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Genetic ablation of solute carrier family 7a3a leads to hepatic steatosis in zebrafish during fasting
Author(s) -
Gu Qilin,
Yang Xiaojie,
Lin Li,
Li Shaoyang,
Li Qing,
Zhong Shan,
Peng Jinrong,
Cui Zongbin
Publication year - 2014
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27356
Subject(s) - endocrinology , medicine , steatosis , ampk , fatty liver , nonalcoholic fatty liver disease , biology , beta oxidation , peroxisome , peroxisome proliferator activated receptor , protein kinase a , receptor , biochemistry , kinase , metabolism , disease
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. Conclusion : These findings have revealed a NO‐AMPK‐PPAR‐α–signaling pathway that is crucial for the control of hepatic FAO in vertebrates. (H epatology 2014;60:1928–1940)