Early use of dexamethasone increases Nr4a1 in Kupffer cells ameliorating acute liver failure in mice in a glucocorticoid receptor-dependent manner.

BACKGROUND AND OBJECTIVE: Acute liver failure (ALF) is a type of disease with high mortality and rapid progression with no specific treatment methods currently available. Glucocorticoids exert beneficial clinical effects on therapy for ALF. However, the mechanism of this effect remains unclear and when to use glucocorticoids in patients with ALF is difficult to determine. The purpose of this study was to investigate the specific immunological mechanism of dexamethasone (Dex) on treatment of ALF induced by lipopolysaccharide (LPS)/D-galactosamine (D-GaIN) in mice. METHODS: Male C57BL/6 mice were given LPS and D-GaIN by intraperitoneal injection to establish an animal model of ALF. Dex was administrated to these mice and its therapeutic effect was observed. Hematoxylin and eosin (H&E) staining was used to determine liver pathology. Multicolor flow cytometry, cytometric bead array (CBA) method, and next-generation sequencing were performed to detect changes of messenger RNA (mRNA) in immune cells, cytokines, and Kupffer cells, respectively. RESULTS: A mouse model of ALF can be constructed successfully using LPS/D-GaIN, which causes a cytokine storm in early disease progression. Innate immune cells change markedly with progression of liver failure. Earlier use of Dex, at 0 h rather than 1 h, could significantly improve the progression of ALF induced by LPS/D-GaIN in mice. Numbers of innate immune cells, especially Kupffer cells and neutrophils, increased significantly in the Dex-treated group. In vivo experiments indicated that the therapeutic effect of Dex is exerted mainly via the glucocorticoid receptor (Gr). Sequencing of Kupffer cells revealed that Dex could increase mRNA transcription level of nuclear receptor subfamily 4 group A member 1 (Nr4a1), and that this effect disappeared after Gr inhibition. CONCLUSIONS: In LPS/D-GaIN-induced ALF mice, early administration of Dex improved ALF by increasing the numbers of innate immune cells, especially Kupffer cells and neutrophils. Gr-dependent Nr4a1 upregulation in Kupffer cells may be an important ALF effect regulated by Dex in this process.

Effect of dietary fatty acids on serum parameters, fatty acid compositions, and liver histology in Shaoxing laying ducks.

The effects of different fatty acid (FA) contents in diet on serum parameters, FA compositions of eggs and meat, and liver morphological changes were studied in Shaoxing laying ducks. A total of 264 ducks at 17 weeks were fed a control diet or a diet containing 30 g/kg fish oil (FO), 25 g/kg sunflower oil (SO), or 30 g/kg palm oil with 20 g/kg beef tallow (PBO). Malondialdehyde (MDA) content in the liver and the serum of ducks fed the PBO diet was significantly (P<0.05) higher than that of ducks fed the other diets. Triglyceride (TG) and total cholesterol (TC) levels were significantly lower (P<0.05) in ducks fed the FO diet. Serum TC also was lower in ducks fed the SO diet. Superoxide dismutase (SOD) activity was also affected by diets. The contents of polyunsaturated FAs (PUFAs) in eggs and meat were significantly higher (P<0.001) in ducks fed the FO and SO diets than in ducks fed the control diet. The level of C22:6 (n-3) FA in ducks fed the FO diet was significantly higher than that in ducks fed the other diets. However, the conversion efficiency of the longer-chain C20:5 (n-3) FA was higher than that of C22:6 (n-3). Ducks fed the PBO diet exhibited lipid droplet accumulation in the liver. These results demonstrate that a diet enriched with different FAs has strong effects on serum lipid levels and the deposition of PUFAs into tissue lipids.