Zinc (Zn) deficiency is the most consistently discovered nutritional manifestations of fatty liver disease. Although Zn is known to stimulate hepatic lipid oxidation, little is known about its underlying mechanism of action in lipolysis. Given the potential role of lipophagy in lipid metabolism, the purpose of this study was to test the hypothesis that Zn attenuates hepatic lipid accumulation by modulating lipophagy. The present study indicated that Zn is a potent promoter of lipophagy. Zn administration significantly alleviated hepatocellular lipid accumulation and increased the release of free fatty acids in association with enhanced fatty acid oxidation and inhibited lipogenesis, which was accompanied by activation of autophagy. Moreover, Zn reduced lipid accumulation and stimulated lipolysis by autophagy-mediated lipophagy. Zn-induced up-regulation of autophagy and lipid depletion is free Zn-dependent in the cytosols. Zn-induced autophagy and lipid turnover involved up-regulation of the calcium/calmodulin-dependent protein kinase kinase-β (Ca/CaMKKβ)/AMPK pathway. Meanwhile, Zn-activated autophagy and lipid depletion were via enhancing metal response element-binding transcription factor (MTF)-1 DNA binding at PPARα promoter region, which in turn induced transcriptional activation of the key genes related to autophagy and lipolysis. Zn activated the pathways of Zn/MTF-1/ Peroxisome proliferator-activated receptor (PPAR)α and Ca/CaMKKβ/AMPK, resulting in the up-regulation of lipophagy and accordingly reduced hepatic lipid accumulation. Our study, for the first time, provided innovative evidence of the direct relationship between metal elements (Zn) and lipid metabolism. The present study also indicated the novel mechanism for Zn-induced lipolysis by the activation of Zn/MTF-1/PPARα and Ca/CaMKKβ/AMPK pathways, which induced the occurrence of lipophagy. These results provide new insight into Zn nutrition and its potential beneficial effects on the prevention of fatty liver disease in vertebrates.-Wei, C.-C., Luo, Z., Hogstrand, C., Xu, Y.-H., Wu, L.-X., Chen, G.-H., Pan, Y.-X., Song, Y.-F. Zinc reduces hepatic lipid deposition and activates lipophagy via Zn/MTF-1/PPARα and Ca/CaMKKβ/AMPK pathways.
Highlights d Chronic spike blockade with tetrodotoxin causes homeostatic spike broadening d Alternative splicing of BK channels by exclusion of a specific exon is responsible d Synaptic homeostasis starts CaM kinase signaling to drive nuclear exit of Nova-2 d Chronic inactivity and hyperactivity can initiate similar LTPlike events
The present study was performed to determine the effect of Zn exposure influencing endoplasmic reticulum (ER) stress, explore the underlying molecular mechanism of Zn-induced hepatic lipolysis in a fish species of significance for aquaculture, yellow catfish Pelteobagrus fulvidraco. We found that waterborne Zn exposure evoked ER stress and unfolded protein response (UPR), and activated cAMP/PKA pathway, and up-regulated hepatic lipolysis. The increase in ER stress and lipolysis were associated with activation of cAMP/PKA signaling pathway. Zn also induced an increase in intracellular Ca level, which could be partially prevented by dantrolene (RyR receptor inhibitor) and 2-APB (IP3 receptor inhibitor), demonstrating that the disturbed Ca homeostasis in ER contributed to ER stress and dysregulation of lipolysis. Inhibition of ER stress by PBA attenuated UPR, inhibited the activation of cAMP/PKA pathway and resulted in down-regulation of lipolysis. Inhibition of protein kinase RNA-activated-like ER kinase (PERK) by GSK2656157 and inositol-requiring enzyme (IRE) by STF-083010 differentially influenced Zn-induced changes of lipid metabolism, indicating that PERK and IRE pathways played different regulatory roles in Zn-induced lipolysis. Inhibition of PKA by H89 blocked the Zn-induced activation of cAMP/PKA pathway with a concomitant inhibition of ER stress-mediated lipolysis. Taken together, our findings highlight the importance of the ER stress-cAMP/PKA axis in Zn-induced lipolysis, which provides new insights into Zn toxicology in fish and probably in other vertebrates.
The hypothesis of our study was that waterborne Zn exposure evoked phospholipids (PL) biosynthesis to compensate for the loss of membrane integrity, and the pathways of oxidative stress and endoplasmic reticulum (ER) stress mediated the Zn-evoked changes of PL biosynthesis. Thus, we conducted RNA sequencing to analyze the differences in the intestinal transcriptomes between the control and Zn-treated P. fulvidraco. The 56-day Zn exposure increased the intestinal Zn accumulation, and mRNA levels of 816 genes were markedly up-regulated, while that of 263 genes were down-regulated. Many differentially expressed genes in the pathways of PL biosynthesis and protein processing in ER were identified. Their expression profiles indicated that waterborne Zn exposure injured protein metabolism, induced PL biosynthesis caused oxidative stress and ER stress, and activated the unfolded protein response. Then, using the primary enterocytes, we identified the mechanism of oxidative and ER stress mediating Zn-induced PL biosynthesis, and indicated that the activation of these pathways constituted adaptive mechanisms to reduce Zn toxicity. Our study demonstrated that Zn exposure via the water increased Zn accumulation and PL biosynthesis, and that oxidative stress and ER stress were interdependent and mediated the Zn-induced PL biosynthesis of the intestine in the freshwater teleost.
Magnesium influences hepatic lipid deposition in vertebrates, but the underlying mechanism is unknown. We used yellow catfish and their isolated hepatocytes to test the hypothesis that magnesium influences lipid deposition by modulating lipogenesis and lipolysis. Juvenile yellow catfish (mean ± SEM weight: 3.43 ± 0.02 g, 3 mo old, mixed sex) were fed a 0.14- (low), 0.87- (intermediate) or 2.11- (high) g Mg/kg diet for 56 d. Primary hepatocytes were incubated for 48 h in control or MgSO-containing medium with or without 2-h pretreatment with an inhibitor (AG490, GW6471, or Compound C). Growth performance, cell viability, triglyceride (TG) concentrations, and expression of enzymes and genes involved in lipid metabolism were measured. Compared with fish fed low magnesium, those fed intermediate or high magnesium had lower hepatic lipids (18%, 22%) and 6-phosphogluconate dehydrogenase (6PGD; 3.7%, 3.8%) and malic enzyme (ME; 35%, 48%) activities and greater mRNA levels of the lipolytic genes adipose triacylglyceride lipase (; 82% and 1.7-fold) and peroxisome proliferator-activated receptor (; 18% and 1.0-fold), respectively ( < 0.05). Relative mRNA levels of AMP-activated protein kinase () ,, ,, ,, Janus kinase , and signal transducers and activators of transcription () in fish fed high magnesium were higher (24% to 3.1-fold, < 0.05) than in those fed low or intermediate magnesium. Compared with cells incubated with MgSO alone, those incubated with MgSO and pretreated with AG490, GW6471, or Compound C had greater TG concentrations (42%, 31%, or 56%), (98%, 59%, or 51%), (68%, 73%, or 32%) mRNA expression, and activities of G6PD (35%, 45%, or 16%) and ME (1.5-fold, 1.3-fold, or 13%), and reduced upregulation (61%, 25%, or 45%) of the lipolytic gene, ( < 0.05). Magnesium reduced hepatic lipid accumulation in yellow catfish and the variation might be attributed to inhibited lipogenesis and increased lipolysis. PPARA, JAK-STAT, and AMPK pathways mediated the magnesium-induced changes in lipid deposition and metabolism. These results offer new insight into magnesium nutrition in vertebrates.
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