Laboratory of Metabolic Signaling
By investigating the molecular basis by which metabolites in general, and bile acids in particular, signal to convey adaptive responses in metabolic organs, our laboratory aims to identify novel mechanisms and strategies to target metabolic disorders.
Research areas, approaches and achievements
The liver-gut axis is a physiological system specialized in the sensing and processing of nutrients. Our research aims to focus on this system and gain insight into the mechanisms by which nutrient-derived metabolites in general and bile acids in particular coordinate metabolism, immune function and cancer. A major part in this research applies to the study of a subset of nuclear receptors directly or indirectly affecting bile acid signaling. A second axis in this research focuses on the non-genomic effects of bile acids by investigating the role of the bile acid-responsive GPCR TGR5.
We are using state-of-the-art approaches in biochemistry, molecular biology and mouse genetics. An integrative approach combining genetically engineered mouse models, metabolic phenotyping and in-depth cellular and molecular profiling in cellular models is used to reconstruct the networks that are modified by GPCR mediated bile acid signaling and by other nutrient-derived metabolites.
In the past we established the metabolic role of several nuclear receptors and causally linked these functions to immune regulation and cancer. An example is the enterohepatic orphan nuclear receptor, Liver Receptor Homolog 1 (LRH-1), which we identified as a critical regulator of the steroid balance and of bile acid homeostasis. We showed that these actions, if perturbed by inappropriate activity of LRH-1, have far-reaching effects on multiple intestinal diseases, including IBD and colorectal cancer. More recently, we identified LRH-1 as an upstream regulator of the hepatic glucose sensing system that coordinates a functional network of enzymes and transcription factors important for the maintenance of energy homeostasis and systemic glycemia.
Earlier work from our laboratory also demonstrated that bile acids, through TGR5 activation, exert systemic metabolic effects by promoting energy expenditure, thereby preventing obesity and insulin resistance. Other studies of our lab revealed that activation of TGR5 signaling improves glycemic control by increasing the secretion of the antidiabetic gut hormone glucagon-like peptide-1 (GLP-1) and suppresses inflammation in macrophages via a mechanism that involves inhibition of NF-kappaB activity. These discoveries have underscored the importance of TGR5 activation in metabolic homeostasis and have identified TGR5 as a novel target to prevent and combat metabolic diseases such as type 2 diabetes (T2D) and atherosclerosis.