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Lipid Signaling Pathways in Physiology and Disease
Summary: Peter Tontonoz studies the regulation of gene expression by nuclear receptors and the relationship of these signaling pathways to human diseases such as obesity, diabetes, and atherosclerosis.
Obesity, diabetes, and cardiovascular disease are the leading causes of morbidity and mortality in industrialized societies. The common thread that links these disorders is dysregulation of lipid metabolism. Our long-term goal is to understand the mechanisms whereby lipids control gene expression and impact the development of metabolic disease. With the discovery of nuclear receptors that are activated by lipids, the past 15 years have seen a new paradigm emerge for the transcriptional regulation of metabolic pathways. Dissection of these pathways is advancing our understanding of basic mechanisms that control metabolism and highlighting new opportunities for therapeutic intervention in disease.
Control of Cholesterol Homeostasis by LXRs
The liver X receptor (LXR) has emerged as a key transcriptional regulator of sterol metabolism. Elevated levels of cellular cholesterol are accompanied by the increased production of oxysterol agonists of LXR, allowing LXRs to function as cholesterol sensors. In response to activation, LXRs act in a coordinated fashion to maintain cholesterol homeostasis by directing the tissue-specific expression of genes involved in sterol transport and metabolism. A principal function of LXR in macrophages is to promote cholesterol removal from the cell through the induction of ABCA1, ABCG1, and apolipoprotein E.
The observation that the LXR pathway is critical for cholesterol efflux in vitro led us to explore the role of these receptors in the context of the atherosclerotic lesion. Treatment of atherosclerosis-susceptible mice with a synthetic LXR ligand reduced lesion formation. Conversely, mice transplanted with LXR-null bone marrow developed accelerated atherosclerosis. These studies established a central role for LXR in macrophage cholesterol homeostasis and have stimulated interest in LXR agonists as cardiovascular therapeutics. Recently, we showed that targeting LXRβ with synthetic agonists inhibits atherosclerosis in the absence of LXRα. Since the major side effects of LXR agonists (hypertriglyceridemia and fatty liver) are due to LXRα, these findings provide strong support for drug development strategies targeting LXRβ.
A Novel Mechanism for Sterol-Dependent Regulation of LDL Uptake
The low-density lipoprotein receptor (LDLR) is central to the maintenance of plasma cholesterol levels. As Michael Brown and Joseph Goldstein (University of Texas Southwestern Medical Center at Dallas) elucidated, transcription of the LDLR gene is controlled primarily by sterol regulatory element-binding protein (SREBP) transcription factors, which are active when cellular cholesterol levels are low and inactive when they are high. Until recently, feedback inhibition of the SREBP pathway was believed to be the only mechanism for sterol-dependent regulation of LDLR activity. Our dissection of the LXR signaling pathway has led to the discovery of a second, SREBP-independent mechanism for regulation of the lipoprotein uptake.
Treatment of many different cell types with LXR agonists removes the LDLR from the plasma membrane and promotes its degradation, thereby blocking LDL uptake. We discovered that LXR down-regulates the LDLR pathway through the transcriptional induction of an E3 ubiquitin ligase that we termed Idol (inducible degrader of the LDLR). Idol triggers ubiquitination of the LDLR on its cytoplasmic domain, thereby targeting it for degradation. Inactivation of Idol by siRNA knockdown or genetic deletion inhibits LDLR degradation and promotes LDL uptake. The LXR-Idol-LDLR axis defines a previously unrecognized pathway for sterol regulation of LDL metabolism and a potential target for pharmacologic intervention. This work has also advanced our understanding of how the two major sterol-regulated transcriptional factors, SREBP and LXR, act in a complementary and coordinated fashion to maintain cholesterol homeostasis.
Dissection of the Idol pathway will be a major focus of my laboratory in the coming years. Foremost among the issues to be addressed are the contribution of the LXR-Idol-LDLR pathway to tissue-specific cholesterol homeostasis and its interrelationship with other regulatory pathways, such as SREBP and PCSK9. Recent work further suggests that Idol may play an unexpected role in the brain. We have found that Idol also targets the very low density lipoprotein receptor (VLDLR) and apoER2 for degradation. These two LDLR family members are critical for neuronal development because of their function as Reelin receptors. A particularly provocative question is the identity of the sterol signals that may activate LXR/Idol and modulate Reelin signaling in the brain. Clarification of the mechanisms of Idol regulation in this setting may provide insight into links between lipid metabolism and neuronal biology.
Nuclear Receptors as Integrators of Metabolic and Immune Signaling
Inflammation is an integral component of metabolic disorders, including atherosclerosis and type 2 diabetes. An unexpected insight to emerge from our study of LXR was the recognition that lipid metabolic and inflammatory signaling pathways in macrophages are intimately connected. Recent work has extended these observations and provided support for the relevance of these connections for immune homeostasis in vivo.
It has long been appreciated that cholesterol is required for cell proliferation as a key membrane constituent. However, the mechanisms that link metabolism to proliferation are still poorly understood. We found that sterols and the LXR pathway are physiologically regulated determinants of acquired immune responses. Contrary to expectations, the requirement for cholesterol in cell reproduction is not simply due to the consequences of defective membrane synthesis. Rather, we showed that endoplasmic reticulum (ER) sterol levels, LXR, and ABC transporters participate in a "metabolic checkpoint" that modulates cell cycle progression. During normal T cell activation, the LXR signaling pathway is rapidly down-regulated, at least in part because of induction of the oxysterol-metabolizing enzyme SULT2B1, which inactivates LXR ligands. Inactivation of LXR leads to down-regulation of the sterol transporters ABCA1 and ABCG1, which efflux sterols from the plasma membrane and ER, respectively. In vivo, loss of LXR expression confers a proliferative advantage to lymphocytes as a result of increased sterol availability, resulting in enhanced antigen-driven responses and lymphoid hyperplasia. This work provided a mechanistic context in which to view the relationship between sterol metabolism and cell proliferation. We believe this pathway may have relevance for other rapidly proliferating cell types as well.
LXRs Link Sterol Signaling, Apoptotic Cell Clearance, and Immune Tolerance
Effective clearance of apoptotic cells by macrophages is essential for immune homeostasis, because the accumulation of cellular debris can activate inflammatory pathways and lead to the development of autoimmunity. The transcriptional pathways engaged by macrophages during phagocytosis are incompletely understood. Mechanisms whereby phagocytes distinguish between engulfment of apoptotic cells and engulfment of pathogens also remain to be clarified. Given the ability of LXR to sense and respond to elevated levels of cellular sterols, we hypothesized that accumulated membrane-derived lipids in macrophages following phagocytosis of apoptotic cells might activate LXR signaling. As cholesterol is not a component of many pathogens, we postulated that apoptotic cell activation of LXR might provide a mechanism for modulation of inflammatory responses.
We discovered that LXR-deficient macrophages are impaired in their ability to engulf apoptotic cells and we tracked this defect to altered expression of Mer, a key surface receptor for apoptotic cells. We also showed that LXR is activated by sterols present in apoptotic cells during normal phagocytosis. Activation of LXR in this context leads not only to increased expression of Mer but also to the suppression of proinflammatory pathways. We suspected that disruption of normal LXR-Mer regulation might lead to loss of tolerance, because defects in Mer signaling have previously been reported to result in lupus-like disease. Indeed, we found that mice lacking LXRs develop autoantibodies and marked autoimmune disease. Treatment with synthetic LXR agonist ameliorated disease severity in a mouse model of autoimmunity. Our data suggest that activation of LXR by apoptotic cells engages a virtuous cycle that promotes their own clearance and couples engulfment to the suppression of inflammatory pathways.
This work is also supported by grants from the National Institutes of Health.
As of May 30, 2012
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