Kruitwagen HD, Oosterhoff LA, et al. Long-term adult feline liver organoid cultures for disease modeling of hepatic steatosis. Stem Cell Reports. 2017 Apr 11;8(4):822-830. Winn-funded study (W15-037)
Fatty liver disease or hepatic steatosis is a common liver disease in humans and animals. In cats, a severe form also occurs known as feline hepatic lipidosis (FHL). The condition occurs in humans and cats when an increased amount of free fatty acids (FFA) are delivered to the liver, and where known risk factors for development are obesity and insulin resistance. Liver organoids have previously demonstrated the potential for modeling genetic diseases. The authors established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation possibility toward hepatocyte-like cells. They compared organoids from mouse, human, dog, and cat livers to assess species differences in lipid accumulation capacity.
The organoids were provided with fatty acids such as oleate and palmitate which represent the most abundant fatty acids in healthy and steatotic (fatty) human and cat livers. Hepatocytes have three major routes to handle FFA. In this situation, the cells can 1) enter b-oxidation to provide energy or a substrate for ketogenesis, or they can be re-esterified to triglycerides, and either 2) become excreted in very-low-density lipoproteins (VLDL) or 3) be stored as intracellular lipid droplets.
The results demonstrated that feline liver organoids accumulated more lipids than did human liver organoids. This exaggerated response of lipid overload in feline liver cells accompanies the fact that steatosis in cats often results in liver failure and severe disease. The authors speculate that the other metabolic pathways handling excess FFA (b-oxidation, VLDL secretion) are quickly saturated in feline hepatocytes, therefore, creating extensive lipid-droplet formation.
The study also tested the effect of small molecules on lipid metabolism. The result indicates that b-oxidation is an important metabolic pathway handling excess fatty acids in feline liver cells. It was also noted that supplementation of L-carnitine of feline liver organoids lessened lipid accumulations in high-fat conditions along with improving cellular viability. This supports the finding that administering L-carnitine supplementation can aid FFA oxidation in cats with FHL.
The authors state feline liver organoids can be successfully cultured and display a tendency for lipid accumulation. Therefore, these organoids can become a valuable research method exploring new therapies for FHL in cats. (VT)
Drost J, Clevers H. Translational applications of adult stem cell-derived organoids. Development. 2017 Mar 15;144(6):968-975.