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Identifying potential drugs for treatment of feline hepatic lipidosis

Haaker MW, Kruitwagen HS, Vaandrager AB, et al. Identification of potential drugs for treatment of hepatic lipidosis in cats using an in vitro feline liver organoid system. J Vet Intern Med. 2019;1–7.   This study was funded by a grant (W17-015 ) from the Winn Feline Foundation.

Hepatic lipidosis is an important cause of morbidity and mortality in cats. The condition occurs when fat is rapidly broken down to free fatty acids (FFA) and transported to the liver, where they accumulate as triacylgycerol (TAG) in lipid droplets within hepatocytes. No specific cure exists, and treatment is primarily supportive, consisting of fluid and nutritional therapy. The reported mortality rate is approximately 38%. The aim of the present study was to utilize feline hepatic organoids loaded with TAG, which have been previously described and applied as in vitro models of hepatic lipidosis. The study’s objective was to use the model to test drugs that may aid in the treatment of feline hepatic lipidosis, without the use of live cats.

Liver organoids were derived from 6 different cats, whereby samples were obtained post-mortem from liver tissue. The absence of liver disease was confirmed histologically prior to further cell processing. No animals were euthanized or harmed for the purposes of the study. The harvested tissue was sampled and cultured following a previously described protocol, to obtain hepatocyte-like cell populations. Fatty acids were then applied to mimic hepatic lipidosis in live cats.

The 8 drugs initially chosen for the present investigation were based on previous literature regarding their possible effects on hepatic lipidosis. After primary application of the initial drugs and performing a TAG assay to determine the remaining TAG levels, 3 drugs were selected for further testing: 5-aminoimidazole-4-carboxamide 1-beta-D-ribofuranoside (AICAR), T863, and PF 06424439.

Overall, AICAR results in a 46% decrease in TAG accumulation in liver organoids, and T863 resulted in a 55% decrease in TAG accumulation. The third drug, PF 06424439 did not significantly decrease TAG accumulation when evaluated alone. However, when PF 06424439 was combined with T863, TAG synthesis was entirely prevented.

The authors were able to demonstrate that undifferentiated liver organoids produced similar results as differentiated organoids, thus reinforcing the use of undifferentiated organoids for future drug screening and mechanistic studies. This decreases the time and resources required to carry out such experiments, while preserving their validity.

In conclusion, the authors identified 2 potential drugs that may be useful in the treatment of cats with hepatic lipidosis: T863 (which may act to inhibit the primary enzyme responsible for TAG synthesis from external fatty acids in feline liver organoids) and AICAR (which may act as a lipid-lowering compound by decreasing expression of an adipose-differentiation protein). Further studies are needed to explore the safety and efficacy of these drugs in greater detail. (HM)

See also:

Valtolina, Chiara, et al. “Gene Expressions of de Novo Hepatic Lipogenesis in Feline Hepatic Lipidosis.” J Feline Med Surg, July 2019.

Valtolina, Chiara, et al. “Immunohistochemical Characterisation of the Hepatic Stem Cell Niche in Feline Hepatic Lipidosis: A Preliminary Morphological Study.” J Feline Med Surg, vol. 21, no. 2, Feb. 2019, pp. 165–172.