The physiological and pathophysiological significance of the nuclear receptors Oestrogen receptor beta and Liver X receptor beta - Ivan Nalvarte

Our research group studies the field of nuclear receptors, a family of transcription factors of very high physiological and pathophysiological significance. They regulate expression of several hundreds of genes and are often activated or inactivated by low molecular weight ligands, e g steroid hormones or intermediary metabolites.

Our main focus lies on two nuclear receptor (NR) transcription factors that were discovered in our laboratory; the Oestrogen receptor beta (ERβ) and the Liver X receptor beta (LXRβ). We study their implications in neurodevelopment, neurodegeneration, cholesterol homeostasis, fertility, and cancer.

illustration of a circle, NR in the middle and arrows pointing to environment, development and so on
NRs are ligand activated nuclear transcription factors. They function downstream of endocrine processes to mediate the response to external and internal stimuli, thereby controlling the expression of genes involved in homeostasis, metabolism, growth and development. Since they often bind low molecular weight ligands they pose promising targets for therapeutic interventions. Our research group study a subset of nuclear receptors, the oestrogen receptors (ERs) and the liver X receptors (LXRs) that are involved in inflammation, metabolism, proliferation and development. Illustration: Ivan Nalvarte

We are particularly interested in Oestrogen receptor beta (ERbeta) and Liver X receptor beta (LXRbeta), two receptors that were discovered in our laboratory in the middle of the 90’s. ERbeta is antiproliferative in many tissues including mammary gland and the prostate, which is of great interest since it may be an antitumour agent in breast and prostate cancer. We work with various ERbeta ligands which we hope will qualify as drugs against breast and prostate cancer. Furthermore, both ERbeta and LXRbeta have important functions in the developing and adult brain. For example, ERbeta is anxiolytic and is needed for proper corticogenesis, and LXRbeta is important for brain cholesterol metabolism, and is involved in Parkinson’s disease by influencing dopamine signalling. Loss of either ERbeta or LXRbeta results in increased vulnerability to neurodegeneration, where in particular disrupted ERbeta signalling may be of relevance to the sex differences observed in Alzheimer’s disease. Therefore, ERbeta and LXRbeta ligands hold great promise as drugs against neurological diseases.

Group members

Mukesh Varshney

Affiliated to research

Selected Publications

Motor function deficits in the estrogen receptor beta knockout mouse: Role on excitatory neurotransmission and myelination in the motor cortex.
Varshney MK, Yu NY, Katayama S, Li X, Liu T, Wu WF, et al
Neuroendocrinology 2020 Jan:

Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.
Warner M, Wu WF, Montanholi L, Nalvarte I, Antonson P, Gustafsson JA
Proc. Natl. Acad. Sci. U.S.A. 2020 Mar;117(9):4902-4909

Immunoregulatory Functions of Nuclear Receptors: Mechanisms and Therapeutic Implications.
Zhao L, Gimple RC, Yang Z, Wei Y, Gustafsson JÅ, Zhou S
Trends Endocrinol. Metab. 2020 Feb;31(2):93-106

Liver X Receptor Alpha Is Important in Maintaining Blood-Brain Barrier Function.
Wouters E, de Wit NM, Vanmol J, van der Pol SMA, van Het Hof B, Sommer D, et al
Front Immunol 2019 ;10:1811

Oestrogen receptor β mediates the actions of bisphenol-A on ion channel expression in mouse pancreatic beta cells.
Martinez-Pinna J, Marroqui L, Hmadcha A, Lopez-Beas J, Soriano S, Villar-Pazos S, et al
Diabetologia 2019 09;62(9):1667-1680

Nuclear Receptors: Recent Drug Discovery for Cancer Therapies.
Zhao L, Zhou S, Gustafsson JÅ
Endocr. Rev. 2019 10;40(5):1207-1249

Sex-specific lipid molecular signatures in obesity-associated metabolic dysfunctions revealed by lipidomic characterization in ob/ob mouse.
González-Granillo M, Helguero LA, Alves E, Archer A, Savva C, Pedrelli M, et al
Biol Sex Differ 2019 02;10(1):11

ERβ activation in obesity improves whole body metabolism via adipose tissue function and enhanced mitochondria biogenesis.
González-Granillo M, Savva C, Li X, Fitch M, Pedrelli M, Hellerstein M, et al
Mol. Cell. Endocrinol. 2019 01;479:147-158

Retinal and optic nerve degeneration in liver X receptor β knockout mice.
Song XY, Wu WF, Gabbi C, Dai YB, So M, Chaurasiya SP, et al
Proc. Natl. Acad. Sci. U.S.A. 2019 08;116(33):16507-16512

LXR Suppresses Inflammatory Gene Expression and Neutrophil Migration through cis-Repression and Cholesterol Efflux.
Thomas DG, Doran AC, Fotakis P, Westerterp M, Antonson P, Jiang H, et al
Cell Rep 2018 12;25(13):3774-3785.e4

Estrogen receptor β controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage.
D'Errico F, Goverse G, Dai Y, Wu W, Stakenborg M, Labeeuw E, et al
Proc. Natl. Acad. Sci. U.S.A. 2018 05;115(22):5798-5803

Role of estrogen receptor beta in neural differentiation of mouse embryonic stem cells.
Varshney MK, Inzunza J, Lupu D, Ganapathy V, Antonson P, Rüegg J, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 11;114(48):E10428-E10437

Estrogen receptor β, a regulator of androgen receptor signaling in the mouse ventral prostate.
Wu WF, Maneix L, Insunza J, Nalvarte I, Antonson P, Kere J, et al
Proc. Natl. Acad. Sci. U.S.A. 2017 05;114(19):E3816-E3822

Estrogen Receptor β as a Pharmaceutical Target.
Warner M, Huang B, Gustafsson JA
Trends Pharmacol. Sci. 2017 01;38(1):92-99

Liver X receptors regulate cerebrospinal fluid production.
Dai YB, Wu WF, Huang B, Miao YF, Nadarshina S, Warner M, et al
Mol. Psychiatry 2016 06;21(6):844-56

Memo interacts with c-Src to control Estrogen Receptor alpha sub-cellular localization.
Frei A, MacDonald G, Lund I, Gustafsson JÅ, Hynes NE, Nalvarte I
Oncotarget 2016 Aug;7(35):56170-56182

Prizes/Awards

Selection of prizes awarded to Prof. Jan-Åke Gustafsson:

  • The Grand Silver Medal of the Karolinska Institutet, 2011
  • The Grand Nordic Fernström Prize of the University of Lund, 2009
  • Geoffrey Harris Prize, 2009
  • Bristol-Meyers Squibb / Mead Johnson Award for Nutrition Research, 2004
  • Medal from Biomedicum Helsinki, 2004
  • Fred Conrad Koch Award (Endocrine Society USA), 2002
  • Chairman of the Nobel Assembly of the Karolinska Institutet, 2002
  • Foreign Honorary Member of the US National Academy of Sciences, 2002
  • The Söderberg Prize in Medicine, 1998
  • The Anders Jahre Prize, Oslo, 1992

Looking for a student project or internship?

We are looking for students interested in an internship or degree project in the field of estrogen signaling in the brain. The project aims at deciphering estrogen receptor beta’s (ERbeta’s) neuroprotective role in Alzheimer’s disease (AD) and why women are more affected by this disease than men. The project involves cell biological and biochemical characterizations of models of AD where ERbeta is activated or lost. Research on the neuroprotective contribution of ERbeta during sensitive periods in life may open up for new preventive and more personalized recommendations to new AD risk groups.

Contact Ivan Nalvarte for more information.