Lipid droplets and liver disease: from basic biology to clinical implications

Abstract

Lipid droplets are dynamic organelles that store neutral lipids during times of energy excess and serve as an energy reservoir during deprivation. Many prevalent metabolic diseases, such as the metabolic syndrome or obesity, often result in abnormal lipid accumulation in lipid droplets in the liver, also called hepatic steatosis. Obesity-related steatosis, or NAFLD in particular, is a major public health concern worldwide and is frequently associated with insulin resistance and type 2 diabetes mellitus. Here, we review the latest insights into the biology of lipid droplets and their role in maintaining lipid homeostasis in the liver. We also offer a perspective of liver diseases that feature lipid accumulation in these lipid storage organelles, which include NAFLD and viral hepatitis. Although clinical applications of this knowledge are just beginning, we highlight new opportunities for identifying molecular targets for treating hepatic steatosis and steatohepatitis.

Figure 1 |. Hepatic steatosis results from an imbalance in lipid storage and lipolysis or secretion.

Hepatic steatosis can result from different processes: increased fatty acid (FA) uptake, de novo lipogenesis and triglyceride synthesis combined with lipid droplet (LD) biogenesis or growth; decreased LD catabolism (including decreased fatty acid oxidation); or impaired triglyceride or very-low-density lipoprotein (VLDL) secretion. Factors associated with these processes are listed in the figures, those that upregulate steatosis (green boxes) and those that downregulate steatosis (orange boxes).

Figure 2 |. Histopathology of NAFLD showing areas of macrosteatosis and microsteatosis.

A haematoxylin and eosin-stained tissue sample from a human showing hepatocytes exhibiting microvesicular (arrowheads) and macrovesicular (arrows) steatosis. Hepatocytes with microvesicular steatosis have abnormal accumulation of lipid with preserved cellular architecture, including a non-displaced nucleus, whereas hepatocytes with macrovesicular steatosis have one large droplet that displaces the nucleus. We thank S. Alexandrescu at Boston Children’s Hospital, USA, for this image.

Figure 3 |. Lipid droplet formation and expansion.

a | Lipid droplets (LDs) consist of a neutral lipid core surrounded by a phospholipid monolayer. Proteins access the LD surface by relocalizing from the ER bilayer (class I) or from the cytosol (class II). b | LD formation begins with neutral lipid synthesis. The lipids accumulate in the ER bilayer to form a lens. c | Eventually, the bilayer deforms and causes the droplet to bud forming an initial LD (iLD). d | COPI can bud nano-LDs from the iLD, resulting in increased surface tension and reconnection of the iLD with the ER. This contact allows class I proteins to access the droplet, including GPAT4 and DGAT2. These enzymes are involved in triglyceride synthesis and result in LD growth, forming an expanding LD.

Figure 4 |. Giant lipid droplet formation.

Giant lipid droplets (LDs) form in one of two ways. a | Coalescence, which occurs for example during relative phosphatidylcholine deficiency, results in rapid fusion of two LDs. b | In a process called ripening, neutral lipids are transferred by the slower process of diffusion with a net transfer from smaller to larger LDs. Ripening seems to be facilitated by proteins such as CIDEC (also known as FSP27).

Figure 5 |. Lipid droplet consumption.

a | Lipid droplets (LDs) can be degraded by lipolysis. As the surface of the LD shrinks, there is protein crowding and some proteins, especially class II proteins, fall off. b | Other proteins are removed from the LD surface and brought to the lysosome by chaperone-mediated autophagy. Small LDs or parts of an LD can be engulfed by a membrane bilayer to form autophagosomes that can be delivered to the lysosome for degradation.

Figure 6 |. Possible therapeutic targets to decrease hepatic steatosis.

Interventions designed to decrease triglyceride (TG) synthesis, increase lipolysis, increase fatty acid (FA) oxidation, or increase very-low-density lipoprotein (VLDL) secretion could decrease hepatic TG content. ER, endoplasmic reticulum.