Modulation of Kupffer cell activity: physio-pathological consequences on hepatic metabolism.

Classically, the maintenance and control of liver homeostasis are assigned to the metabolic activity of parenchymal cells. However, recent evidence highlights complex and tightly regulated interactions between hepatocytes and other intra-hepatic cells. Kupffer cells--the resident macrophages of the liver--are able to release a tremendous array of mediators upon inflammatory conditions, such as infection, and their role in innate immunity is well described in the literature. However, the impact of these Kupffer cell-derived mediators on liver homeostasis is unknown. In this study, we investigated the physiological involvement of Kupffer cells in the regulation of hepatic metabolism. It was first necessary to validate the use of a compound able to selectively deplete Kupffer cells. We confirmed that gadolinium chloride (GdCl3) injection to rats eliminated ED2-positive Kupffer cells and strongly decreased both their phagocytic and peroxidase activities. Moreover, we demonstrated that precision-cut liver slices (PCLS)--an original in vitro model allowing to maintain intact hepatic architecture and cellular heterogeneity--obtained from GdCl3-treated rats released lower amounts of inflammatory mediators. Therefore, we proposed to use GdCl3 prior to PCLS preparation in order to investigate the role of Kupffer cells in the control of hepatic metabolism. Among various metabolic functions of the liver, we focused, in particular, on paracetamol and lipid metabolism as example of drug and intermediary metabolism, respectively. Our results suggest that the presence of Kupffer cells in liver tissue can affect the viability of PCLS in culture and are involved in the regulation of paracetamol metabolism, in particular the glucuronidation pathway. Furthermore, inhibition of Kupffer cells leads to a metabolic shift of fatty acids towards their esterification (at least, in fasted rats) and accumulation in the liver tissue, supporting a key role of Kupffer cells in the regulation of intra-hepatic lipid metabolism. Results obtained from in vitro studies suggest that Kupffer cell-derived prostaglandin E2 might be involved in the higher capacity of lipid synthesis observed in PCLS obtained from GdCl3-treated rats. Final objectives of this work were devoted to highlight the impact of the diet on Kupffer cell activity, offering possibilities to modulate Kupffer cell functions by nutrients under various physio-pathological conditions, such as inflammation. Our results demonstrate that a supplementation of glycine, a simple amino acid, in the diet could influence lipid metabolism, namely in the liver. A direct relationship between those metabolic effects and Kupffer cell activity has not been demonstrated. Nevertheless, we have shown that the use of glycine in vitro offers the possibility to elucidate complex interactions between Kupffer cells and hepatocytes, by using PCLS in culture, and could constitute an alternative tool to inhibit in vitro Kupffer cell-derived mediators. Furthermore, dietary oligofructose, a fermentable and nondigestible carbohydrate known as prebiotic, was able to increase phagocytic activity of the liver and the production of Kupffer cell-derived mediators by PCLS. Our results indicate that improvement of Kupffer cell activities might be involved in the hepatoprotection against septic challenge observed after a diet enriched with oligofructose.