Chronic subhepatotoxic exposure to arsenic enhances hepatic injury caused by high fat diet in mice

Abstract

Arsenic is a ubiquitous contaminant in drinking water. Whereas arsenic can be directly hepatotoxic, the concentrations/doses required are generally higher than present in the US water supply. However, physiological/biochemical changes that are alone pathologically inert can enhance the hepatotoxic response to a subsequent stimulus. Such a '2-hit' paradigm is best exemplified in chronic fatty liver diseases. Here, the hypothesis that low arsenic exposure sensitizes liver to hepatotoxicity in a mouse model of non-alcoholic fatty liver disease was tested. Accordingly, male C57Bl/6J mice were exposed to low fat diet (LFD; 13% calories as fat) or high fat diet (HFD; 42% calories as fat) and tap water or arsenic (4.9 ppm as sodium arsenite) for ten weeks. Biochemical and histologic indices of liver damage were determined. High fat diet (± arsenic) significantly increased body weight gain in mice compared with low-fat controls. HFD significantly increased liver to body weight ratios; this variable was unaffected by arsenic exposure. HFD caused steatohepatitis, as indicated by histological assessment and by increases in plasma ALT and AST. Although arsenic exposure had no effect on indices of liver damage in LFD-fed animals, it significantly increased the liver damage caused by HFD. This effect of arsenic correlated with enhanced inflammation and fibrin extracellular matrix (ECM) deposition. These data indicate that subhepatotoxic arsenic exposure enhances the toxicity of HFD. These results also suggest that arsenic exposure might be a risk factor for the development of fatty liver disease in human populations.

Review: Mechanisms of How the Intestinal Microbiota Alters the Effects of Drugs and Bile Acids

“…The Bacteroidetes were not altered, but four Firmicutes families were decreased (Lu et al, 2014). A high-fat (Western) diet fed to mice will produce nonalcoholic hepatic steatosis, and the addition of arsenic to the water of mice fed a high-fat diet enhances the liver injury, which is characterized by enhanced inflammation (Tan et al, 2011). Feeding the prebiotic oligofructose protected mice against the enhanced liver damage caused by arsenic in the presence of a high-fat diet.…”

Extracellular matrix proteins and the liver-lung axis in disease.

“…Previously, the enhancement of HFD-induced liver injury caused by arsenic correlated with a significant increase in hepatic expression of PAI-1 (98). PAI-1 is a major inhibitor of both tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), and is therefore a key inhibitor of fibrin degradation (i.e., fibrinolysis) by plasmin.…”

“…For example, rural communities, which have both artesian water supplies that are unregulated by Clean Water Act, often have high arsenic concentrations; these areas also generally have a high prevalence of obesity. In a study investigating the possible interaction between obesity and arsenic, this group demonstrated that low levels of arsenic synergistically enhance liver damage caused by high fat diet (98). These data suggest that underlying risk factors, such as obesity, may modify the risk of hepatic injury caused by subhepatotoxic levels of arsenic exposure.…”

Chronic ethanol exposure sensitizes the lung in a mouse model of endotoxemia-induced acute lung injury : potential role of plasminogen activator inhibitor-1.

“…Immunohistochemical staining for markers of macrophages (F4/80) and oxidative stress (4-HNE) were performed as previously described (40). Briefly, …”