Effect of Obesity on the Hepatotoxicity of High Dose Oral (‐)‐Epigallocatechin‐3‐gallate

Fatty liver disease is a co‐morbidity of obesity which is characterized by increased hepatic oxidative stress and increased sensitivity to drug induced liver injury (DILI). Green tea based dietary supplements containing high levels of the polyphenol (‐)‐epigallocatechin‐3‐gallate (EGCG) have become popular for weight loss. Case‐studies have reported hepatotoxicity associated with consumption of green tea‐based supplements and laboratory studies have shown the potential hepatotoxicity of EGCG in animals. With a growing body of evidence of high dose EGCG mediated liver toxicity, and studies showing increased sensitivity to DILI in obese subjects, it is reasonable to hypothesize that obesity may increase susceptibility to EGCG mediated hepatotoxicity. We tested this hypothesis in high fat‐fed obese C57BL/6J mice. Obese and age‐matched lean controls were treated with 0, 500, or 750 mg/kg EGCG by oral gavage, once daily for 2 d. At 500 mg/kg, EGCG treatment increased plasma alanine aminotransferase (ALT) and hepatic malondialdehyde (MDA) levels to a greater extent in obese mice compared to lean, age‐matched controls. By contrast, plasma ALT and hepatic MDA levels were greater in lean mice treated with 750 mg/kg EGCG compared to obese mice. EGCG treatment dose‐dependently reduced hepatic mRNA expression of peroxisome proliferator‐activator receptor g coactivator‐1a and forkhead box O3 in obese mice. Since these genes are related to antioxidant response, further studies are underway to determine the effect of EGCG on the expression and activity of antioxidant enzymes. The results of these experiments provide insight into factors that moderate sensitivity to EGCG mediated hepatotoxicity.