Emerging evidence suggests that mitochondrial dysfunction mediates the pathogenesis for non-alcoholic fatty liver disease (NAFLD). Hydroxytyrosol (HT) is a key component of extra virgin olive oil which can exert beneficial effects on NAFLD through modulating mitochondria. However, the mechanism of the impacts of HT still remains elusive. Thus, an in vivo and a series of in vitro experiments were carried out to examine the impacts of hydroxytyrosol (HT) on lipid metabolism and mitochondrial function in fish. For the in vivo experiment, two diets were produced to contain 10% and 16% fat as normal-fat and high-fat diets (NFD and HFD) and two additional diets were prepared by supplementing 200 mg/kg of HT to the NFD and HFD. The test diets were fed to triplicate groups of spotted seabass (Lateolabrax maculatus) juveniles for 8 weeks. The results showed that feeding HFD leads to increased fat deposition in the liver and induces oxidative stress, both of which were ameliorated by HT application. Furthermore, transmission electron microscopy revealed that HFD destroyed mitochondrial cristae and matrix and induced severe hydropic phenotype, while HT administration relieved these alterations. The results of in vitro studies using zebrafish liver cell line (ZFL) showed that HT promotes mitochondrial function and activates PINK1-mediated mitophagy. These beneficial effects of HT disappeared when the cells were treated with cyclosporin A (Csa) as a mitophagy inhibitor. Moreover, the PINK1-mediated mitophagy activation by HT was blocked when compound C (CC) was used as an AMPK inhibitor. In conclusion, our findings demonstrated that HT alleviates fat accumulation, oxidative stress and mitochondrial dysfunction, and its effects are deemed to be mediated via activating mitophagy through the AMPK/PINK1 pathway.
Oxidative stress is a common phenomenon in aquaculture, which can be induced by nutritional or environmental factors. Generally, oxidative stress causes poor growth performance, metabolic dysregulation, and even the death of aquatic animals. To identify a nutritional intervention strategy, high-fat diet (HFD) feeding (Experiment I) and acute ammonia nitrogen challenge (Experiment II) tests were carried out. In Experiment I, HFD feeding significantly decreased the growth performance concomitantly with excessive fat deposition in the liver and abdomen. The addition of 4-PBA in the diet improved the excessive fat accumulation. The activities of antioxidative enzymes were suppressed, and the levels of lipid and protein peroxidation were increased, indicating that HFD feeding induced oxidative stress. The endoplasmic reticulum stress (ERs) related genes were downregulated in the HFD group. Under a transmission electron microscope (TEM), more swollen and dilated ER lumen could be observed. These results indicated that the HFD induced ERs activation. Although 4-PBA acted as a potent ERs inhibitor, as evidenced by the alleviated alterations of ERs molecules and the ER ultrastructure, the oxidative stress was also attenuated by 4-PBA. In Experiment II, dietary 4-PBA improved the tolerance to the acute ammonia nitrogen challenge, as lower mortality and serum aminotransferase activity was found. Further results showed that 4-PBA decreased the peroxidation content and attenuated ERs, thus confirming the correlation between oxidative stress and ERs. Our findings showed that dietary 4-PBA supplementation can attenuate oxidative stress induced by a HFD or acute ammonia challenge; the mechanism is related to its potent inhibition effect for ERs.
Excessive fat accumulation is a common phenomenon in cultured fish, which can cause metabolic disease such as fatty liver. However, the relative regulatory approach remains to be explored. Based on this, two feeding trials were conducted. Firstly, fish were fed either a normal-fat diet (NFD) or a high-fat diet (HFD) for eight weeks and sampled at the 2nd, 4th, 6th, and 8th week after feeding (Experiment I). In the first four weeks, fish fed an HFD grew faster than those fed an NFD. Conversely, the body weight and weight gain were higher in the NFD group at the 6th and 8th weeks. Under light and transmission electron microscopes, fat accumulation of the liver was accompanied by an obvious endoplasmic reticulum (ER) swell. Accordingly, the expressions of atf-6, ire-1, perk, eif-2α, atf-4, grp78, and chop showed that ER stress was activated at the 6th and 8th weeks. In Experiment II, 50 mg/kg 4-PBA (an ERs inhibitor) was supplemented to an HFD; this was named the 4-PBA group. Then, fish was fed with an NFD, an HFD, and a 4-PBA diet for eight weeks. As the result, the excessive fat deposition caused by an HFD was reversed by 4-PBA. The expression of ER stress-related proteins CHOP and GRP78 was down-regulated by 4-PBA, and the transmission electron microscope images also showed that 4-PBA alleviated ER stress induced by the feeding of an HFD. Furthermore, 4-PBA administration down-regulated SREBP-1C/ACC/FAS, the critical pathways of fat synthesis. In conclusion, the results confirmed that ER stress plays a contributor role in the fat deposition by activating the SREBP-1C/ACC/FAS pathway. 4-PBA as an ER stress inhibitor could reduce fat deposition caused by an HFD via regulating ER stress.
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