Lipotoxicity in NASH

Abstract

Exposure to a sedentary lifestyle, fat-rich and fiber-poor diets, positive caloric imbalance and an extended life disrupt the metabolic homeostasis causing non-alcoholic fatty liver disease. A subset of patients with this emerging public health problem may develop non-alcoholic steatohepatitis (NASH) and progress to cirrhosis and liver cancer [1]. Understanding the molecular mechanisms promoting liver injury in NASH is not only of biomedical and public health interest, but also key to develop new avenues for specific treatment interventions. In this Snapshot article, we will outline current evolving concepts of signaling cascades that may be linked to liver injury in NASH. It is important to acknowledge that a significant amount of information has been obtained from in vitro and animal studies that may not entirely reflect the situation in the liver of patients with NASH. In addition, multiple pathways leading to apoptosis may be operational in NASH patients at the same time, but the relative contribution of each one is unknown. Nevertheless, targeting apoptotic pathways in NASH may represent a viable therapeutic strategy particularly in the context of acute liver injury augmented by fatty liver or in the setting of transplantation using highly steatotic donor livers. Major sources of hepatic saturated fatty acids (SFAs) are adipose tissue, diet, and de novo lipogenesis from glucose. Under physiological conditions, SFA are transported to mitochondria for b-oxidation or esterified for either excretion in very low density lipoproteins or storage as lipid droplets. SFA can be released from lipid droplets via macrolipophagy (Fig. 1A). Multiple mechanisms are concurrently operative to produce liver injury in hepatocytes overwhelmed by SFA, primarily from adipocyte lipolysis, and free cholesterol from de novo synthesis [1,2]. These lipids, and in particular SFA, can activate a variety of intracellular responses resulting in lipotoxic stress in the endoplasmic reticulum (ER) and mitochondria, respectively. As a consequence, apoptosis occurs which represents a key pathogenic feature of NASH. Metabolic stress from lipids has also been linked to macrolipophagy dysfunction, presumably at the level of autophagosome-lysosome fusion [3]. Whether this promotes additional lipid accumulation or increased lipolysis in NASH remains to be addressed.