Liver plays a key role in the control of lipid metabolism including the uptake, oxidation and de novo synthesis of fatty acids. Nonalcoholic fatty liver disease (NAFLD) is the most common chronic human liver disorder that is often associated with the metabolic syndromes such as prolonged starvation, obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and atherogenic dyslipidaemia; however, intracellular signaling pathways that control the development of NAFLD under physiological and pathological conditions remain largely undefined.   

A research group led by Prof. CUI Zongbin at the Institute of Hydrobiology, Chinese Academy of Sciences (IHB) has previously generated a transgenic zebrafish line (Gu et al., 2013; Journal of Genetics and Genomics, 40: 523-531), in which a single copy of rtTA-transgene has inserted into the second exon of slc7a3a gene and thus produced a null-mutation. Zebrafish Slc7a3a is a transmembrane protein that plays an important role in transporting arginine, the precursor of nitric oxide synthesis. They have noticed that homozygous slc7a3a-null mutants are fertile under standard rearing conditions, but severely hepatic steatosis can be induced in slc7a3a-null mutants during fasting.    

They further investigated the molecular mechanism of lipid accumulation in the livers of fasted slc7a3a-null mutants. Main results include: i) NO synthesis is impaired in slc7a3a-null mutants due to the deprivation of Slc7a3a, an arginine transporter; ii) the impairment of NO synthesis directly inhibited the synthesis of downstream cGMP and the activation of AMPK; iii) impaired activation of AMPK reduced the expression of transcription factors PGC-1α and PPARα in liver, which then limited the expression of CPT-1, the key enzyme catalyzing the production of β-hydroxybutyrate during β-oxidation and increased the de novo synthesis of fatty acids. Thus, decreased hepatic fatty acid oxidation and increased lipogenesis are the main causes for the development of severe hepatic steatosis in fasted Slc7a3a-null zebrafish(Fig.).    

Fig. A schematic model demonstrates an essential role of Slc7a3ain the control of fatty acid oxidation via NO-AMPK-PPARα signaling

Moreover, knockdown of Slc7a3 in the liver of mice or SLC7A3 in human liver cells impaired AMPK-PPARα signaling and led to lipid accumulation under fasting or glucose starvation, respectively. These findings have revealed a novel NO-AMPK-PPARa signaling pathway that is crucial for the control of hepatic fatty acid oxidation in vertebrates.   

These findings of this work in details were shown in a paper entitled “Genetic ablation of solute carrier family 7a3a leads to hepatic steatosis in zebrafish during fasting”, which is published online in Hepatology. This work was supported by grants from the National Basic Research Program of China, the National Natural Science Foundation of China and the State Key Laboratory of Freshwater Ecology and Biotechnology.