Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

Maya W Haaker; Hedwig S Kruitwagen; Arie B Vaandrager; Martin Houweling; Louis C Penning; Martijn R Molenaar; Monique E van Wolferen; Loes A Oosterhoff; Bart Spee; J Bernd Helms

doi:10.1111/jvim.15670

Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

Maya W Haaker, Hedwig S Kruitwagen, Arie B Vaandrager, Martin Houweling, Louis C Penning, Martijn R Molenaar, Monique E van Wolferen, Loes A Oosterhoff, Bart Spee, J Bernd Helms

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Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver.

OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system.

ANIMALS: Liver organoids obtained from 6 cats.

METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR.

RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863.

CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.

Original language	English
Pages (from-to)	132-138
Number of pages	7
Journal	Journal of Veterinary Internal Medicine
Volume	34
Issue number	1
DOIs	https://doi.org/10.1111/jvim.15670
Publication status	Published - Jan 2020

Keywords

AICAR
diacylglycerol O-acyltransferase 1 inhibitor
hepatic
organoids
perilipin 2
steatosis

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Haaker, M. W., Kruitwagen, H. S., Vaandrager, A. B., Houweling, M., Penning, L. C., Molenaar, M. R., van Wolferen, M. E., Oosterhoff, L. A., Spee, B., & Helms, J. B. (2020). Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system. Journal of Veterinary Internal Medicine, 34(1), 132-138. https://doi.org/10.1111/jvim.15670

@article{b7a6125e487b4fc28f4d09c9cbb237da,

title = "Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system",

abstract = "BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver.OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system.ANIMALS: Liver organoids obtained from 6 cats.METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR.RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863.CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.",

keywords = "AICAR, diacylglycerol O-acyltransferase 1 inhibitor, hepatic, organoids, perilipin 2, steatosis",

author = "Haaker, {Maya W} and Kruitwagen, {Hedwig S} and Vaandrager, {Arie B} and Martin Houweling and Penning, {Louis C} and Molenaar, {Martijn R} and {van Wolferen}, {Monique E} and Oosterhoff, {Loes A} and Bart Spee and Helms, {J Bernd}",

note = "{\textcopyright} 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.",

year = "2020",

month = jan,

doi = "10.1111/jvim.15670",

language = "English",

volume = "34",

pages = "132--138",

journal = "Journal of Veterinary Internal Medicine",

issn = "0891-6640",

publisher = "Wiley-Blackwell",

number = "1",

}

Haaker, MW , Kruitwagen, HS , Vaandrager, AB , Houweling, M , Penning, LC, Molenaar, MR, van Wolferen, ME, Oosterhoff, LA, Spee, B & Helms, JB 2020, 'Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system', Journal of Veterinary Internal Medicine, vol. 34, no. 1, pp. 132-138. https://doi.org/10.1111/jvim.15670

TY - JOUR

T1 - Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

AU - Haaker, Maya W

AU - Kruitwagen, Hedwig S

AU - Vaandrager, Arie B

AU - Houweling, Martin

AU - Penning, Louis C

AU - Molenaar, Martijn R

AU - van Wolferen, Monique E

AU - Oosterhoff, Loes A

AU - Spee, Bart

AU - Helms, J Bernd

PY - 2020/1

Y1 - 2020/1

N2 - BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver.OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system.ANIMALS: Liver organoids obtained from 6 cats.METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR.RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863.CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.

AB - BACKGROUND: Hepatic lipidosis is increasing in incidence in the Western world, with cats being particularly sensitive. When cats stop eating and start utilizing their fat reserves, free fatty acids (FFAs) increase in blood, causing an accumulation of triacylglycerol (TAG) in the liver.OBJECTIVE: Identifying potential new drugs that can be used to treat hepatic lipidosis in cats using a feline hepatic organoid system.ANIMALS: Liver organoids obtained from 6 cats.METHODS: Eight different drugs were tested, and the 2 most promising were further studied using a quantitative TAG assay, lipid droplet staining, and qPCR.RESULTS: Both T863 (a diacylglycerol O-acyltransferase 1 [DGAT1] inhibitor) and 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside (AICAR; an adenosine monophosphate kinase activator) decreased TAG accumulation by 55% (P < .0001) and 46% (P = .0003), respectively. Gene expression of perilipin 2 (PLIN2) increased upon the addition of FFAs to the medium and decreased upon treatment with AICAR but not significantly after treatment with T863.CONCLUSIONS AND CLINICAL IMPORTANCE: Two potential drugs useful in the treatment of hepatic lipidosis in cats were identified. The drug T863 inhibits DGAT1, indicating that DGAT1 is the primary enzyme responsible for TAG synthesis from external fatty acids in cat organoids. The drug AICAR may act as a lipid-lowering compound via decreasing PLIN2 mRNA. Liver organoids can be used as an in vitro tool for drug testing in a species-specific system and provide the basis for further clinical testing of drugs to treat steatosis.

KW - AICAR

KW - diacylglycerol O-acyltransferase 1 inhibitor

KW - hepatic

KW - organoids

KW - perilipin 2

KW - steatosis

U2 - 10.1111/jvim.15670

DO - 10.1111/jvim.15670

M3 - Article

C2 - 31830357

SN - 0891-6640

VL - 34

SP - 132

EP - 138

JO - Journal of Veterinary Internal Medicine

JF - Journal of Veterinary Internal Medicine

IS - 1

ER -

Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system

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