title: Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis.
abstract: Human patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with increased liver fat content and liver injury. Here, we show that nutritional status regulates PNPLA3 gene expression in the mouse liver. Sterol response element binding protein-1 (SREBP-1) activated PNPLA3 gene transcription via sterol regulatory elements (SREs) mapped to the promoter region. Chromatin immunoprecipitation and electrophoretic mobility shift assays confirmed that SREBP-1 proteins bound to the identified SREs. Furthermore, SREBP-1c mediated the insulin and liver X receptor agonist TO901317-dependent induction of PNPLA3 gene expression in hepatocytes. Adenovirus-mediated overexpression of mouse PNPLA3 increased intracellular triglyceride content in primary hepatocytes, and knockdown of PNPLA3 suppressed the ability of SREBP-1c to stimulate lipid accumulation in hepatocytes. Finally, the overexpression of PNPLA3 in mouse liver increased the serum triglyceride level and impaired glucose tolerance; in contrast, the knockdown of PNPLA3 in db/db mouse liver improved glucose tolerance.
  
  
  CONCLUSIONS
  Our data suggest that mouse PNPLA3, which is a lipogenic gene directly targeted by SREBP-1, promotes lipogenesis in primary hepatocytes and influences systemic lipid and glucose metabolism.
authors.affiliation: National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Aijun
authors.initials: A
authors.lastname: Qiao
authors.forename: Jichao
authors.initials: J
authors.lastname: Liang
authors.forename: Yaojun
authors.initials: Y
authors.lastname: Ke
authors.forename: Chenghong
authors.initials: C
authors.lastname: Li
authors.forename: Ying
authors.initials: Y
authors.lastname: Cui
authors.forename: Lian
authors.initials: L
authors.lastname: Shen
authors.forename: Huabing
authors.initials: H
authors.lastname: Zhang
authors.forename: Anfang
authors.initials: A
authors.lastname: Cui
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Liu
authors.forename: Changzheng
authors.initials: C
authors.lastname: Liu
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Fude
authors.initials: F
authors.lastname: Fang
authors.forename: Yongsheng
authors.initials: Y
authors.lastname: Chang
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D054512:Phospholipases A2, Calcium-Independent / Q000235:genetics / Q000502:physiology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000502:physiology; D000217:Acyltransferases
chemical_list: D005947:Glucose; D054512:Phospholipases A2, Calcium-Independent; D051780:Sterol Regulatory Element Binding Protein 1; C497388:Srebf1 protein, mouse; C549791:PNPLA3 protein, mouse; D000217:Acyltransferases