PMID- 15693545
OWN - NLM
STAT- MEDLINE
DCOM- 20050719
LR  - 20051117
IS  - 0377-8231 (Print)
IS  - 0377-8231 (Linking)
VI  - 159
IP  - 5-6
DP  - 2004
TI  - Modulation of Kupffer cell activity: physio-pathological consequences on hepatic 
      metabolism.
PG  - 358-66
AB  - 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.
FAU - Neyrinck, A
AU  - Neyrinck A
AD  - Unite de Pharmacocinetique, Metabolisme, Nutrition et Toxicologie, UCL.
LA  - eng
PT  - Journal Article
PL  - Belgium
TA  - Bull Mem Acad R Med Belg
JT  - Bulletin et memoires de l'Academie royale de medecine de Belgique
JID - 7608462
SB  - IM
MH  - Animals
MH  - Diet
MH  - Humans
MH  - Kupffer Cells/*physiology
MH  - Lipid Metabolism
MH  - Liver/*metabolism/physiopathology
EDAT- 2005/02/08 09:00
MHDA- 2005/07/20 09:00
CRDT- 2005/02/08 09:00
PHST- 2005/02/08 09:00 [pubmed]
PHST- 2005/07/20 09:00 [medline]
PHST- 2005/02/08 09:00 [entrez]
PST - ppublish
SO  - Bull Mem Acad R Med Belg. 2004;159(5-6):358-66.