Determining the role for Nuclear receptor SHP in liver and kidney metabolism

Abstract

Nuclear receptors are a unique family of ligand‐activated transcription factors that can modulate gene expression across various cellular functions. Nuclear receptor SHP (Small Heterodimer Partner), is atypical such that it lacks the DNA binding domain and its endogenous ligand is currently unknown. SHP is well known for regulating hepatic bile acid synthesis as a downstream target of nuclear receptor FXR. But previously published reports suggest that SHP may control heart function, germ cell differentiation, and cellular transport. Therefore, we set to investigate SHP function in both liver and extra‐hepatic tissues using mouse models. Since SHP can regulate nuclear receptor Constitutive Androstane Receptor (CAR) that is primarily responsible for drug metabolism, we examined a role for SHP in coordinating detoxification pathways. In the liver, absence of SHP resulted in robust increases in cyclins in response to CAR activation despite no liver growth. Detoxification is largely controlled by a trifecta of organs consisting of the liver, gut, and kidney, where SHP expression is noticeable. In fact, some of the detoxifying phase I, II and III genes also control bile acid homeostasis. We have found under cholestatic conditions liver expression of phase I metabolic pathway genes (CYP1A2 and CYP2E10) were significantly repressed whereas phase II metabolic genes (GSTM1 and GSTA2) are upregulated in the absence of SHP. We also found that the deletion of FXR and SHP altered organic solute transporters and GSTA1/2 mRNA levels in kidneys. This data suggests that murine SHP may regulate phase I and II metabolic processes distinctly in the liver and potentially contribute towards glutathione conjugation in the kidney.Support or Funding InformationNIDDK(R01 DK113080 AE433)