title: CAR Suppresses Hepatic Gluconeogenesis by Facilitating the Ubiquitination and Degradation of PGC1α.
abstract: 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.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (J.G., J.Y., M.X., S.R., W.X.), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (J.G., J.Y., M.X., S.R., W.X.), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Jiong
authors.initials: J
authors.lastname: Yan
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (J.G., J.Y., M.X., S.R., W.X.), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Meishu
authors.initials: M
authors.lastname: Xu
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (J.G., J.Y., M.X., S.R., W.X.), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Songrong
authors.initials: S
authors.lastname: Ren
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences (J.G., J.Y., M.X., S.R., W.X.), and Department of Pharmacology and Chemical Biology (W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261.
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
mesh_terms: D000818:Animals; D002460:Cell Line; D000090702:Constitutive Androstane Receptor; D004734:Energy Metabolism / Q000502:physiology; D005786:Gene Expression Regulation / Q000235:genetics*; D005943:Gluconeogenesis / Q000502:physiology*; D005947:Glucose / Q000378:metabolism; D008658:Inactivation, Metabolic / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000071156:Promyelocytic Leukemia Protein; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D034622:RNA Interference; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination
chemical_list: D000090702:Constitutive Androstane Receptor; D009687:Nuclear Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C513293:Pml protein, mouse; C485290:Ppargc1a protein, mouse; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases; D005947:Glucose