title: PCAF improves glucose homeostasis by suppressing the gluconeogenic activity of PGC-1α.
abstract: PGC-1α plays a central role in hepatic gluconeogenesis and has been implicated in the onset of type 2 diabetes. Acetylation is an important posttranslational modification for regulating the transcriptional activity of PGC-1α. Here, we show that PCAF is a pivotal acetyltransferase for acetylating PGC-1α in both fasted and diabetic states. PCAF acetylates two lysine residues K328 and K450 in PGC-1α, which subsequently triggers its proteasomal degradation and suppresses its transcriptional activity. Adenoviral-mediated expression of PCAF in the obese mouse liver greatly represses gluconeogenic enzyme activation and glucose production and improves glucose homeostasis and insulin sensitivity. Moreover, liver-specific knockdown of PCAF stimulates PGC-1α activity, resulting in an increase in blood glucose and hepatic glucose output. Our results suggest that PCAF might be a potential pharmacological target for developing agents against metabolic disorders associated with hyperglycemia, such as obesity and diabetes.
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC. Electronic address: suncheng1975@ntu.edu.cn.
authors.forename: Cheng
authors.initials: C
authors.lastname: Sun
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Meihong
authors.initials: M
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Geratology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Geratology, Affiliated Hospital of Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Kaixuan
authors.initials: K
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Shuqiang
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Yumin
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC.
authors.forename: Fei
authors.initials: F
authors.lastname: Ding
authors.affiliation: Jiangsu Key Laboratory of Neuroregeneration, Nantong University, 19 Qixiu Road, Nantong, Jiangsu 226001, PRC; Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, PRC. Electronic address: nervegu@ntu.edu.cn.
authors.forename: Xiaosong
authors.initials: X
authors.lastname: Gu
mesh_terms: D000107:Acetylation; D000818:Animals; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D059748:Proteolysis; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050880:p300-CBP Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000099224:p300-CBP-Associated Factor
chemical_list: D005947:Glucose; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; C485290:Ppargc1a protein, mouse