title: α-Lipoic acid attenuates LPS-induced liver injury by improving mitochondrial function in association with GR mitochondrial DNA occupancy.
abstract: α-Lipoic acid (LA) has been demonstrated to be a key regulator of energy metabolism. However, whether LA can protect the liver from inflammation, as well as the underlying mechanism involved, are still largely unclear. In the present study, mice treated with lipopolysaccharide (LPS) and injected with LA were used as a model. Liver injury, energy metabolism and mitochondrial regulation were investigated to assess the protective effect of LA on the liver and explore the possible mechanisms involved. Our results showed that LA attenuated liver injury, as evidenced by the decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels after LA treatment compared with the LPS-treated group. The hepatic ATP and NADH levels, expression levels of most mitochondrial DNA (mtDNA)-encoded genes as well as mitochondrial complex I, IV and V activities were all significantly increased in the LA-treated group compared with the LPS-treated group. Levels of Sirt3 protein, which is essential for the regulation of mitochondrial metabolism, were also increased in the LA-treated group. Regarding the regulation of mtDNA-encoded genes expression, we observed no obvious change in the methylation status of the mtDNA D-loop region. However, compared to the LPS-treated group, LA treatment increased glucocorticoid receptor (GR) protein expression in the liver, as well as the level of GR occupancy on the mtDNA D-loop region. Our study demonstrates that LA exerts a liver-protective effect in an inflammation state by improving mitochondrial function. Furthermore, to the best of our knowledge, we demonstrate for the first time that GR may be involved in this effect via an enhanced binding to the mtDNA transcriptional control region, thereby regulating the expression of mtDNA-encoded genes.
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Jun
authors.initials: J
authors.lastname: Guo
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Hailin
authors.initials: H
authors.lastname: Sun
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Yanping
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China.
authors.forename: Ruqian
authors.initials: R
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Animal Physiology & Biochemistry, Nanjing Agricultural University, Nanjing 210095, PR China. Electronic address: yangxj@njau.edu.cn.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yang
mesh_terms: D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D015153:Blotting, Western; D004272:DNA, Mitochondrial / Q000235:genetics*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011965:Receptors, Glucocorticoid / Q000235:genetics*; D008063:Thioctic Acid / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; D008063:Thioctic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: LA; LPS; Liver-protective; Mice; Mitochondria