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Title: An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo

Abstract

The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube–based optical reporter that noninvasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. The reporter detected lipid accumulation in Niemann-Pick disease, atherosclerosis, and NAFLD models in vivo. By applying the reporter to the study of NAFLD, we found that elevated lipid quantities in hepatic macrophages caused by a high-fat diet persist long after reverting to a normal diet. The reporter dynamically monitored endolysosomal lipid accumulation in vivo over time scales ranging from minutes to weeks, indicating its potential to accelerate preclinical research and drug development processes.

Authors:
ORCiD logo; ORCiD logo; ; ORCiD logo; ; ORCiD logo; ; ORCiD logo; ; ; ; ; ; ; ; ORCiD logo
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC); Univ. of California, Oakland, CA (United States); Lehigh Univ., Bethlehem, PA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1475480
Alternate Identifier(s):
OSTI ID: 1544006
Grant/Contract Number:  
SC0013979; AC02-05CH11231
Resource Type:
Published Article
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Name: Science Translational Medicine Journal Volume: 10 Journal Issue: 461; Journal ID: ISSN 1946-6234
Publisher:
American Association for the Advancement of Science (AAAS)
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; Cell Biology; Research & Experimental Medicine

Citation Formats

Galassi, Thomas V., Jena, Prakrit V., Shah, Janki, Ao, Geyou, Molitor, Elizabeth, Bram, Yaron, Frankel, Angela, Park, Jiwoon, Jessurun, Jose, Ory, Daniel S., Haimovitz-Friedman, Adriana, Roxbury, Daniel, Mittal, Jeetain, Zheng, Ming, Schwartz, Robert E., and Heller, Daniel A. An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo. United States: N. p., 2018. Web. doi:10.1126/scitranslmed.aar2680.
Galassi, Thomas V., Jena, Prakrit V., Shah, Janki, Ao, Geyou, Molitor, Elizabeth, Bram, Yaron, Frankel, Angela, Park, Jiwoon, Jessurun, Jose, Ory, Daniel S., Haimovitz-Friedman, Adriana, Roxbury, Daniel, Mittal, Jeetain, Zheng, Ming, Schwartz, Robert E., & Heller, Daniel A. An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo. United States. doi:10.1126/scitranslmed.aar2680.
Galassi, Thomas V., Jena, Prakrit V., Shah, Janki, Ao, Geyou, Molitor, Elizabeth, Bram, Yaron, Frankel, Angela, Park, Jiwoon, Jessurun, Jose, Ory, Daniel S., Haimovitz-Friedman, Adriana, Roxbury, Daniel, Mittal, Jeetain, Zheng, Ming, Schwartz, Robert E., and Heller, Daniel A. Wed . "An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo". United States. doi:10.1126/scitranslmed.aar2680.
@article{osti_1475480,
title = {An optical nanoreporter of endolysosomal lipid accumulation reveals enduring effects of diet on hepatic macrophages in vivo},
author = {Galassi, Thomas V. and Jena, Prakrit V. and Shah, Janki and Ao, Geyou and Molitor, Elizabeth and Bram, Yaron and Frankel, Angela and Park, Jiwoon and Jessurun, Jose and Ory, Daniel S. and Haimovitz-Friedman, Adriana and Roxbury, Daniel and Mittal, Jeetain and Zheng, Ming and Schwartz, Robert E. and Heller, Daniel A.},
abstractNote = {The abnormal accumulation of lipids within the endolysosomal lumen occurs in many conditions, including lysosomal storage disorders, atherosclerosis, nonalcoholic fatty liver disease (NAFLD), and drug-induced phospholipidosis. Current methods cannot monitor endolysosomal lipid content in vivo, hindering preclinical drug development and research into the mechanisms linking endolysosomal lipid accumulation to disease progression. We developed a single-walled carbon nanotube–based optical reporter that noninvasively measures endolysosomal lipid accumulation via bandgap modulation of its intrinsic near-infrared emission. The reporter detected lipid accumulation in Niemann-Pick disease, atherosclerosis, and NAFLD models in vivo. By applying the reporter to the study of NAFLD, we found that elevated lipid quantities in hepatic macrophages caused by a high-fat diet persist long after reverting to a normal diet. The reporter dynamically monitored endolysosomal lipid accumulation in vivo over time scales ranging from minutes to weeks, indicating its potential to accelerate preclinical research and drug development processes.},
doi = {10.1126/scitranslmed.aar2680},
journal = {Science Translational Medicine},
number = 461,
volume = 10,
place = {United States},
year = {2018},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1126/scitranslmed.aar2680

Citation Metrics:
Cited by: 17 works
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Figures / Tables:

Fig. 1 Fig. 1: Characterization of the ssCTTC3TTC-(9,4) optical reporter. (A) Photoluminescence excitation emission plot of ssCTTC3TTC-(9,4). (B) Nanotube emission center wavelength ± standard deviation in cell culture media with 1% FBS at near-saturating concentrations of bovine serum albumin (BSA, 20 mg/mL), salmon testes dsDNA (1 mg/mL), carboxymethyl cellulose (CMC, 5 mg/mL),more » mPEG-phosphoethanolamine 18:0 (mPEG-PE 18:0, 5.93 mM), PEG-cholesterol (5.93 mM), or mPEG-ceramide (5.93 mM). Error bars represent standard deviation from N=3 technical replicates. (C) Frames from molecular dynamics simulations showing equilibrated structures of the ssCTTC3TTC-(9,4) nanotube complex in the presence of cholesterol and sphingomyelin. (D) Water density as a function of distance from the surface of ssCTTC3TTC-(9,4) nanotube complexes, in the presence of sphingomyelin or cholesterol, or with no lipids present. (E) Overlays of transmitted light and NIR hyperspectral images of the reporter in RAW 264.7 macrophages cultured in complete cell culture media with or without U18666A (3 μg/mL), Lalistat 3a2 (10 μM), or imipramine hydrochloride (10 μM). (F) Histogram of emission center wavelengths from all pixels with NIR emission from the NIR hyperspectral images of cells under the conditions described in (E).« less

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