Ligand‐dependent nucleo‐cytoplasmic shuttling of peroxisome proliferator‐activated receptors, PPARα and PPARγ

Peroxisome proliferator–activated receptors ( PPAR s) play important roles in diverse biological processes including metabolisms of sugars and lipids and differentiation of cells such as adipocytes. PPAR s are transcription factors belonging to the ligand‐dependent hormone receptor group. To function as transcription factors, PPAR s translocate into nucleus where they associate with transcription apparatus. However, mechanisms underlying nuclear transport of PPAR s remain enigmatic. We show here that PPAR α and PPAR γ dynamically shuttle between nucleus and cytoplasm, although they constitutively and predominantly appear in nucleus. With a series of truncation mutants, we identify that PPAR nuclear transport is mediated by at least two nuclear localization signals ( NLS s) in DNA ‐binding domain ( DBD )–hinge and activation function 1 ( AF 1) regions and their respective receptors including importinα/β, importin 7, and an unidentified receptor. PPAR s also harbor two nuclear export signals in DBD and ligand‐binding domain regions that are recognized by distinct export receptors, calreticulin and CRM 1. Moreover, we show that nuclear–cytoplasmic shuttling of PPAR s is regulated by respective PPAR ligands and C a 2+ concentration. Taken together, we suggest that the multiple pathways for the nuclear–cytoplasmic transport of PPAR s regulate the biological functions of PPAR s in response to external signals.