The Effect Of Lipopolysaccharide On Animal Hepatic Mitochondrial Function And Mitigative Effect Of A-lipoic Acid

In the practical commercial pig farms,inflammation is a perennial problem.It may induce a massive loss of hepatocytes and exacerbate the severity of various hepatic conditions.Thus inhibition of hepatic inflammation is extremely important for the health of the body.α-lipoic acid(LA),a naturally occurring short chain fatty acid,is a necessary cofactor for mitochondrial pyruvate dehydrogenase complex and a-ketoglutarate dehydrogenase complex.LA not only plays an important role in mitochondrial metabolism,may also affect liver function,as well as alleviate the damage of LPS to different organizations.But whether LA can affect mitochondrial function to relieve liver damage induced by inflammation and its possible mechanism is not clear.In addition,most studies to growing pigs with inflammation focus on the immune response,there are few studies focus on mitochondrial dysfunction.Therefore,this study has two parts:the first part uses mice as a model to investigate the functin of LA on liver mitochondria under inflammatory conditions and the mechanism;the second part uses growing pigs as a model to investigate the effect of inflammation on hepatic mitochondria of growing pigs.1 LA attenuates LPS-induced mitochondrial disfunction and possible mechanismMice were used as a model.After a 5-day adaptation period,mice were assigned to three experimental groups for five more days.On the fifth day,the control group received an intraperitoneal injection of saline and the LPS group received LPS at a dose of 5mg/kg.The LA+LPS group was co-treated with LPS and(±)-α-Lipoic acid.In the LA+LPS group,LA was administered intraperitoneally at a dose of 100 mg/kg daily,and on the fifth day,LPS was injected 1h after the last LA injection,at a dose of 5 mg/kg.Six hours after the LPS injection,half of each group was randomly selected and anesthetized for blood and liver collection.Twenty-four hours later,the remaining mice were processed in the same way.Liver injury,energy metabolism and mitochondrial function and regulation were investigated.The results showed LA attenuated the liver injury evidenced by decreased plasma alanine aminotransferase(ALT)and aspartate aminotransferase(AST)compared with LPS group.The content of hepatic ATP and NADH content,the expression of most mitochondrial DNA(mtDNA)encoded genes and the activities of mitochondrial complex I,IV and V significantly increased in LA group compared with LPS group.Sirt3 protein which is essential for the regulation of mitochondrial metabolism also increased in LA treated group.For the mtDNA coding genes expression regulation,the present study showed the methylation state of the D-loop region of mtDNA didn’t exhibit obviously changes.However,LA increased the glucocorticoid receptor(GR)protein expression in liver and the level of GR binding to the D-loop region of mtDNA in LA group compared with LPS group.The present study demonstrated that LA exerted the liver-protective effect in an inflammation state by improving mitochondrial function.Furthermore,it is the first time as we know to demonstrate that GR may involve in the effect by improving its binding to mtDNA control region and regulating the mtDNA genes expression.2 The effect of LPS on hepatic mitochondria function of growing pigsGrowing pigs were used as a model,which were randomly divided into two groups,a control group and a LPS group.After one week adaption,the LPS group pigs were intramuscular injected with 2 mL LPS at a dose of 15 μg/kg bodyweight,while the control received the same volume of saline.Six hours after LPS injection,the pigs were euthanized and sampled.Liver injury,energy metabolism and mitochondrial function were investigated.The results showed LPS up-regulated the content of plasma AST,induced damage to the livers of growing pigs.The gene expression of TNF-α,NF-κB and IL-1α in liver were also increased by LPS.Although LPS led to a increased energy consumption which confirmed by decreased liver triglycerides and glycogen content,but the hepatic ATP,ADP,AMP and energy charge were not affected by the LPS.The gene expression of mtDNA encoded genes and the activities of mitochondrial complex IV and V were also not changed.