Lipid Droplet Biology and Fatty Liver

Fatty liver disease, also called hepatic steatosis, has become the most common disease of the liver in the United States. Over 40% of Americans have a fatty liver that can lead to liver fibrosis, inflammation (hepatitis), cirrhosis and cancer. Moreover, because the liver is a central detoxification organ, it is especially susceptible to damage from alcohol. Most heavy drinkers exhibit fatty liver, called ethanol-induced hepatic steatosis, and 40% to 50% of these people can develop life-threatening disease. The central organelle within the hepatocyte that stores excess fat is the lipid droplet (LD). Scores of different proteins control the formation and use of LDs. A deficit in LD breakdown is believed to play a central role in fatty liver disease.

The Membrane Trafficking in Disease 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 autophago-lysosomes engulf LDs in a process termed "lipophagy" to mediate catabolism.
• The mechanisms by which LDs-autophago-lysosomes-mitochondria interact to expedite lipid catabolism.
• How alcohol alters LD composition, function and breakdown.
• How alcohol alters the association of LD-bound proteins that can contribute to fat catabolism and autophagy.

Selected publications

• Thomes PG, Strupp MS, Donohue TM Jr, Kubik JL, Sweeney S, Mahmud R, Schott MB, Schulze RJ, McNiven MA, Casey CA. Hydroxysteroid 17β-dehydrogenase 11 accumulation on lipid droplets promotes ethanol-induced cellular steatosis. Journal of Biological Chemistry. 2023; doi:10.1016/j.jbc.2023.103071.
• Schulze RJ, Krueger EW, Weller SG, Johnson KM, Casey CA, Schott MB, McNiven MA. Direct lysosome-based autophagy of lipid droplets in hepatocytes. Proceedings of the National Academy of Sciences of the United States of America. 2020; doi:10.1073/pnas.2011442117.
• Drizyte-Miller K, Chen J, Cao H, Schott MB, McNiven MA. The small GTPase Rab32 resides on lysosomes to regulate mTORC1 signaling. Journal of Cell Science. 2020; doi:10.1242/jcs.236661.
• Li Z, Weller SG, Drizyte-Miller K, Chen J, Krueger EW, Mehall B, Casey CA, Cao H, McNiven MA. Maturation of lipophagic organelles in hepatocytes is dependent upon a Rab10/Dynamin-2 complex. Hepatology. 2020; doi:10.1002/hep.31059.
• Schott MB, Weller SG, Schulze RJ, Krueger EW, Drizyte-Miller K, Casey CA, McNiven MA. Lipid droplet size directs lipolysis and lipophagy catabolism in hepatocytes. Journal of Cell Biology. 2019; doi:10.1083/jcb.201803153.
• Schulze RJ, Rasineni K, Weller SG, Schott MB, Schroeder B, Casey CA, McNiven MA. Ethanol exposure inhibits hepatocyte lipophagy by inactivating the small guanosine triphosphatase Rab7. Hepatology Communications. 2017; doi:10.1002/hep4.1021.
• Schott MB, Rasineni K, Weller SG, Schulze RJ, Sletten AC, Casey CA, McNiven MA. β-Adrenergic induction of lipolysis in hepatocytes is inhibited by ethanol exposure. Journal of Biological Chemistry. 2017; doi:10.1074/jbc.M117.777748.
• 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; doi:10.1126/sciadv.1601470.
• 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; doi:10.1002/hep.27667.
• 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; doi:10.1083/jcb.201306140.