CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α

The constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC1 alpha) are master regulators of drug metabolism and gluconeogenesis, respectively. In supporting the cross talk between drug metabolism and energy metabolism, activation of CAR has been shown to suppress hepatic gluconeogenesis and ameliorate hyperglycemia in vivo, but the underlying molecular mechanism remains elusive. In this study, we demonstrated that CAR suppressed hepatic gluconeogenic gene expression through posttranslational regulation of the subcellular localization and degradation of PGC1 alpha. Activated CAR translocated into the nucleus and served as an adaptor protein to recruit PGC1 alpha to the Cullin1 E3 ligase complex for ubiquitination. The interaction between CAR and PGC1 alpha also led to their sequestration within the promyelocytic leukemia protein-nuclear bodies, where PGC alpha and CAR subsequently underwent proteasomal degradation. Taken together, our findings revealed an unexpected function of CAR in recruiting an E3 ligase and targeting the gluconeogenic activity of PGC1 alpha. Both drug metabolism and gluconeogenesis are energy-demanding processes. The negative regulation of PGC1 alpha by CAR may represent a cellular adaptive mechanism to accommodate energy-restricted conditions.