
Keywords: Atherosclerosis, Cholesterol efflux, Diabetes, Liver x receptor, Parp1, Transcription
Publication Number: 10260780
ISBN: 9780355128161
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