ABSTRACT
Long-term alcohol overconsumption impairs intestinal and hepatic structure and function, along with dysregulation of zinc homeostasis. We previously found that zinc-glutathione (Zn-GSH) complex effectively suppressed alcohol-induced liver injury in mice. This study was undertaken to test the hypothesis that Zn-GSH suppresses alcohol-induced liver injury by modulating intestinal zinc transporters. Mice were subjected to long-term ethanol feeding, as per the NIAAA model, with groups receiving either an ethanol diet alone or an ethanol diet supplemented with Zn-GSH. Treatment groups were carefully monitored for alcohol consumption and subjected to a final binge drinking exposure. The results showed that Zn-GSH increased the survival rate and decreased the recovery time from binge drinking-induced drunkenness. Histopathological analyses demonstrated a reduction in liver steatosis and the preservation of intestinal integrity by Zn-GSH. It was observed that Zn-GSH prevented the reduction of Zn and GSH levels while increasing alcohol dehydrogenase and aldehyde dehydrogenase in both liver and intestine. Importantly, the expression and protein abundance of zinc transporters ZnT-1, ZIP-1, ZIP-4, ZIP-6, and ZIP-14, all of which are critically involved in intestinal zinc transport and homeostasis, were significantly increased or preserved by Zn-GSH in response to alcohol exposure. This study thus highlights the critical role of Zn-GSH in maintaining intestinal zinc homeostasis by modulating zinc transporters, thereby preventing alcohol-induced intestinal and hepatic injury.
ABSTRACT
Zinc depletion is associated with alcohol-associated liver injury. We tested the hypothesis that increasing zinc availability along with alcohol consumption prevents alcohol-associated liver injury. Zinc-glutathione (ZnGSH) was synthesized and directly added to Chinese Baijiu. Mice were administered a single gastric dose of 6 g/kg ethanol in Chinese Baijiu with or without ZnGSH. ZnGSH in Chinese Baijiu did not change the likeness of the drinkers but significantly reduced the recovery time from drunkenness along with elimination of high-dose mortality. ZnGSH in Chinese Baijiu decreased serum AST and ALT, suppressed steatosis and necrosis, and increased zinc and GSH concentrations in the liver. It also increased alcohol dehydrogenase and aldehyde dehydrogenase in the liver, stomach, and intestine and reduced acetaldehyde in the liver. Thus, ZnGSH in Chinese Baijiu prevents alcohol-associated liver injury by increasing alcohol metabolism timely with alcohol consumption, providing an alternative approach to the management of alcohol-associated drinking.
ABSTRACT
Zinc deficiency is common in the liver of patients with chronic liver disease. Zinc supplementation suppresses the progression of liver fibrosis induced by bile duct ligation (BDL) in mice. The present study was undertaken to specifically investigate a possible mechanism by which zinc plays this role in the liver. Kunming mice were subjected to BDL for 4 weeks to induce liver fibrosis, and concomitantly treated with zinc sulfite or saline as control by gavage once a day. The results showed that zinc supplementation significantly suppressed liver fibrosis and inflammation along with inhibition of hepatic stellate cells activation induced by BDL. These inhibitory effects were accompanied by the reduction of collagen deposition and a significant reduction of macrophage infiltration affected livers. Importantly, zinc selectively inhibited M1 macrophage polarization and M1-related inflammatory cytokines. This inhibitory effect was further confirmed by the reduction of relevant biomarkers of M1 macrophages including inducible NO synthase (iNOS), monocyte chemotactic protein-1 (MCP-1/CCL2), and tumor necrosis factor-α in the zinc supplemented BDL livers. In addition, zinc inhibition of M1 macrophages was associated with a decrease of Notch1 expression. Taken together, these data indicated that zinc supplementation inhibited liver inflammation and fibrosis in BDL mice through selective suppression of M1 macrophages, which is associated with inhibition of Notch1 pathway in M1 macrophage polarization.
