Between Melpomene and Thalia: The multiple faces of hepatic stellate cells and lipids in the liver

Abstract

The liver plays an important role in processing (nutritional) substances that enter our body through the intestines. This includes breakdown of alcohol and many forms of medication. The liver also handles the storage or onward transport of sugars, fats and vitamin A. In the Western world, alcohol and a diet with excessive fat, sugar and cholesterol are increasingly part of the causes of liver disease in humans. Initially, fat will accumulate in the liver, but can cause liver damage at later stages. Repeated damage leads to excessive formation of extracellular matrix, the development of liver fibrosis and ultimately liver cirrhosis. As a result, liver function is hampered with increased chances for liver cancer. The main producers of the extracellular matrix proteins are activated hepatic stellate cells (HSCs). This cell type can behave in very different ways. Liver damage leads to various stages of activation and extracellular matrix production, but in a healthy liver the HSCs are quiescent and serve as the main storage site for vitamin A in the body. This thesis investigates how factors from the cellular environment (matrix and presence of hepatic progenitor cells) can be of influence to the activation stage of HSCs with particular emphasis on changes in vitamin A and lipid metabolism. We show that, by making use of a different matrix, HSCs can be kept quiescent in cell culture and used for research of vitamin A metabolism in quiescent HSCs. At the same time, we show unexpected retinyl ester (the storage form of vitamin A) synthesis during early activation. Co-culture of HSCs and progenitor cells in a 3D organoid system shows that these cell types can directly interact with each other, mimicking cellular responses seen during ductular reaction. Many different lipids exist, and in this thesis we show how influencing the metabolism of specific lipids influences the communication, functioning and survival of the HSC. If we can let HSCs wear their quiescent, happy mask (Thalia) this will help animal and human liver patients prevent tragedy (Melpomene).