Liver X Receptors: Regulators of Cholesterol Metabolism, Inflammation, Autoimmunity, and Cancer

Abstract

The interplay between cellular stress and immune response can be variable and sometimes contradictory. The mechanisms by which stress-activated pathways regulate the inflammatory response to a pathogen, in autoimmunity or during cancer progression remain unclear in many aspects, despite our recent knowledge of the signalling and transcriptional pathways involved in these diseases. In this context, over the last decade many studies demonstrated that cholesterol metabolism is an important checkpoint for immune homeostasis and cancer progression. Indeed, cholesterol is actively metabolized and can regulate, through its mobilization and/or production of active derivatives, many aspects of immunity and inflammation. Moreover, accumulation of cholesterol has been described in cancer cells, indicating metabolic addiction. The nuclear receptors liver-X-receptors (LXRs) are important regulators of intracellular cholesterol and lipids homeostasis. They have also key regulatory roles in immune response, as they can regulate inflammation, innate and adaptive immunity. Moreover, activation of LXRs has been reported to affect the proliferation and survival of different cancer cell types that show altered metabolic pathways and accumulation of cholesterol. In this minireview we will give an overview of the recent understandings about the mechanisms through which LXRs regulate inflammation, autoimmunity, and cancer, and the therapeutic potential for future treatment of these diseases through modulation of cholesterol metabolism.

Cytoplasmic LXR expression is an independent marker of poor prognosis for patients with early stage primary breast cancer

“…LXRα is highly expressed in adipose tissue, liver, adrenal glands, lungs, and gastrointestinal tract, while LXRβ is widely expressed (Repa and Mangelsdorf 2000 ). Upon activation by ligands, LXRs heterodimerize with retinoid X receptors (RXRs) and bind to target gene promoters, resulting in the regulation of various cellular parameters such as cholesterol synthesis and transport, glucose homeostasis, inflammatory, and immune responses (Bilotta et al 2020 ; Lin and Gustafsson 2015 ).…”

Myeloid-Derived Suppressive Cells Deficient in Liver X Receptor α Protected From Autoimmune Hepatitis

“…Nonetheless, the anti-inflammatory or proinflammatory role of LXR still remains controversial. Function of these NRs are various depending on the different cell types and disease context ( 25 ). With regard to myeloid differentiation, it has been shown that overexpression of LXRα promoted maturation of DCs and endowed it with enhanced ability to stimulate T-cell proliferation ( 26 ).…”

Multi-Dimensional Transcriptome Analysis Reveals Modulation of Cholesterol Metabolism as Highly Integrated Response to Brain Injury

“…There is also a link between cholesterol metabolism and the inflammatory response. The transcription factor Liver-xreceptor regulates cholesterol metabolism and the inflammatory response (Bilotta et al, 2020). Moreover, the sterol metabolite 25hydroxycholesterol modulates the inflammatory response (Gold et al, 2014).…”