The LXR Research group
The broad research interest of the LXR group aims to investigate the role of LXR signalling in metabolism, inflammation and cancer and further uncover the underlying molecular mechanisms of LXR-associated pathophysiology.
The two oxysterol receptors, liver X receptors (LXRα and LXRβ), are amongst the emerging newer drug targets within the nuclear receptor family. Targeting LXRs represents novel strategies needed for prevention and treatment of diseases where current therapeutics is inadequate. The first studies on the physiological roles of LXRs revealed key functions in the control of cholesterol metabolism and lipogenesis in the liver, a feature mainly linked to LXRα. Further studies established both LXRs as key regulators of multiple metabolic pathways. In addition to lipid and cholesterol metabolism, they control carbohydrate and energy metabolism, and many of the key and rate-limiting genes in these pathways have been identified as target genes of LXRs. Perhaps the most interesting therapeutic aspect of LXRs includes inflammatory diseases and cancer. The inflammatory repertoire of LXRs has become extended as a substantial number of studies indicate that LXRs have anti-inflammatory and immune regulatory roles in many cell types. LXRs also play a significant role in cancer biology and cancerimmunology. LXRs suppress cell proliferation and surprisingly tumours appear to produce modulators of LXRs that affects the immune response towards the tumour.
Because LXRs control diverse pathways in development, reproduction, metabolism, immunity and inflammation, they have potential as therapeutic targets for diseases including metabolic disorders including atherosclerosis, chronic inflammation, autoimmunity, cancer and neurodegenerative diseases. LXRs direct mode of ligand regulation and genome interaction is at the core of modern pharmacology. Various oxysterols are identified as endogenous LXR agonists. LXRβ is ubiquitously expressed in most physiological systems, whereas LXRα expression is mostly restricted to metabolically active tissues. The first studies on the physiological roles of LXRs revealed key functions in the control of cholesterol metabolism and lipogenesis. They also control carbohydrate and energy metabolism, and many of the key and rate-limiting genes in these pathways have been identified as target genes of LXRs. The functions of LXRs in cholesterol metabolism have been studied intensively, and it was shown using different mouse models that activation of LXRs in vivo increases the rate of reverse cholesterol transport (RCT) from macrophages via ABCG1 and ABCA1 cholesterol transporters. The LXRs have gained considerable attention during the last years for their anti-inflammatory role. LXRs are anti-inflammatory in the liver where they dampen the inflammatory acute phase response and thereby provide a lower systemic inflammatory environment. Activation of LXRs decreased the severity and development of experimental autoimmune encephalomyelitis (EAE), a rodent experimental model of multiple sclerosis (MS). Furthermore, LXRs appear to have an important role in arthritis. Activation of LXRs protects against inflammatory reactions in connection with graft-versus-host events and diabetic nephropathy. Together this points towards an important role of LXRs as anti-inflammatory regulators in diseases and conditions with an inflammatory component. LXRs appear to have several roles in cancer biology. Firstly, LXRs have been described to suppress the proliferation of a variety of human cancer cells and secondly, tumours produce LXR agonists (oxysterols) which inhibit a robust immune response - as a mechanism of the tumour to escape immune surveillance. At the molecular level, LXRs target the cell cycle at several points. LXRs reduce the expression of positive cell cycle regulators, whereas they increase the expression of cell cycle inhibitors. Studies in different mouse models confirmed the anti-proliferative effect by demonstrating that LXRs reduced the growth of xenografts from prostate cancer cells and delayed the progression of androgen-dependent tumours towards androgen independency. Moreover, the strong induction LXRs show on ABC-cholesterol transporters lead to export of cholesterol from cells which further leads to reduced cell proliferation – linking proliferation and metabolism together via LXRs.
In an EU-FP7 funded collaborative project (HUMAN – Health and the Understanding of Metabolism, Aging and Nutrition) LXR signalling is investigated in the association of metabolic diseases and healthy aging. The prevalence of metabolic diseases has seen a dramatic surge owing to the great increase of life expectancy and transitions in lifestyle and nutrition. Age is highly associated to development of metabolic disorders. Large research efforts have been devoted to identify the genetic basis of age related diseases. A plethora of reports associate gene variants to hundreds of metabolic conditions. But the functional role of these genetic variants is not known. The differences between mouse and human are so disparate that data gained from mice are not relevant to human pathology; a major limitation to provide functional validation of the identified genes associated to age related diseases. The project will make humanised mouse models with human hepatocytes or β-cells and focus on functional studies of the LXRs as these genes are highly important regulators of metabolic pathways. This innovative approach offers the unique possibility of studying the function of genes associated to metabolic diseases in an integrated living system but in human-derived organs. The strength of this project is that the human cells used to generate hepatocytes or β-cells derive from patients affected by severe metabolic diseases or humans selected for their complete lack of disease and exceptional longevity. The significance of this project is that these models will allow disentangling the complex circuitry of genetics and functional genomics in metabolism that account for longevity and healthy aging.
Research group leader Knut Steffensen
|Knut R Steffensen||Senior research fellow|
- Molecular Biology and in vivo animal studies
EU-FP7, Vetenskapsrådet, KaroBio, Karolinska Institutet Board of Science
Program director DECS (Developmental Biology and Cellular Signalling), a postgradual educational program at Karolinska Institutet
Targeting liver X receptors in inflammation.
Expert Opin. Ther. Targets 2013 Aug;17(8):977-90
Liver × receptor ligands disrupt breast cancer cell proliferation through an E2F-mediated mechanism.
Breast Cancer Res. 2013 Jun;15(3):R51
The oxysterol receptors LXRα and LXRβ suppress proliferation in the colon.
Mol. Carcinog. 2013 Nov;52(11):835-44
LXRβ activation increases intestinal cholesterol absorption, leading to an atherogenic lipoprotein profile.
J. Intern. Med. 2012 Nov;272(5):452-64
Liver X receptor biology and pharmacology: new pathways, challenges and opportunities.
Trends Pharmacol. Sci. 2012 Jul;33(7):394-404