title: Genetic ablation of solute carrier family 7a3a leads to hepatic steatosis in zebrafish during fasting.
abstract: Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder caused by abnormal lipid metabolisms, such as reduced hepatic fatty acid oxidation (FAO), but intracellular control of FAO under physio- and pathological conditions remains largely undefined. Here, we demonstrate that deprivation of Slc7a3a leads to hepatic steatosis in fasted zebrafish as a result of defects in arginine-dependent nitric oxide (NO) synthesis. Fast-induced hepatic steatosis in slc7a3a-null mutants can be rescued by treatments with NO donor, cyclic guanosine monophosphate analog, adenosine-monophosphate-activated protein kinase (AMPK) activator, or peroxisome proliferator-activated receptor alpha (PPAR-α) agonist. In contrast, inhibitors of NO synthases, AMPK, or soluble guanylate cyclase and liver-specifically expressed dominant negatives of peroxisome proliferator-activated receptor-gamma coactivator 1 alpha and PPAR-α are sufficient to induce hepatic steatosis in fasted wild-type larvae. Moreover, knockdown of Slc7a3 in mice or SLC7A3 in human liver cells impaired AMPK-PPAR-α signaling and resulted in lipid accumulation under fasting or glucose starvation, respectively.
  
  
  CONCLUSIONS
  These findings have revealed a NO-AMPK-PPAR-α-signaling pathway that is crucial for the control of hepatic FAO in vertebrates.
authors.affiliation: State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan, China; University of Chinese Academy of Sciences, Beijing, China.
authors.forename: Qilin
authors.initials: Q
authors.lastname: Gu
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Yang
authors.forename: Li
authors.initials: L
authors.lastname: Lin
authors.forename: Shaoyang
authors.initials: S
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.forename: Jinrong
authors.initials: J
authors.lastname: Peng
authors.forename: Zongbin
authors.initials: Z
authors.lastname: Cui
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D026923:Amino Acid Transport Systems, Basic / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D005215:Fasting / Q000502:physiology*; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D009569:Nitric Oxide / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010641:Phenotype; D013217:Starvation / Q000150:complications*; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism; D027201:Cationic Amino Acid Transporter 1
chemical_list: D055372:AMP-Activated Protein Kinases; D026923:Amino Acid Transport Systems, Basic; D006152:Cyclic GMP; D009569:Nitric Oxide; D047493:PPAR alpha; D014157:Transcription Factors; D029961:Zebrafish Proteins; C000595110:Slc7a3 protein, mouse; C572938:ppargc1a protein, zebrafish; C499482:SLC7A3 protein, human; D027201:Cationic Amino Acid Transporter 1