(-)-Epicatechin and its metabolites prevent palmitate-induced NADPH oxidase upregulation, oxidative stress and insulin resistance in HepG2 cells.

While diets rich in fruit and vegetables can decrease the risk for type 2 diabetes (T2D), diets rich in fat and carbohydrates can increase it. The flavanol-3-ol (-)-epicatechin (EC) can improve insulin sensitivity both in humans and animal models of T2D. NADPH oxidases and oxidative stress can contribute to the development of insulin resistance. This study investigated the capacity of EC and EC metabolites (ECM) to downregulate NADPH oxidases and oxidative stress, and its association to an improvement of insulin sensitivity. This was studied in in vivo (high fat-fed mice) and in vitro (HepG2 cells) conditions of hepatic lipid overload. EC decreased NOX3/NOX4 liver expression and mitigated oxidative stress in high fat-fed mice. In HepG2 cells, incubation with palmitate increased: i) lipid deposition, ii) NOX3/NOX4 expression, iii) NADPH oxidase activity, and iv) oxidative stress; promoting v) the activation of redox-sensitive kinases (JNK and IKK), and vi) impaired insulin responses. Physiological concentrations of EC and ECM, and NADPH oxidase inhibitors (apocynin, VAS2870) prevented all those deleterious effects of palmitate. The obtained results points to NADPH oxidases as an important target in the capacity of EC to improve insulin sensitivity in conditions of liver lipid overload, as those associated with Western-style diets.