ALBERT

Description: Reactive oxygen species (ROS) such as superoxide anion (O2•−) and hydrogen peroxide (H2O2) are generated endogenously by processes such as mitochondrial oxidative phosphorylation, or they may arise from exogenous sources like bacterial invasion. ROS can be beneficial (oxidative eustress) as signaling molecules but also harmful (oxidative distress) to cells when ROS levels become unregulated in response to physiological, pathological or pharmacological insults. Indeed, abnormal ROS levels have been shown to contribute to the etiology of a wide variety of diseases. Transcriptional control of metabolic genes is a crucial mechanism to coordinate ROS homeostasis. Therefore, a better understanding of how ROS metabolism is regulated by specific transcription factors can contribute to uncovering new therapeutic strategies. A large body of work has positioned the estrogen-related receptors (ERRs), transcription factors belonging to the nuclear receptor superfamily, as not only master regulators of cellular energy metabolism but, most recently, of ROS metabolism. Herein, we will review the role played by the ERRs as transcriptional regulators of ROS generation and antioxidant mechanisms and also as ROS sensors. We will assess how the control of ROS homeostasis by the ERRs can be linked to physiology and disease and the possible contribution of manipulating ERR activity in redox medicine.

Description: Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.