Date on Senior Honors Thesis

5-2018

Document Type

Senior Honors Thesis

Degree Name

B.S.

Department

Chemistry

Author's Keywords

PVC; TASH; plastic; hepatotoxicity; saturated fat; metabolic syndrome

Abstract

Background: Vinyl chloride (VC), an environmental contaminant, is directly hepatotoxic at high concentrations. However, our group has recently demonstrated that VC and the VC metabolite chloroethanol (CE), at concentrations that are not considered hepatotoxic, enhanced liver injury caused by high-fat diet (HFD). These data therefore suggest that the impact of VC exposure on hepatic tissue may be enhanced with underlying metabolic syndrome and/or liver injury. It is known that there is an axis between adipose and hepatic tissue in non-alcoholic fatty liver disease (NAFLD), with the former impacting pathology in the hepatic tissue via release of pro-inflammatory cytokines and/or lipolysis. The current study investigated the impact of CE on epidydimal white adipose tissue (WAT) inflammation and lipolysis.

Methods: Mice were administered CE (or vehicle) once, 10 weeks after being fed a diet high in saturated fatty acids (HFD: 42% milk fat), or a low fat control diet (LFD: 13% milk fat). Animals were sacrificed 0-24 hours after CE exposure. Plasma, liver and WAT samples were harvested for determination of liver damage, changes in energy metabolism, endoplasmic reticulum (ER) stress, and inflammation.

Results: Hepatic steatosis and inflammation caused by HFD was significantly enhanced by CE. Moreover, while HFD significantly increased the size of epididymal fat pads, this increase was enhanced by CE. Adipocyte lipid droplets relative size was also increased in the HFD/CE group; which correlated with the increased expression of lipid-associated proteins (e.g., perilipin; PLINs). Although adipose tissue of LFD-fed mice was not affected by CE, CE significantly enhanced HFD-increased indices of WAT inflammation, and ER stress. It has been shown that hepatic-derived fibroblast growth factor 21 (FGF21) is a major modulator of WAT lipolysis and is hypothesized to thereby regulate hepatic steatosis [1, 2]. Here we demonstrate that circulating levels of FGF21 are significantly increased by CE in animals fed a HFD, suggesting a possible role for WAT-mediated hepatic steatosis due to changes in WAT lipolysis.

Conclusion: Chloroethanol (as a VC surrogate) can enhance local inflammation and alter lipid metabolism in WAT in experimental obesity. Taken together these data support the hypothesis that environmental toxicant exposure can exacerbate the severity of NAFLD or non-alcoholic steatohepatitis (NASH) and supports a role of the liver-adipose axis in this process.

Lay Summary

It has been established that there is a link between liver injury and adipose tissue inflammation. The purpose of the current study was to determine the effect of chloroethanol (CE), a known hepatotoxicant, on white adipose tissue (WAT) health by examining its contribution to damage within the liver-adipose axis. A mouse model was implemented where mice were fed a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks. Animals were administered CE at the end of 10 weeks and sacrificed 0-24 hours after CE exposure. Plasma, liver and WAT samples were harvested for determination of liver damage, changes in energy metabolism, and endoplasmic reticulum (ER) stress, and inflammation. It was shown that epididymal fat pads and adipocyte lipid droplet relative size were increased in the HFD/CE group. CE significantly enhanced HFD-increased indices of WAT inflammation and ER stress. Furthermore, it was demonstrated that circulating levels of FGF21 were significantly increased by CE in animals fed a HFD, suggesting a possible role for WAT-mediated hepatic steatosis due to changes in WAT lipolysis.

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