A new perspective on NAFLD: Focusing on lipid droplets

Lipid droplets (LDs) are complex and metabolically active organelles. They are composed of a neutral lipid core surrounded by a monolayer of phospholipids and proteins. LD accumulation in hepatocytes is the distinctive characteristic of non-alcoholic fatty liver disease (NAFLD), which is a chronic, heterogeneous liver condition that can progress to liver fibrosis and hepatocellular carcinoma. Though recent research has improved our understanding of the mechanisms linking LD accumulation to NAFLD progression, numerous aspects of LD biology are either poorly understood or unknown. In this review, we provide a description of several key mechanisms that contribute to LD accumulation in hepatocytes, favouring NAFLD progression. First, we highlight the importance of LD architecture and describe how the dysregulation of LD biogenesis leads to endoplasmic reticulum stress and inflammation. This is followed by an analysis of the causal nexus that exists between LD proteome composition and LD degradation. Finally, we describe how the increase in size of LDs causes activation of hepatic stellate cells, leading to liver fibrosis and hepatocellular carcinoma. We conclude that acquiring a more sophisticated understanding of LD biology will provide crucial insights into the heterogeneity of NAFLD and assist in the development of therapeutic approaches for this liver disease. (c) 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.