flavin-adenine-dinucleotide and Chemical-and-Drug-Induced-Liver-Injury

Acute liver injury is a severe clinical syndrome with markedly high mortality and poor prognosis. An accumulating body of evidence has demonstrated that epigenetic mechanisms have essential roles in the pathogenesis of acute liver injury. Lysine-specific demethylase 1 (LSD1) belongs to the amine oxidase superfamily of flavin adenine dinucleotide (FAD)-dependent enzymes, specifically demethylates H3 lysine 4. In the study, we investigated the effects and mechanisms of LSD1 in lipopolysaccharide (LPS)/D-Galactosamine (D-Gal)-induced acute liver injury in mice. Western blot analysis showed that LSD1 phosphorylation and di-methylated histone H3 on lysine 4 (H3K4me2) protein expression were significantly increased after LPS/D-Gal treatment (2.3 and 2.4 times higher than control respectively). GSK-LSD1 2HCl is an irreversible and selective LSD1 inhibitor. Pre-treatment with LSD1 inhibitor alleviated LPS/D-Gal-induced liver damage, decreased serum levels of alanine transaminase and aspartate aminotransferase in mice. Moreover, the LSD1 phosphorylation level in low, medium, and high LSD1 inhibitor groups was lower by a factor of 1.6, 1.9, and 2.0 from the LPS/D-Gal group, respectively. Mechanistically, LSD1 inhibitor further inhibited NF-κB signaling cascades and subsequently inhibited the production of pro-inflammatory cytokine TNF-α, IL-6, and IL-1β induced by LPS/D-Gal in liver tissues. Furthermore, LSD1 inhibitor upregulated the protein expression of Nrf2/HO-1 signaling pathways, and the activities of related antioxidant enzymes were enhanced. Collectively, our data demonstrated that LSD1 inhibitor protected against the LPS/D-Gal-induced acute liver injury via inhibiting inflammation and oxidative stress, and targeting the epigenetic marker may be a potent therapeutic strategy for acute liver injury.

Topics: Alanine Transaminase; Amines; Animals; Antioxidants; Aspartate Aminotransferases; Chemical and Drug Induced Liver Injury; Cytokines; Flavin-Adenine Dinucleotide; Galactosamine; Histone Demethylases; Histones; Interleukin-6; Lipopolysaccharides; Liver; Lysine; Mice; NF-E2-Related Factor 2; NF-kappa B; Oxidoreductases; Tumor Necrosis Factor-alpha

Topics: Animals; Biotransformation; Castration; Chemical and Drug Induced Liver Injury; Cocaine; Cytochrome P-450 Enzyme System; Flavin-Adenine Dinucleotide; Male; Mice; Mice, Inbred C3H; Mixed Function Oxygenases; Oxidoreductases

Topics: Animals; Biometry; Cell Nucleus; Chemical and Drug Induced Liver Injury; Endoplasmic Reticulum; Female; Flavin Mononucleotide; Flavin-Adenine Dinucleotide; Golgi Apparatus; Histocytochemistry; Liver; Liver Diseases; Lysosomes; Membranes; Mice; Microscopy, Electron; Microsomes, Liver; Mitochondria, Liver; Mitochondrial Swelling; Riboflavin; Time Factors; Vitamin B Deficiency

Topics: Animals; Aspartate Aminotransferases; Carcinoma, Hepatocellular; Chemical and Drug Induced Liver Injury; Electron Spin Resonance Spectroscopy; Flavin-Adenine Dinucleotide; Infrared Rays; Isoenzymes; L-Lactate Dehydrogenase; Lipoproteins; Liver; Liver Diseases; Liver Neoplasms; Mitomycins; Neoplasms, Experimental; p-Dimethylaminoazobenzene; Peroxides; Rats; Riboflavin

Topics: Animals; Carbon Tetrachloride Poisoning; Chemical and Drug Induced Liver Injury; Coenzyme A; Flavin-Adenine Dinucleotide; Liver; Liver Extracts; Phospholipids; Rats; Swine