Effect Of Dicarboxylic Acid On Fatty Acid Metabolism In Rat Liver And Its Mechanism

Dicarboxylic acid（DCA）is a product of fatty acidω-oxidation.Fatty acidω-oxidation could be induced by fasting or genetic defect in fatty acid metabolism,led to enhanced DCA metabolism.However,the influence of DCA metabolism on fatty acid oxidation and its mechanisms are still unclear.In this study,we concentrated mainly on the effect of DCA treatment on fatty acid metabolism and intended to provide theoretical basis for related disease occurrence study.This study is aimed to build a rat model of hepatic steatosis induced by1,10-dodecanedioic acid(DCA₁₂)treatment.Male SD rats were firstly exposed to normal diet for two weeks.After 48 h of fasting,the rats were treated with DCA₁₂（test group）or hexanoic acid（control group）by gavage.After the experiments all the rats were bled from the eyes and then sacrificed.Livers were removed quickly and stored in liquid nitrogen immediately.Visual inspection of livers observed obvious change in organ color and surface fat particles deposition.The densities of fat droplets in liver sections of test group were increased and their shape was mainly macrovascular.Compared with the control group,hepatic triglyceride（TG）,plasma TG and total cholesterol（TC）were significantly elevated by DCA treatment while no alternation for plasma free fatty acid.Compared with the control group,plasma ketone body was significantly reduced by DCA treatment.Still,a sharp decreased plasma glucose level was observed.All those results indicated the successful establishment of rat model,the DCA metabolism in fasting rats induced disorder in fatty acid metabolism.To explore the mechanism of dicarboxylic acid inducing fatty lesion in rat liver.The activity of acyl-Co A oxidase-1（ACOX1）,the rate-limiting enzyme of peroxisomalβ-oxidation,was not enhanced by short-term DCA treatment while hepatic content of hydrogen peroxide,the main by-product of peroxisomalβ-oxidation was significantly increased in livers of DCA treated rat,which was in accordance with previous report,suggested that DCAs are mainly oxidized in peroxisomes.The content of malondialdehyde（MDA）in the liver is significantly increased,which is consistent with the previous study.Moreover,the peroxisomal content of succinyl-Co A was increased,suggested that the peroxisomal oxidation of DCA resulted in succinate formation.The mitochondrial NADH/NAD⁺ratio was increased by DCA oxidation,which negatively regulated mitochondrialβ-oxidation and reduced ketogenesis.DCA treatment reduced the metabolic rate of fasting rats as determined by oxygen consumption.The sodium concentration in urine was not significantly changed.Further study are needed to explore the effect of DCA metabolism on other organs.In conclusion,DCAs are exclusively oxidized in peroxisomes.Hepatic reactive oxygen species（ROS）and succinyl-Co A content were increased along with elevated mitochondrial NADH/NAD⁺ratio.All those contributed to the down-regulation of mitochondrial fatty acid oxidation,and induced a significantly lipid deposition and steatosis in livers of fasting rats.This study proposed a cross-talk between peroxisome and mitochondria in fatty acid oxidation,provided a theoretical basis for related disease occurrence study.