Pathophysiology of lipid droplet proteins in liver diseases

Abstract

Cytosolic lipid droplets (LDs) are present in most cell types, and consist of a core comprising neutral lipids, mainly triglycerides and sterol esters, surrounded by a monolayer of phospholipids. LDs are heterogeneous in their structure, chemical composition, and tissue distribution. LDs are coated by several proteins, including perilipins and other structural proteins, lipogenic enzymes, lipases and membrane-trafficking proteins. Five proteins of the perilipin (PLIN) family (PLIN1 (perilipin), PLIN2 (adipose differentiation-related protein), PLIN3 (tail-interacting protein of 47kDa), PLIN4 (S3-12), and PLIN5 (myocardial lipid droplet protein)), are associated with LD formation. More recently, the CIDE family of proteins, hypoxia-inducible protein 2 (HIG2), and patanin-like phospholipase domain-containing 3 (PNPLA3) have also gained attention in hepatic LD biology. Evidence suggests that LD proteins are involved in the pathophysiology of fatty liver diseases characterized by excessive lipid accumulation in hepatocytes. This review article will focus on how hepatic LDs and their associated proteins are involved in the pathogenesis of three chronic liver conditions: hepatitis C virus infection, non-alcoholic fatty liver disease, and alcoholic liver disease.

Keywords: Alcohol; Diabetes; HCV; Hepatitis; Lipid droplet; Lipids; Liver; NAFLD; Obesity; Perilipin; Steatosis.

Figure 1. Biogenesis of lipid droplets (LDs)

Neutral lipids are synthesized in the ER and stored in the LDs. The canonical model of LD formation shown in the figure posits that neutral lipids form a lens within the ER bilayer which then buds from the membrane and incorporates phospholipids from the cytosolic leaflet. Alternatively, the “bicelle model” of LD formation proposes that neutral lipids accumulate between the ER membrane leaflets instead of budding. The nascent LDs are excised from the ER membrane, and incorporate phospholipids from both cytosolic and luminal leaflets of the ER. The latter model may explain how large unfolded proteins and viruses escape from the ER lumen into the cytoplasm. A “vesicular-budding model” proposes that small bilayer vesicles are tethered to the ER membrane and provide a platform for LD formation. Neutral lipids are synthesized and pumped from the ER into the vesicle bilayer, fill the intermembrane space, and the vesicular lumen eventually becomes a small inclusion inside the LDs.

Figure 2. Interaction of HCV and LDs

The replication of HCV RNA and viral particle production requires lipid droplets (LDs). Newly synthesized or uncoated viral genomic RNA is translated to a viral polyprotein followed by a cleaving polyprotein. Mature non-structural proteins form a complex with host factors. The positive strand of genomic RNA is enclosed with the core proteins, associated with non-structural proteins. The viral core protein is translocated to the LDs. It has been proposed that envelope proteins, e.g. NS2 and p7, determine the recruitment of viral protein from the LDs to the ER membrane. VLDL binds to viral particles before or after budding. The viral core protein increases the synthesis and storage of triglycerides and cholesterol esters in the LDs through interactions with host factors.