Lack of thyroid hormone receptor beta is not detrimental for non-alcoholic steatohepatitis progression
Nuria Lopez-Alcantara,
Rebecca Oelkrug,
Sarah Christine Sentis,
Henriette Kirchner,
Jens Mittag
Affiliations
Nuria Lopez-Alcantara
Institut für Endokrinologie und Diabetes, AG Molekulare Endokrinologie, Universität zu Lübeck / Universitätsklinikum Schleswig-Holstein, Center for Brain Behavior and Metabolism CBBM, Ratzeburger Allee 160, 23562 Lübeck, Germany
Rebecca Oelkrug
Institut für Endokrinologie und Diabetes, AG Molekulare Endokrinologie, Universität zu Lübeck / Universitätsklinikum Schleswig-Holstein, Center for Brain Behavior and Metabolism CBBM, Ratzeburger Allee 160, 23562 Lübeck, Germany
Sarah Christine Sentis
Institut für Endokrinologie und Diabetes, AG Molekulare Endokrinologie, Universität zu Lübeck / Universitätsklinikum Schleswig-Holstein, Center for Brain Behavior and Metabolism CBBM, Ratzeburger Allee 160, 23562 Lübeck, Germany
Henriette Kirchner
Institut für Humangenetik, AG Epigenetik und Metabolismus, Universität zu Lübeck / Universitätsklinikum Schleswig-Holstein, Center for Brain Behavior and Metabolism CBBM, Ratzeburger Allee 160, 23562 Lübeck, Germany
Jens Mittag
Institut für Endokrinologie und Diabetes, AG Molekulare Endokrinologie, Universität zu Lübeck / Universitätsklinikum Schleswig-Holstein, Center for Brain Behavior and Metabolism CBBM, Ratzeburger Allee 160, 23562 Lübeck, Germany; Corresponding author
Summary: Agonists for thyroid hormone receptor β (TRβ) show promise in preclinical studies and clinical trials to improve non-alcoholic fatty liver disease. A recent study on human livers, however, revealed reduced TRβ expression in non-alcoholic steatohepatitis (NASH), indicating a developing thyroid hormone resistance, which could constitute a major obstacle for those agonists.Using a rapid NASH paradigm combining choline-deficient high-fat diet and thermoneutrality, we confirm that TRβ declines during disease progression in mice similar to humans. Contrary to expectations, mice lacking TRβ showed less liver fibrosis, and NASH marker genes were not elevated. Conversely, increasing TRβ expression in wild-type NASH mice using liver-targeted gene therapy did not improve histology, gene expression, or metabolic parameters, indicating that TRβ receptor levels are of minor relevance for NASH development and progression in our model, and suggest that liver—rather than isoform—specificity might be more relevant for NASH treatment with thyroid hormone receptor agonists.
