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

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 29; no. 11; pp. 1558 - 1570
• Main Authors: Gao, Jie, Yan, Jiong, Xu, Meishu, Ren, Songrong, Xie, Wen
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.11.2015; Oxford University Press
• Subjects: Animals; Cell Line; Energy Metabolism - physiology; Gene Expression Regulation - genetics; Gluconeogenesis - physiology; Glucose - metabolism; Inactivation, Metabolic - genetics; Inactivation, Metabolic - physiology; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Proteins - metabolism; Original Research; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Promyelocytic Leukemia Protein; Protein Structure, Tertiary; Proteolysis; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; RNA Interference; RNA Processing, Post-Transcriptional - genetics; RNA, Small Interfering - genetics; Transcription Factors - antagonists & inhibitors; Transcription Factors - metabolism; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - metabolism; Ubiquitination
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2015-1145

The constitutive androstane receptor (CAR) and peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) 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 PGC1α. Activated CAR translocated into the nucleus and served as an adaptor protein to recruit PGC1α to the Cullin1 E3 ligase complex for ubiquitination. The interaction between CAR and PGC1α also led to their sequestration within the promyelocytic leukemia protein-nuclear bodies, where PGC1α 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 PGC1α. Both drug metabolism and gluconeogenesis are energy-demanding processes. The negative regulation of PGC1α by CAR may represent a cellular adaptive mechanism to accommodate energy-restricted conditions.