Lipid Droplet Biology and Fatty Liver

Fatty liver or "hepatic steatosis" has become the most common disease of the liver in the United States. Over 30 percent of Americans have a fatty liver that can lead to liver fibrosis, inflammation (hepatitis), cirrhosis and cancer. The central organelle within the hepatocyte that stores excess fat is the lipid droplet (LD). Scores of different proteins control the formation and utilization of LDs. A deficit in LD breakdown is believed to play a central role in fatty liver disease.

The Cytoskeletal Membrane Dynamics Lab's goals are to define:

  • How the hepatocyte targets different catabolic proteins to the LD surface to mediate LD breakdown
  • The mechanisms by which autophagolysosomes engulf LDs in a process termed "lipophagy" to mediate catabolism
  • The mechanisms by which LDs-autophagolysosomes-mitochondria interact to expedite lipid catabolism

These publications describe the Cytoskeletal Membrane Dynamics Lab's work in lipid droplet biology and fatty liver.

Rab10 distributes to LD-associated structures upon serum starvation (figure 1).

  • Li Z, Schulze RJ, Weller SG, Krueger EW, Schott MB, Zhang X, Casey CA, Liu J, Stöckli J, James DE, McNiven MA. A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets. Science Advances. 2016;2:e1601470.

    A membrane-deforming protein complex regulated by the Rab10 GTPase mediates the autophagic engulfment of lipid droplets during nutrient deprivation. This mechanism provides insight into how the liver uses stored lipids to support the development of therapies for fatty liver disease.

Rab7 mediates LD breakdown by recruiting degradative compartments: A working model (figure 7).

  • Schroeder B, Schulze RJ, Weller SG, Sletten AC, Casey CA, McNiven MA. The small GTPase Rab7 as a central regulator of hepatocellular lipophagy. Hepatology. 2015;61:1896.

    Autophagy is a central mechanism by which hepatocytes catabolize lipid droplets (LDs). The regulatory mechanisms that control this important process, however, are poorly defined. The small guanosine triphosphatase (GTPase) Rab7 has been implicated in the late endocytic pathway and is known to associate with LDs, although its role in LD breakdown has not been tested. In this study, we demonstrate that Rab7 is indispensable for LD breakdown ("lipophagy") in hepatocytes subjected to nutrient deprivation. Importantly, Rab7 is dramatically activated in cells placed under nutrient stress; this activation is required for the trafficking of both multivesicular bodies and lysosomes to the LD surface during lipophagy, resulting in the formation of a lipophagic "synapse." Depletion of Rab7 leads to gross morphological changes of multivesicular bodies, lysosomes and autophagosomes, consequently leading to attenuation of hepatocellular lipophagy.

Dynamin 2 directs lipid droplet breakdown

  • Schulze RJ, Weller SG, Schroeder B, Krueger EW, Chi S, Casey CA, McNiven MA. Lipid droplet breakdown requires dynamin 2 for vesiculation of autolysosomal tubules in hepatocytes. Journal of Cell Biology. 2013;203, 315.

    In the hepatocyte, lipid droplets (LDs) may be catabolized by autophagy for use as an energy source; however, the membrane-trafficking machinery regulating such a process is poorly characterized. We hypothesized that the large GTPase dynamin 2 (Dyn2), well-known for its involvement in membrane deformation and cellular protein trafficking, could orchestrate autophagy-mediated LD breakdown. These findings provide new evidence for the participation of the autolysosome in LD metabolism and demonstrate a novel role for dynamin in the function and maturation of an autophagic compartment.

Review published research articles from the Cytoskeletal Membrane Dynamics Lab related to lipid droplet biology and fatty liver on PubMed.