In vitro, liver sinusoidal endothelial cells (LSECs) from healthy liver prevent hepatic stellate cell (HSC) activation and promote inactivation of activated HSC, but LSECs that have "capillarized" do not. Capillarization, the loss of LSEC fenestration and formation of a more organized basement membrane in the space of Disse, precedes fibrosis. In vivo, pharmacological reversal of capillarization after discontinuing a fibrotic insult accelerates inactivation of HSC and regression of fibrosis, whereas reversal of capillarization while a fibrotic stimulus is continued prevents progression of cirrhosis. Thus capillarization doesn't just precede fibrosis, but is permissive for hepatic fibrosis. The goals of this proposal are two-fold. First, examine how LSECs promote HSC quiescence. Second, elucidate the mechanisms that lead to capillarization. This proposal has three specific aims.
In specific aim 1 the protein secreted by LSECs that promotes HSC quiescence will be identified, its in vivo activity will be confirmed, expression patterns within the liver will be immunolocalize, and its signaling within HSC will be examined. Specific 2 will examine the genesis of "capillarized" LSECs in a model of toxin-induced fibrosis and confirm that capillarized LSECs in a model of diet-induced non-alcoholic steatohepatitis have the same origin. Integrin expression, endocytosis and endocytosis receptors, and transcriptomic profiling in in vivo capillarized LSECs will be compared with LSECs from normal liver and in vitro capillarized LSECs to better understand capillarization. Preliminary data for specific aim 3 has identified a change within the fibrotic liver associated with loss of LSEC fenestration and with angiogenesis.
Specific aim 3 will determine which type of liver cell is responsible for the change;confirm the association with loss of fenestration, HSC activation, fibrosis and angiogenesis;examine signaling pathways in the LSEC;and characterize the regulation of the change in the capillarized liver. Successful completion of these aims will transform our understanding of the mechanisms underlying capillarization and provide potential therapeutic targets to treat fibrosis.

Public Health Relevance

The final common pathway of chronic liver disease is fibrosis and cirrhosis. Fibrosis is a wound-healing response that is normally held at bay by a complex interplay of the various types of liver cells. This proposal examines the earliest changes in intercellular communication that begin the fibrotic process. By uncovering the pathways that regulate the changes, new therapeutic strategies will be revealed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK100580-01A1
Application #
8756248
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$357,878
Indirect Cost
$140,378
Name
University of Southern California
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
DeLeve, Laurie D (2015) Liver sinusoidal endothelial cells in hepatic fibrosis. Hepatology 61:1740-6