Peroxisome-generated succinate induces lipid accumulation and oxidative stress in the kidneys of diabetic mice

Abstract

Diabetes normally causes lipid accumulation and oxidative stress in the kidneys, which plays a critical role in the onset of diabetic nephropathy; however, the mechanism by which dysregulated fatty acid metabolism increases lipid and reactive oxygen species (ROS) formation in the diabetic kidney is not clear. As succinate is remarkably increased in the diabetic kidney, and accumulation of succinate suppresses mitochondrial fatty acid oxidation and increases ROS formation, we hypothesized that succinate might play a role in inducing lipid and ROS accumulation in the diabetic kidney. Here we demonstrate a novel mechanism by which diabetes induces lipid and ROS accumulation in the kidney of diabetic animals. We show that enhanced oxidation of dicarboxylic acids by peroxisomes leads to lipid and ROS accumulation in the kidney of diabetic mice via the metabolite succinate. Furthermore, specific suppression of peroxisomal β-oxidation improved diabetes-induced nephropathy by reducing succinate generation and attenuating lipid and ROS accumulation in the kidneys of the diabetic mice. We suggest that peroxisome-generated succinate acts as a pathological molecule inducing lipid and ROS accumulation in kidney, and that specifically targeting peroxisomal β-oxidation might be an effective strategy in treating diabetic nephropathy and related metabolic disorders. Diabetes normally causes lipid accumulation and oxidative stress in the kidneys, which plays a critical role in the onset of diabetic nephropathy; however, the mechanism by which dysregulated fatty acid metabolism increases lipid and reactive oxygen species (ROS) formation in the diabetic kidney is not clear. As succinate is remarkably increased in the diabetic kidney, and accumulation of succinate suppresses mitochondrial fatty acid oxidation and increases ROS formation, we hypothesized that succinate might play a role in inducing lipid and ROS accumulation in the diabetic kidney. Here we demonstrate a novel mechanism by which diabetes induces lipid and ROS accumulation in the kidney of diabetic animals. We show that enhanced oxidation of dicarboxylic acids by peroxisomes leads to lipid and ROS accumulation in the kidney of diabetic mice via the metabolite succinate. Furthermore, specific suppression of peroxisomal β-oxidation improved diabetes-induced nephropathy by reducing succinate generation and attenuating lipid and ROS accumulation in the kidneys of the diabetic mice. We suggest that peroxisome-generated succinate acts as a pathological molecule inducing lipid and ROS accumulation in kidney, and that specifically targeting peroxisomal β-oxidation might be an effective strategy in treating diabetic nephropathy and related metabolic disorders. Diabetes has been well known to induce lipid accumulation and oxidative stress in the kidney, which plays a critical role in the development of diabetic nephropathy (1Kang H.M. Ahn S.H. Choi P. Ko Y.A. Han S.H. Chinga F. Park A.S. Tao J. Sharma K. Pullman J. Bottinger E.P. Goldberg I.J. Susztak K. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.Nat. Med. 2015; 21: 37-46Google Scholar, 2De Vries A.P.J. Ruggenenti P. Ruan X.Z. Praga M. Cruzado J.M. Bajema I.M. D'Agati V.D. Lamb H.J. Pongrac Barlovic D. Hojs R. Abbate M. Rodriquez R. Mogensen C.E. Porrini E. Fatty kidney: Emerging role of ectopic lipid in obesity-related renal disease.Lancet Diabetes Endocrinol. 2014; 2: 417-426Google Scholar, 3Herman-Edelstein M. Scherzer P. Tobar A. Levi M. Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.J. Lipid Res. 2014; 55: 561-572Google Scholar, 4Bonnet F. Cooper M.E. Potential influence of lipids in diabetic nephropathy: Insights from experimental data and clinical studies.Diabetes Metab. 2000; 26: 254-264Google Scholar). However, the mechanism by which dysregulated glucose and fatty acid oxidation (FAO) in diabetes causes ectopic lipid deposition and excessive formation of reactive oxygen species (ROS) in kidney is not fully demonstrated. Although malonyl-CoA plays a critical role in controlling mitochondrial FAO, we noted the fact that hepatic and kidney malonyl-CoA level is significantly reduced under the condition of diabetes or fasting (5McGarry J.D. Stark M.J. Foster D.W. Hepatic malonyl-CoA levels of fed, fasted and diabetic rats as measured using a simple radioisotopic assay.J. Biol. Chem. 1978; 253: 8291-8293Google Scholar, 6Singh B. Bremer J. Borrebaek B. Malonyl-CoA in rat heart, kidney and liver.Z. Physiol. Chem. 1982; 363: 920-921Google Scholar), indicating that malonyl-CoA may not play a role in inducing lipid accumulation in the diabetic kidney. Therefore, identification of the pivotal molecule that might suppress mitochondrial fatty acid oxidation in the kidney of diabetic animals will be critical. To explore such a molecule, we focused on succinate, a unique molecule that exhibited multiple physiological functions (7Tannahill G.M. Curtis A.M. Adamik J. Palsson-McDermott E.M. McGettrick A.F. Goel G. Frezza C. Bernard N.J. Kelly B. Foley N.H. Zheng L. Gardet A. Tong Z. Jany S.S. Corr S.C. et al.Succinate is an inflammatory signal that induces IL-1β through HIF-1α.Nature. 2013; 496: 238-242Google Scholar, 8Rubic T. Lametschwandtner G. Jost S. Hinteregger S. Kund J. Carballido-Perrig N. Schwärzler C. Junt T. Voshol H. Meingassner J.G. Mao X. Werner G. Rot A. Carballido J.M. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity.Nat. Immunol. 2008; 9: 1261-1269Google Scholar, 9Tretter L. Patocs A. Chinopoulos C. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis.Biochim. Biophys. Acta. 2016; 1857: 1086-1101Google Scholar). The cross talk between succinate oxidation and lipid accumulation in kidney is not established so far; however, we noted the well-known concept that excessive succinate oxidation causes robust reduction of mitochondrial NAD+ by blocking the electron flow from the NADH to the cytochromes (10Chance B. Hollunger G. Energy-linked reduction of mitochondrial pyridine nucleotide.Nature. 1960; 185: 666-672Google Scholar, 11Krebs H.A. Eggleston L.V. d'Alessandro A. The effect of succinate and amytal on the reduction of acetoacetate in animal tissues.Biochem. J. 1961; 79: 537-549Google Scholar, 12Krebs H.A. The physiological role of the ketone bodies.Biochem. J. 1961; 80: 225-233Google Scholar), which causes accumulation of the intermediates in fatty acid oxidation and feedback suppression of mitochondrial FAO (13Bremer J. Comparison of acylcarnitines and pyruvate as substrates for rat-liver mitochondria.Biochem. Biophys. Acta. 1966; 116: 1-11Google Scholar, 14Latipää P.M. Kärki T.T. Hiltunen J.K. Hassinen I.E. Regulation of palmitoylcarnitine oxidation in isolated rat liver mitochondria. Role of the redox state of NAD (H).Biochim. Biophys. Acta. 1986; 875: 293-300Google Scholar, 15Bremer J. controlling the of fatty acid β-oxidation in rat liver mitochondria.Biochem. Biophys. Acta. Scholar). excessive oxidation of succinate in leads to ROS formation reactive oxygen species in the and Biol. Chem. Scholar, reactive oxygen J. Scholar). As succinate increased remarkably in the kidney of the diabetic animals A. S. E. F. E. J. receptor GPR91 a between glucose levels and in and 2008; Scholar), we hypothesized that succinate might play a role in inducing lipid and ROS accumulation in the diabetic kidney and related nephropathy in the role of succinate in mitochondrial FAO and ROS in the kidney of diabetic mice and the mechanism by which diabetes succinate generation and lipid and ROS accumulation in kidney. As the of succinate increased significantly in the kidney of diabetic as in which in A. S. E. F. E. J. receptor GPR91 a between glucose levels and in and 2008; Scholar). To succinate might mitochondrial fatty acid oxidation in the kidney, β-oxidation in the isolated from kidney in the of succinate. acid a specific for mitochondrial FAO, as a for mitochondrial β-oxidation and a of in the The that of succinate to mitochondrial oxidation of as by accumulation of which by of an for succinate as a of and the that of succinate remarkably in in accumulation of and in the of and which feedback for and J. H. The of by and the effect of on fatty acid Scholar, D. C. of substrates and kidney 26: Scholar, S. K. of in rat liver J. Scholar). of the of succinate on the NADH redox state and accumulation of FAO intermediates Therefore, the mitochondrial β-oxidation as by succinate to the in mitochondrial redox state and accumulation of the of succinate to the isolated significantly formation, as by of The that accumulation of succinate suppression mitochondrial β-oxidation and increased ROS which might play a role in diabetes-induced lipid and ROS accumulation in kidney. As succinate is not J.K. S. R. M. F. S. C. C. M.J. H. E. succinate mitochondrial 2016; Scholar), the increased succinate in the diabetic kidney be kidney be noted that the formation of succinate in the acid is the J. Regulation of mitochondrial metabolism by Biol. Chem. Scholar), the succinate not to of the that diabetes not in Therefore, the increased succinate in the kidney of the diabetic mice not to succinate in the To the of succinate, we that dicarboxylic acids the of fatty acids to on J. Scholar, B. K. of fatty acids in rat Biol. Chem. Scholar), might be a for succinate succinate is the of to β-oxidation S. Bremer J. of dicarboxylic acids in and in the kidney of the Biophys. Acta. Scholar, of dicarboxylic acids to succinate in rat liver Biol. Chem. Scholar, H. Bremer J. of peroxisomal Biophys. Acta. Scholar). is that by peroxisomal β-oxidation and the kidney is the for metabolism of H. Bremer J. of peroxisomal Biophys. Acta. Scholar, H. J. T. T. of dicarboxylic acid β-oxidation in rat of peroxisomes in the metabolism of dicarboxylic Biophys. Acta. Scholar, X. T. S. L. X. K. P. X. J. induces hepatic lipid accumulation by peroxisomal dicarboxylic acid Biol. Chem. Scholar). that in peroxisomes from kidney as by the specific of mitochondrial and peroxisomal mitochondrial to for in of J. S. P. L. of by an acid hepatic lipid and reactive oxygen species (ROS) metabolism in rats a Biol. Chem. Scholar), a specific for peroxisomal β-oxidation peroxisomal β-oxidation of as in We peroxisomal and the that peroxisomal increased remarkably in the kidney of diabetic mice which well that the increased generation of succinate in the kidney of diabetic mice of peroxisomal Diabetes in in fatty acids and increased of fatty acids by the kidney, as in and which plays a critical role in inducing fatty acid and peroxisomal The of fatty acid and peroxisomal β-oxidation in the kidney of the diabetic mice and peroxisomal β-oxidation enhanced significantly in the kidney of diabetic which to of and Therefore, of peroxisomal oxidation might to increased succinate generation in the diabetic kidney. We that peroxisomal β-oxidation might play a role in inducing lipid and ROS accumulation in the diabetic kidney through the metabolite succinate. We isolated peroxisomes from kidney to peroxisomal β-oxidation of succinate. The that of of to peroxisomes to generation of and succinate, as by of a specific for peroxisomal β-oxidation and generation of to the of peroxisomal which to accumulation of β-oxidation of specific in kidney peroxisomes a of The identification of a a novel for succinate in Biol. Chem. Scholar), the and of in the kidney of diabetic mice significantly the and which succinate formation from in the kidney of diabetic animals. To peroxisomal oxidation of might suppression of mitochondrial fatty acid oxidation and ROS formation in kidney, we acid a to specifically peroxisomal β-oxidation of and acid a specific for peroxisomal β-oxidation to peroxisomal of the of kidney to formation of succinate as reduced by of The of remarkably which mitochondrial β-oxidation of and accumulation of as by the or significantly formation in the kidney and reduced by the of or The that mitochondrial fatty acid oxidation and increased ROS generation through the metabolite succinate. To the role of peroxisome-generated succinate in kidney lipid and ROS of the diabetic a specific for to suppress peroxisomal β-oxidation of β-oxidation in the kidney increased and significantly increased peroxisomal and succinate in the kidney of diabetic as reduced by the of and significantly in the kidney of the diabetic mice and by the of to in in the kidney of the diabetic in accumulation of and intermediates in the kidney of diabetic which significantly increased level in the kidney of significantly reduced the of and intermediates and in the kidney of the diabetic mice. level in kidney significantly in the diabetic mice and reduced by the of remarkably increased in the kidney of the diabetic and kidney of the diabetic and a in kidney malonyl-CoA significantly in the diabetic mice the or increased significantly in the kidney of the diabetic mice the as reduced by a in generation in the diabetic kidney and as a for oxidative stress increased significantly in the kidney of diabetic mice the as increased by the of and reduced The that peroxisome-generated succinate through oxidation of accumulation of lipid and ROS in the kidney of diabetic mice. that accumulation of lipids of of the such as and Z. T. J. G. S. S. Levi M. Regulation of renal lipid metabolism, lipid and in mice Scholar, M. T. H. K. of cells to and in diabetic Scholar, H. S. T. K. T. N. N. A. T. M. role of in the of kidney in diabetic of an and an receptor Metab. Res. Scholar), which been to play an role in and and to the development of diabetic nephropathy Z. T. J. G. S. S. Levi M. Regulation of renal lipid metabolism, lipid and in mice Scholar, M. T. H. K. of cells to and in diabetic Scholar, H. S. T. K. T. N. N. A. T. M. role of in the of kidney in diabetic of an and an receptor Metab. Res. Scholar, R. A. Sharma M. of isolated rat via 2000; Scholar). of ROS will in oxidative stress and induce of the inflammatory such as and in the diabetic kidney Sharma R. Sharma M. increases of isolated rat through the generation of 9: Scholar, C. Cooper M.E. K. Diabetes and kidney Role of oxidative 2016; Scholar, between oxidative stress and inflammatory in diabetic Scholar). As peroxisome-generated succinate lipid and ROS accumulation in the diabetic kidney, we that molecule play a role in the development and onset of diabetic The that significantly increased level of and in the kidney of the diabetic as by the and The of and in the kidney increased significantly in the diabetic mice the as by the of and by and as a for diabetic nephropathy significantly in the diabetic mice as and significantly by The that peroxisome-generated succinate lipid and ROS accumulation and a role in the onset of diabetic specific of peroxisomal β-oxidation reduced renal succinate generation and improved diabetes-induced a novel mechanism by which diabetes lipid and ROS accumulation in kidney, the mechanism in in in diabetes in increased of fatty acids in the kidney, and fatty acid and peroxisomal β-oxidation in the kidney of diabetic mice. peroxisomal β-oxidation of succinate formation and remarkably increases mitochondrial which suppresses mitochondrial β-oxidation and and leads to lipid and ROS accumulation in kidney, and to the development and onset of diabetic of fatty acid or peroxisomal β-oxidation reduced succinate generation and improved lipid and ROS in the diabetic kidney. has been well known to multiple physiological metabolism, signal transduction, ROS and (7Tannahill G.M. Curtis A.M. Adamik J. Palsson-McDermott E.M. McGettrick A.F. Goel G. Frezza C. Bernard N.J. Kelly B. Foley N.H. Zheng L. Gardet A. Tong Z. Jany S.S. Corr S.C. et al.Succinate is an inflammatory signal that induces IL-1β through HIF-1α.Nature. 2013; 496: 238-242Google Scholar, 8Rubic T. Lametschwandtner G. Jost S. Hinteregger S. Kund J. Carballido-Perrig N. Schwärzler C. Junt T. Voshol H. Meingassner J.G. Mao X. Werner G. Rot A. Carballido J.M. Triggering the succinate receptor GPR91 on dendritic cells enhances immunity.Nat. Immunol. 2008; 9: 1261-1269Google Scholar, 9Tretter L. Patocs A. Chinopoulos C. Succinate, an intermediate in metabolism, signal transduction, ROS, hypoxia, and tumorigenesis.Biochim. Biophys. Acta. 2016; 1857: 1086-1101Google Scholar). However, molecule might a role in fatty acid oxidation is not fully in the kidney level of succinate is As mitochondrial β-oxidation is under the of the redox state of NAD+ S. of mitochondrial Lipid Res. Scholar), in mitochondrial leads to suppression of mitochondrial fatty acid oxidation P.M. Kärki T.T. Hiltunen J.K. Hassinen I.E. Regulation of palmitoylcarnitine oxidation in isolated rat liver mitochondria. Role of the redox state of NAD (H).Biochim. Biophys. Acta. 1986; 875: 293-300Google Scholar, 15Bremer J. controlling the of fatty acid β-oxidation in rat liver mitochondria.Biochem. Biophys. Acta. Scholar, reactive oxygen species in the and Biol. Chem. Scholar). succinate oxidation causes robust reduction of mitochondrial NAD+ by blocking the electron flow from the NADH to the cytochromes as by and (10Chance B. Hollunger G. Energy-linked reduction of mitochondrial pyridine nucleotide.Nature. 1960; 185: 666-672Google Scholar, 11Krebs H.A. Eggleston L.V. d'Alessandro A. The effect of succinate and amytal on the reduction of acetoacetate in animal tissues.Biochem. J. 1961; 79: 537-549Google Scholar, 12Krebs H.A. The physiological role of the ketone bodies.Biochem. J. 1961; 80: 225-233Google Scholar), which accumulation of intermediates and suppression of mitochondrial fatty acid oxidation in the liver J. controlling the of fatty acid β-oxidation in rat liver mitochondria.Biochem. Biophys. Acta. Scholar, X. T. S. L. X. K. P. X. J. induces hepatic lipid accumulation by peroxisomal dicarboxylic acid Biol. Chem. Scholar). succinate as a for mitochondrial and accumulation of succinate to lipid accumulation in the kidney of diabetic which well the mechanism for succinate of mitochondrial β-oxidation in the kidney. is well that excessive generation of ROS causes oxidative which plays an role in the development of diabetic nephropathy reactive oxygen species in the and Biol. Chem. Scholar, reactive oxygen J. Scholar). that the the for of ROS and might to oxidative stress reactive oxygen J. however, the role of succinate in ROS generation and inducing oxidative stress in the kidney is of succinate has been well known to and in reactive oxygen species in the and Biol. Chem. Scholar, reactive oxygen J. and might to oxidative stress and As succinate increased remarkably in the kidney of the diabetic molecule might play a critical role in inducing oxidative stress and related we that the increased formation of succinate in the diabetic kidney in to peroxisomal oxidation of reducing the of or peroxisomal β-oxidation significantly succinate generation and reduced ROS formation in the kidney of diabetic animals. Fatty acid and in the kidney and of animals and in the on J. Scholar). As fatty acid is and in the kidney of diabetic animals and might play a physiological role under such as Although has been for a the physiological functions of of fatty acid not clear. is that the generation of may the oxidation of fatty acids B. K. of fatty acids in rat Biol. Chem. Scholar). to be through generation of succinate in animals F. M. on fatty acid effect and of dicarboxylic Biophys. Acta. Scholar, The and effect of the of fatty acids in Biophys. Acta. Scholar). that of to diabetic rats and ketone in diabetic animals F. M. on fatty acid effect and of dicarboxylic Biophys. Acta. Scholar), indicating that might play a role in mitochondrial that mitochondrial FAO and to hepatic lipid accumulation through in mitochondrial redox state in the liver of the fasting rats X. T. S. L. X. K. P. X. J. induces hepatic lipid accumulation by peroxisomal dicarboxylic acid Biol. Chem. Scholar). a physiological of in the kidney and that a role of fatty acid to substrates for metabolism in peroxisomes for the of succinate, which is increased significantly in the kidney and of the diabetic animals. Therefore, increases in generation will mitochondrial fatty acid oxidation by mitochondrial and ROS formation in the kidney of the diabetic animals through the metabolite succinate. β-oxidation in in the C. fatty in rat liver by a U. S. A. however, the physiological of fatty acid oxidation in lipid and ROS in animals not fully demonstrated. that metabolism to excessive fatty acids that by mitochondrial fatty acid which the to for S. H. T. in peroxisomal fatty acid oxidation in the diabetic rat Scholar). the the that in peroxisomal FAO might be for of fatty acids or The role of peroxisomes in Metab. Scholar, A. R. B. F. induces hepatic fatty acid and in Biol. Chem. Scholar). that peroxisomal β-oxidation plays a role in inducing hepatic and oxidative stress in rats by formation of malonyl-CoA and formation J. S. P. L. of by an acid hepatic lipid and reactive oxygen species (ROS) metabolism in rats a Biol. Chem. Scholar, A. X. M. D. X. J.M. B. I.J. from hepatic peroxisomal β-oxidation and via 79: Scholar). of peroxisomal β-oxidation lipid accumulation in the liver of the fasting animals by oxidation X. T. S. L. X. K. P. X. J. induces hepatic lipid accumulation by peroxisomal dicarboxylic acid Biol. Chem. Scholar). that the from hepatic peroxisomal β-oxidation and hepatic through of X. L. S. P. K. T. X. Z. J. oxidation of acid suppresses mitochondrial fatty acid oxidation by malonyl-CoA formation in the rat Biol. Chem. Scholar). of the on peroxisomal β-oxidation in the however, as the in peroxisomal FAO in the kidney and under the condition of metabolism might play a role in lipid and ROS metabolism in kidney. a cross talk between peroxisomal β-oxidation and lipid accumulation in the kidney of diabetic animals that peroxisomal oxidation of mitochondrial β-oxidation and lipid and ROS accumulation through the metabolite succinate, which as a novel mechanism for diabetes-induced renal and As we is the a role of peroxisomal β-oxidation in the kidney. lipids and ROS renal and related nephropathy (1Kang H.M. Ahn S.H. Choi P. Ko Y.A. Han S.H. Chinga F. Park A.S. Tao J. Sharma K. Pullman J. Bottinger E.P. Goldberg I.J. Susztak K. Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.Nat. Med. 2015; 21: 37-46Google Scholar, 2De Vries A.P.J. Ruggenenti P. Ruan X.Z. Praga M. Cruzado J.M. Bajema I.M. D'Agati V.D. Lamb H.J. Pongrac Barlovic D. Hojs R. Abbate M. Rodriquez R. Mogensen C.E. Porrini E. Fatty kidney: Emerging role of ectopic lipid in obesity-related renal disease.Lancet Diabetes Endocrinol. 2014; 2: 417-426Google Scholar, 3Herman-Edelstein M. Scherzer P. Tobar A. Levi M. Gafter U. Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy.J. Lipid Res. 2014; 55: 561-572Google Scholar, 4Bonnet F. Cooper M.E. Potential influence of lipids in diabetic nephropathy: Insights from experimental data and clinical studies.Diabetes Metab. 2000; 26: 254-264Google Scholar). of ROS and increased oxidative stress induce of a of inflammatory such as and in the diabetic kidney, which plays a critical role in the and development of diabetic the is that excessive lipids deposition the of the such as and which been to play an role in and Sharma R. Sharma M. increases of isolated rat through the generation of 9: Scholar, C. Cooper M.E. K. Diabetes and kidney Role of oxidative 2016; Scholar, between oxidative stress and inflammatory in diabetic Scholar). a novel mechanism by which diabetes induces and as by lipid and ROS in the kidney, which that succinate as a molecule inducing lipid and ROS accumulation in the kidney and might play a critical role in onset of diabetic As fatty acid and peroxisomal β-oxidation in the kidney under the condition of will in excessive succinate formation in the kidney of the diabetic animals. Therefore, the might as a mechanism for diabetes-induced kidney through inducing of the such as and and inflammatory The the of dicarboxylic acids as in the kidney of the diabetic animals and which as substrates for generation of succinate by peroxisomal We suggest that or kidney level of and succinate as of diabetes-induced metabolic for clinical succinate receptor GPR91 is in the kidney, and succinate has been to from the kidney via GPR91 signal and causes of A. S. E. F. E. J. receptor GPR91 a between glucose levels and in and 2008; Scholar, J. H. L. A. of 2013; Scholar). is that in diabetes is a that leads to of the and renal and J. H. L. A. of 2013; Scholar). Therefore, we suggest that excessive generation of succinate by peroxisomal oxidation of might to of the and kidney and will be of to peroxisome-generated succinate plays a role in diabetes-induced in and mechanism by specific peroxisomal β-oxidation of of a specific for peroxisomal β-oxidation to the diabetic mice significantly enhances mitochondrial fatty acid oxidation and reduced lipid and ROS level in the kidney of diabetic mice. data that dicarboxylic acids and succinate in remarkably in the diabetic H.M. of ketone and acids in 1986; Scholar, M. T. K. acids as of fatty acid in 2000; Scholar), the of to β-oxidation in peroxisomes and be from the kidney of the diabetic clinical that peroxisomal β-oxidation of be in the kidney of diabetic is that that specifically fatty acid or peroxisomal β-oxidation might be in treating diabetes-induced nephropathy by reducing peroxisomal generation of succinate, which significantly lipid level and ROS formation in the diabetic kidney. succinate, and from acid and acid from The of acid acid acid and acid by a and by as X. T. S. L. X. K. P. X. J. induces hepatic lipid accumulation by peroxisomal dicarboxylic acid Biol. Chem. Scholar). of or mice the of from the mice in to and under and by of to the mice. the the glucose level by using a and the mice for the the diabetic mice from the the of on fatty acid and ROS metabolism in the kidney, in the and to the diabetic mice for and acid as a to a of by for the the the mice from and kidney and in the animal by the of of and the of Hiltunen J.K. The of peroxisomes in peroxisomes J. Physiol. Physiol. Scholar), and the kidney in the and from kidney isolated by in as C. B. R. R. F. of in rat-liver J. Scholar), the mitochondrial in and in the a of for the of mitochondrial isolated by a the of and Hiltunen J.K. The of peroxisomes in peroxisomes J. Physiol. Physiol. Scholar, C.E. H. of peroxisomal β-oxidation in rat liver by J. Scholar). of on of a of and for on a an the for The and for to The of the isolated mitochondrial and peroxisomal by in the to the as C.E. H. of peroxisomal β-oxidation in rat liver by J. Scholar), as in The mitochondrial or and succinate or succinate of to the succinate or peroxisomal for mitochondrial and the intermediates as for generation of and succinate by the isolated peroxisomes from kidney The of a of and and of isolated peroxisomes in a of to the for the of peroxisomal for the by of acid and succinate in the and in the isolated or by the of and as P.M. Hassinen I.E. Hiltunen J.K. for and intermediates of Scholar). from kidney using in a using The and and and and and and and and and and and and levels to using the and by lipid from kidney by the of and of lipid and J. Physiol. Scholar), and by a and acetoacetate to the as D. J. H. of acid and acid in J. Scholar). malonyl-CoA by as of by Scholar). and acid reactive measured by from and measured a and a as measured by to the of succinate 1978; Scholar). by succinate as C. of succinate succinate Scholar). on the of from in the of and the rats or increases mitochondrial and in J. Scholar). The and for the by of measured to the of J. E. F. The J. Scholar), as by the of S. S. T. and of rat liver and electron Scholar), as by the as J. S. P. L. of by an acid hepatic lipid and reactive oxygen species (ROS) metabolism in rats a Biol. Chem. Scholar), or as β-oxidation by NAD+ reduction in the of as by of peroxisomal β-oxidation of fatty Scholar), as measured by a isolated peroxisomes K. of an that functions as a of peroxisomal lipid Biol. Chem. Scholar). by the of from and as The of in liver and kidney a peroxisomal Biol. Chem. Scholar), in the as The of the in using data in the The that is of the of We from for the of and J. Z. and X. Z. J. Z. X. H. L. and P. L. X. H. and J. Z. J. Z. J. Z. J. Z. and by from of and

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