Network Partner
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Knut R. Steffensen
Ph.D.Senior Researcher
Department of Biosciences and Nutrition
Karolinska Institutet
S-14157 Huddinge/Stockholm, Sweden
Phone: +46 86083339
e-mail: knut.steffensen@ki.se
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My research focus is centered on the oxysterol nuclear receptor LXR (Liver X Receptor). The two genes, LXRα and LXRß, are crucial sensors and regulators of cholesterol and lipid homeostasis in several metabolic tissues including liver, macrophages and intestine and they have recently emerged as key regulators of inflammation and cell cycle pathways.
Since LXRs respond to small molecular ligands, they are particularly attractive as drugable targets for the development of novel therapeutics. Current indications include the treatment of disorders such as hyperlipidemia, diabetes, atherosclerosis and chronic inflammatory disorders. Although some LXRs are highly interesting drug targets, their function and physiological impact as well as molecular mechanisms behind disease development is not fully understood. However, LXRs important position as transducers of signals mediated by small molecules into genomic regulations makes them a pivotal element in understanding development of cancer, metabolic disorders and inflammatory diseases. Understanding the mode of interaction of LXRs with the genome is at the core of modern pharmacology and therapy and my research is focused on the role of LXRs in metabolic diseases, inflammatory diseases and regulatory pathways of the cell cycle.
The oxysterol receptors (liver X receptors (LXRα and LXRβ)) are established sensors of intracellular cholesterol and lipid metabolism which become transcriptionally active upon binding of certain oxysterols. LXRs mediate their biological effects through transcriptional regulation of their target genes many of which are key regulatory genes involved in lipogenesis and cholesterol metabolism. These genes include sterol regulatory element binding protein 1c (SREBP1c), stearoyl-Coenzyme A desaturase 1 (SCD1), fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC) which increase fatty acid and triglyceride (TG) production. These transcriptional effects are reflected physiologically in vivo as LXRα-/- mice fed a high fat diet show significantly lower hepatic TG levels compared to wild type mice, and serum and hepatic TG levels are dramatically reduced in LXRαβ-/- mice.
Recent work has identified LXRs as anti-proliferative factors suppressing growth of both normal and cancer cells. Activation of LXRs suppresses proliferation, in particular, activation of LXRs reduces proliferation of human breast cancer cell lines and acts as an androgen receptor antagonist in prostate cancer cells.
LXRs have recently emerged as key regulators of inflammation. LXRs antagonize inflammatory gene expression downstream of TLR4, IL1 and TNFα signaling pathways by repressing several NF-ĸB target genes, such as iNOS, IL6, cyclooxygenase 1, MMP9, CCL2, CCL7 and IL1. Systemic administration of LXR agonists, consequently activating LXRs, is reported to reduce inflammation and pro-inflammatory pathways in vivo.
