Lysosomal Regulation of Gene Expression

 
 
 
 

Lysosomal Regulation of Gene Expression

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Title: Lysosomal Regulation of Gene Expression
Author: Heur, J. Martin
Description: The function of lysosomes in degradation of materials is well documented. The purpose of these current studies is to determine whether lysosomes have functions beyond degradation, such as initiation of signaling pathways. More specifically, the topics addressed include exploring different receptor mediated endocytosis (RME)pathways used by cells for lysosomal trafficking of lipids and determining the mechanism of signaling between lysosomes and the nucleus. To explore the topics, the lysosomal acid lipase (LAL) null ( lal-/- ) mouse was used. LAL is the lysosomal hydrolase that cleaves cholesteryl esters (CE) and triglycerides (TG) delivered to the lysosomes by various RME pathways. The absence of LAL results in massive lysosomal storage of CE and TG in various organs, including liver, spleen, and small intestine. Livers of lal-/- mice also show an age dependent proliferation of Kupffer cells. Because lipids delivered to the lysosomes of lal-/- cells are retained, questions about RME pathways used by cells in lysosomal trafficking of lipids could be addressed directly breeding lal-/- mice to various RME pathway null mice. The coincidence of lysosomal lipid storage with proliferation of Kupffer cells suggests that lysosomal retention of a lipid lead to either the activation of a positive signal or an inactivation of a negative signal for cell proliferation. These results indicate that cells, especially macrophages, have multiple RME pathways for lysosomal trafficking of lipids where the absence of a pathway does not abolish the trafficking process. These results also suggest that lysosomes signal to the nucleus through a fatty acid to maintain tonic suppression of macrophage-colony stimulating factor (M-CSF) transcription. This signaling pathway appears to be mediated by peroxisome proliferator activated receptor (PPAR) gamma, a nuclear receptor whose ligands include essential fatty acids. The inactivation of this pathway by lysosomal retention of the inhibitory signal results in removal of transcriptional suppression with the subsequent increase in M-CSF expression. This is hypothesized to drive proliferation of Kupffer cells and set up a positive feedback cycle leading to massive hepatomegaly in lal-/- mice.
Permanent Link: http://rave.ohiolink.edu/etdc/view?acc_num=ucin1026512116
http://hdl.handle.net/2374.OX/12089
Date: 2002

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