A System for In Vivo Imaging of Hepatic Free Fatty Acid Uptake

Park, Hyo Min; Russo, Kim A.; Karateev, Grigory; Park, Michael; Dubikovskaya, Elena A.; Kriegsfeld, Lance J.; Stahl, Andreas

doi:10.1053/j.gastro.2016.10.002

Cited by 8 publications

(8 citation statements)

References 7 publications

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“…Thus, in vivo optical imaging has predominantly focused on single‐channel fluorescence or bioluminescence on a macro level (<15× magnification) in mice or other small animals. Bioluminescence is not practical in clinical settings because it requires transfection with an invertebrate luminescent protein, but it is a highly sensitive reporter that, in the field of lipid metabolism, has been adapted to map regions of heightened fatty acid uptake . Advances in CCD sensitivity have recently sparked renewed interest in Cerenkov radiation as an additional source of emitted light that can be detected in vivo .…”

Section: Imaging Metabolic Lipid Changesmentioning

confidence: 99%

Imaging of cancer lipid metabolism in response to therapy

et al. 2019

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Lipids represent a diverse array of molecules essential to the cell's structure, defense, energy, and communication. Lipid metabolism can often become dysregulated during tumor development. During cancer therapy, targeted inhibition of cell proliferation can likewise cause widespread and drastic changes in lipid composition. Molecular imaging techniques have been developed to monitor altered lipid profiles as a biomarker for cancer diagnosis and treatment response. For decades, MRS has been the dominant non-invasive technique for studying lipid metabolite levels. Recent insights into the oncogenic transformations driving changes in lipid metabolism haverevealed new mechanisms and signaling molecules that can be exploited using optical imaging, mass spectrometry imaging, and positron emission tomography. These novel imaging modalities have provided researchers with a diverse toolbox to examine changes in lipids in response to a wide array of anticancer strategies including chemotherapy, radiation therapy, signal transduction inhibitors, gene therapy, immunotherapy, or a combination of these strategies. The understanding of lipid metabolism in response to cancer therapy continues to evolve as each therapeutic method emerges, and this review seeks to summarize the current field and areas of unmet needs.

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Section: Imaging Metabolic Lipid Changesmentioning

confidence: 99%

Imaging of cancer lipid metabolism in response to therapy

et al. 2019

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“…The mice were generated by crossing mice bearing the Gt(ROSA)26Sor tm1(Luc)Kael allele and Tg(Alb-cre)21Mgn mice (54). In a similar protocol as was used for the FVB-luc + mice, the L-Luc mice were first treated with vehicle (Dulbecco's phosphate-buffered saline), CuCl 2 (3 mg/kg), or both ATN-224 (5 mg/kg) and CuCl 2 (Fig.…”

Section: Ccl-1 Visualizes Changes In Exchangeable Copper Pools In Livingmentioning

confidence: 99%

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

Heffern

Park

Au‐Yeung

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Copper is a required metal nutrient for life, but global or local alterations in its homeostasis are linked to diseases spanning genetic and metabolic disorders to cancer and neurodegeneration. Technologies that enable longitudinal in vivo monitoring of dynamic copper pools can help meet the need to study the complex interplay between copper status, health, and disease in the same living organism over time. Here, we present the synthesis, characterization, and in vivo imaging applications of Copper-Caged Luciferin-1 (CCL-1), a bioluminescent reporter for tissue-specific copper visualization in living animals. CCL-1 uses a selective copper(I)-dependent oxidative cleavage reaction to release d-luciferin for subsequent bioluminescent reaction with firefly luciferase. The probe can detect physiological changes in labile Cu+ levels in live cells and mice under situations of copper deficiency or overload. Application of CCL-1 to mice with liver-specific luciferase expression in a diet-induced model of nonalcoholic fatty liver disease reveals onset of hepatic copper deficiency and altered expression levels of central copper trafficking proteins that accompany symptoms of glucose intolerance and weight gain. The data connect copper dysregulation to metabolic liver disease and provide a starting point for expanding the toolbox of reactivity-based chemical reporters for cell- and tissue-specific in vivo imaging.

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“…The traditional methods for directly assessing BAT activity, which rely on radiolabeled probe uptake, are unable to sufficiently assess rapid functional changes in these transporters. Recently, bioluminescence-based methods have become increasingly useful tools for measuring real-time transporter activity and other cellular processes (19,25,26). In our study, we designed a novel method that relies on a small molecule probe, designated as CA-SS-Luc, which is composed of a cholic acid moiety conjugated to firefly luciferin via a cleavable disulfide linker.…”

Section: Discussionmentioning

confidence: 99%

“…Although several attempts have been made to monitor bile acids in real time (16,33), none have been designed to assess bile acid transporter function directly. Recently, bioluminescence-based methods have been used to measure the real-time function of fatty acid transporters (19,26). Therefore, our objective was to develop a bioluminescence-based method for measuring bile acid transport activity in real time to precisely evaluate the rapid changes in their function.…”

Section: Introductionmentioning

confidence: 99%

A novel bioluminescence-based method to investigate uptake of bile acids in living cells

Ticho

Lee

Gill

et al. 2018

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acid transporters, including the ileal apical sodium-dependent bile acid transporter (ASBT) and the hepatic sodium-taurocholate cotransporting polypeptide (NTCP), are crucial for the enterohepatic circulation of bile acids. Our objective was to develop a method for measuring bile acid transporter activity in real time to precisely evaluate rapid changes in their function. We designed a reporter system relying on a novel probe: cholic acid attached to luciferin via a disulfide-containing, self-immolating linker (CA-SS-Luc). Incubation of human embryonic kidney-293 cells coexpressing luciferase and ASBT with different concentrations of CA-SS-Luc (0.01-1 μM) resulted in bioluminescence with an intensity that was concentration- and time-dependent. The bioluminescence measured during incubation with 1 μM CA-SS-Luc was dependent on the levels of ASBT or NTCP expressed in the cells. Coincubation of CA-SS-Luc with natural bile acids enhanced the bioluminescence in a concentration-dependent manner with kinetic parameters for ASBT similar to those previously reported using conventional methods. These findings suggest that this method faithfully assesses ASBT function. Further, incubation with tyrosine phosphatase inhibitor III (PTPIII) led to significantly increased bioluminescence in cells expressing ASBT, consistent with previous studies showing an increase in ASBT function by PTPIII. We then investigated CA-SS-Luc in isolated mouse intestinal epithelial cells. Ileal enterocytes displayed significantly higher luminescence compared with jejunal enterocytes, indicating a transport process mediated by ileal ASBT. In conclusion, we have developed a novel method to monitor the activity of bile acid transporters in real time that has potential applications both for in vitro and in vivo studies. NEW & NOTEWORTHY This article reports the development of a real-time method for measuring the uptake of bile acids using a bioluminescent bile acid-based probe. This method has been validated for measuring uptake via the apical sodium-dependent bile acid transporter and the sodium-taurocholate cotransporting polypeptide in cell culture and ex vivo intestinal models.

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A System for In Vivo Imaging of Hepatic Free Fatty Acid Uptake

Cited by 8 publications

References 7 publications

Imaging of cancer lipid metabolism in response to therapy

Imaging of cancer lipid metabolism in response to therapy

In vivo bioluminescence imaging reveals copper deficiency in a murine model of nonalcoholic fatty liver disease

A novel bioluminescence-based method to investigate uptake of bile acids in living cells

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