International Journal of Molecular Sciences

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16 pages, 3923 KiB

Open AccessArticle

Phytosterols Inhibit Side-Chain Oxysterol Mediated Activation of LXR in Breast Cancer Cells

by Samantha A. Hutchinson, Priscilia Lianto, J. Bernadette Moore, Thomas A. Hughes and James L. Thorne

Int. J. Mol. Sci. 2019, 20(13), 3241; https://doi.org/10.3390/ijms20133241 - 2 Jul 2019

Cited by 21 | Viewed by 6279

Abstract

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic [...] Read more.

Low fruit and vegetable consumption and high saturated fat consumption causes elevated circulating cholesterol and are breast cancer risk factors. During cholesterol metabolism, oxysterols form that bind and activate the liver X receptors (LXRs). Oxysterols halt breast cancer cell proliferation but enhance metastatic colonization, indicating tumour suppressing and promoting roles. Phytosterols and phytostanols in plants, like cholesterol in mammals, are essential components of the plasma membrane and biochemical precursors, and in human cells can alter LXR transcriptional activity. Here, a panel of breast cancer cell lines were treated with four dietary plant sterols and a stanol, alone or in combination with oxysterols. LXR activation and repression were measured by gene expression and LXR-luciferase reporter assays. Oxysterols activated LXR in all cell lines, but surprisingly phytosterols failed to modulate LXR activity. However, phytosterols significantly inhibited the ability of oxysterols to drive LXR transcription. These data support a role for phytosterols in modulating cancer cell behaviour via LXR, and therefore suggest merit in accurate dietary recordings of these molecules in cancer patients during treatment and perhaps supplementation to benefit recovery. Full article

(This article belongs to the Special Issue Liver X Receptors)

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10 pages, 1172 KiB

Open AccessReview

Cholesterol, Oxysterols and LXRs in Breast Cancer Pathophysiology

by Hassan Nazih and Jean Marie Bard

Int. J. Mol. Sci. 2020, 21(4), 1356; https://doi.org/10.3390/ijms21041356 - 17 Feb 2020

Cited by 42 | Viewed by 7431

Abstract

Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress [...] Read more.

Breast cancer is the most frequent cancer among women. In 2018, it is estimated that 627,000 women died from breast cancer. This is approximately 15% of all cancer deaths among women (WHO 2018). Breast cancer is a multifactorial chronic disease. While important progress has been made to treat patients, many questions regarding aspects of this disease relating to carcinogenesis are still open. During carcinogenesis, cells exhibit cholesterol homeostasis deregulation. This results in an accumulation of intracellular cholesterol, which is required to sustain their high growth rate. Cholesterol efflux and influx are two metabolic pathways that are necessary to prevent cholesterol accumulation in the cells. Liver X receptors (LXRs) are nuclear receptors that, upon activation, induce the expression of ABC transporters, responsible for promoting cholesterol efflux, and the expression of IDOL (inducible degrader of low-density lipoprotein receptor), in charge of reducing cholesterol influx. Oxysterols, oxygenated derivatives of cholesterol formed through different pathways, have been discovered as LXR-specific ligands. Some oxysterols are involved in tumor formation while others are considered anti-tumor agents. In the present review, we discuss the involvement of cholesterol, oxysterols and LXRs in breast cancer pathophysiology, with an emphasis on the biological effects of LXR ligands. Full article

(This article belongs to the Special Issue Liver X Receptors)

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14 pages, 1553 KiB

Open AccessReview

Liver X Receptors and Male (In)fertility

by Sheba Jarvis, Catherine Williamson and Charlotte L Bevan

Int. J. Mol. Sci. 2019, 20(21), 5379; https://doi.org/10.3390/ijms20215379 - 29 Oct 2019

Cited by 11 | Viewed by 4678

Abstract

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. [...] Read more.

Liver X receptors (LXRs) are ligand-dependent transcription factors acting as ‘cholesterol sensors’ to regulate lipid homeostasis in cells. The two isoforms, LXRα (NR1H3) and LXRβ (NR1H2), are differentially expressed, with the former expressed predominantly in metabolically active tissues and the latter more ubiquitously. Both are activated by oxidised cholesterol metabolites, endogenously produced oxysterols. LXRs have important roles in lipid metabolism and inflammation, plus a number of newly emerging roles. They are implicated in regulating lipid balance in normal male reproductive function and may provide a link between male infertility and lipid disorders and/or obesity. Studies from Lxr knockout mouse models provide compelling evidence to support this. More recently published data suggest distinct and overlapping roles of the LXR isoforms in the testis and recent evidence of a role for LXRs in human male fertility. This review summarises the current literature and explores the likely link between LXR, lipid metabolism and male fertility as part of a special issue on Liver X receptors in International Journal of Molecular Sciences. Full article

(This article belongs to the Special Issue Liver X Receptors)

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16 pages, 1139 KiB

Open AccessReview

Liver X Receptors Regulate Cholesterol Metabolism and Immunity in Hepatic Nonparenchymal Cells

by Kaori Endo-Umeda and Makoto Makishima

Int. J. Mol. Sci. 2019, 20(20), 5045; https://doi.org/10.3390/ijms20205045 - 11 Oct 2019

Cited by 45 | Viewed by 6864

Abstract

Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate [...] Read more.

Excess dietary cholesterol intake and the dysregulation of cholesterol metabolism are associated with the pathogenesis and progression of nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and fibrosis. Hepatic accumulation of free cholesterol induces activation of nonparenchymal cells, including Kupffer cells, macrophages, and hepatic stellate cells, which leads to persistent inflammation and fibrosis. The nuclear receptors liver X receptor α (LXRα) and LXRβ act as negative regulators of cholesterol metabolism through the induction of hepatocyte cholesterol catabolism, excretion, and the reverse cholesterol transport pathway. Additionally, LXRs exert an anti-inflammatory effect in immune cell types, such as macrophages. LXR activation suppresses acute hepatic inflammation that is mediated by Kupffer cells/macrophages. Acute liver injury, diet-induced steatohepatitis, and fibrosis are exacerbated by significant hepatic cholesterol accumulation and inflammation in LXR-deficient mice. Therefore, LXRs regulate hepatic lipid metabolism and immunity and they are potential therapeutic targets in the treatment of hepatic inflammation that is associated with cholesterol accumulation. Full article

(This article belongs to the Special Issue Liver X Receptors)

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16 pages, 844 KiB

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Oxysterols in Autoimmunity

by Donovan Duc, Solenne Vigne and Caroline Pot

Int. J. Mol. Sci. 2019, 20(18), 4522; https://doi.org/10.3390/ijms20184522 - 12 Sep 2019

Cited by 34 | Viewed by 5402

Abstract

Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated [...] Read more.

Cholesterol is a member of the sterol family that plays essential roles in biological processes, including cell membrane stability and myelin formation. Cholesterol can be metabolized into several molecules including bile acids, hormones, and oxysterols. Studies from the last few decades have demonstrated that oxysterols are not only active metabolites but are further involved in the modulation of immune responses. Liver X Receptors (LXRs), nuclear receptors for oxysterols, are important for cholesterol homeostasis and regulation of inflammatory response but are still poorly characterized during autoimmune diseases. Here we review the current knowledge about the role of oxysterols during autoimmune conditions and focus on the implication of LXR-dependent and LXR-independent pathways. We further highlight the importance of these pathways in particular during central nervous system (CNS) autoimmunity and inflammatory bowel diseases (IBD) in both experimental models and human studies. Finally, we discuss our vision about future applications and research on oxysterols related to autoimmunity. Full article

(This article belongs to the Special Issue Liver X Receptors)

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32 pages, 1579 KiB

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Xenobiotic Receptors and Their Mates in Atopic Dermatitis

by Deborah Minzaghi, Petra Pavel and Sandrine Dubrac

Int. J. Mol. Sci. 2019, 20(17), 4234; https://doi.org/10.3390/ijms20174234 - 29 Aug 2019

Cited by 10 | Viewed by 4111

Abstract

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis [...] Read more.

Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. It is a chronic, relapsing and pruritic skin disorder which results from epidermal barrier abnormalities and immune dysregulation, both modulated by environmental factors. AD is strongly associated with asthma and allergic rhinitis in the so-called ‘atopic march’. Xenobiotic receptors and their mates are ligand-activated transcription factors expressed in the skin where they control cellular detoxification pathways. Moreover, they regulate the expression of genes in pathways involved in AD in epithelial cells and immune cells. Activation or overexpression of xenobiotic receptors in the skin can be deleterious or beneficial, depending on context, ligand and activation duration. Moreover, their impact on skin might be amplified by crosstalk among xenobiotic receptors and their mates. Because they are activated by a broad range of endogenous molecules, drugs and pollutants owing to their promiscuous ligand affinity, they have recently crystalized the attention of researchers, including in dermatology and especially in the AD field. This review examines the putative roles of these receptors in AD by critically evaluating the conditions under which the proteins and their ligands have been studied. This information should provide new insights into AD pathogenesis and ways to develop new therapeutic interventions. Full article

(This article belongs to the Special Issue Liver X Receptors)

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13 pages, 1697 KiB

Open AccessReview

Liver X Receptors and Their Implications in the Physiology and Pathology of the Peripheral Nervous System

by Venkat Krishnan Sundaram, Charbel Massaad and Julien Grenier

Int. J. Mol. Sci. 2019, 20(17), 4192; https://doi.org/10.3390/ijms20174192 - 27 Aug 2019

Cited by 6 | Viewed by 5690

Abstract

Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in [...] Read more.

Recent research in the last decade has sought to explore the role and therapeutic potential of Liver X Receptors (LXRs) in the physiology and pathologies of the Peripheral Nervous System. LXRs have been shown to be important in maintaining the redox homeostasis in peripheral nerves for proper myelination, and they regulate ER stress in sensory neurons. Furthermore, LXR stimulation has a positive impact on abrogating the effects of diabetic peripheral neuropathy and obesity-induced allodynia in the Peripheral Nervous System (PNS). This review details these findings and addresses certain important questions that are yet to be answered. The potential roles of LXRs in different cells of the PNS are speculated based on existing knowledge. The review also aims to provide important perspectives for further research in elucidating the role of LXRs and assessing the potential of LXR based therapies to combat pathologies of the Peripheral Nervous System. Full article

(This article belongs to the Special Issue Liver X Receptors)

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17 pages, 1004 KiB

Open AccessReview

Regulation of Brain Cholesterol: What Role Do Liver X Receptors Play in Neurodegenerative Diseases?

by Kevin Mouzat, Aleksandra Chudinova, Anne Polge, Jovana Kantar, William Camu, Cédric Raoul and Serge Lumbroso

Int. J. Mol. Sci. 2019, 20(16), 3858; https://doi.org/10.3390/ijms20163858 - 8 Aug 2019

Cited by 46 | Viewed by 6107

Abstract

Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among [...] Read more.

Liver X Receptors (LXR) alpha and beta are two members of nuclear receptor superfamily documented as endogenous cholesterol sensors. Following conversion of cholesterol in oxysterol, both LXR isoforms detect intracellular concentrations and act as transcription factors to promote expression of target genes. Among their numerous physiological roles, they act as central cholesterol-lowering factors. In the central nervous system (CNS), cholesterol has been shown to be an essential determinant of brain function, particularly as a major constituent of myelin and membranes. In the brain, LXRs act as cholesterol central regulators, and, beyond this metabolic function, LXRs have additional roles such as providing neuroprotective effects and lowering neuroinflammation. In many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), and multiple sclerosis (MS), dysregulations of cholesterol and oxysterol have been reported. In this paper, we propose to focus on recent advances in the knowledge of the LXRs roles on brain cholesterol and oxysterol homeostasis, neuroinflammation, neuroprotection, and their putative involvement in neurodegenerative disorders. We will discuss their potential use as candidates for both molecular diagnosis and as promising pharmacological targets in the treatment of ALS, AD, or MS patients. Full article

(This article belongs to the Special Issue Liver X Receptors)

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10 pages, 768 KiB

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Revisiting the Role of LXRs in PUFA Metabolism and Phospholipid Homeostasis

by Antoine Jalil, Thibaut Bourgeois, Louise Ménégaut, Laurent Lagrost, Charles Thomas and David Masson

Int. J. Mol. Sci. 2019, 20(15), 3787; https://doi.org/10.3390/ijms20153787 - 2 Aug 2019

Cited by 22 | Viewed by 4958

Abstract

Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, [...] Read more.

Liver X receptors (LXRs) play a pivotal role in fatty acid (FA) metabolism. So far, the lipogenic consequences of in vivo LXR activation, as characterized by a major hepatic steatosis, has constituted a limitation to the clinical development of pharmacological LXR agonists. However, recent studies provided a different perspective. Beyond the quantitative accumulation of FA, it appears that LXRs induce qualitative changes in the FA profile and in the distribution of FAs among cellular lipid species. Thus, LXRs activate the production of polyunsaturated fatty acids (PUFAs) and their distribution into phospholipids via the control of FA desaturases, FA elongases, lysophosphatidylcholine acyltransferase (LPCAT3), and phospholipid transfer protein (PLTP). Therefore, LXRs control, in a dynamic manner, the PUFA composition and the physicochemical properties of cell membranes as well as the release of PUFA-derived lipid mediators. Recent studies suggest that modulation of PUFA and phospholipid metabolism by LXRs are involved in the control of lipogenesis and lipoprotein secretion by the liver. In myeloid cells, the interplay between LXR and PUFA metabolism affects the inflammatory response. Revisiting the complex role of LXRs in FA metabolism may open new opportunities for the development of LXR modulators in the field of cardiometabolic diseases. Full article

(This article belongs to the Special Issue Liver X Receptors)

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