Peroxisomal β-oxidation stimulates cholesterol biosynthesis in the liver in diabetic mice

Abstract

Although diabetes normally causes an elevation of cholesterol biosynthesis and induces hypercholesterolemia in animals and human, the mechanism linking diabetes to the dysregulation of cholesterol biosynthesis in the liver is not fully understood. As liver peroxisomal β-oxidation is induced in the diabetic state and peroxisomal oxidation of fatty acids generates free acetate, we hypothesized that peroxisomal β-oxidation might play a role in liver cholesterol biosynthesis in diabetes. Here, we used erucic acid, a specific substrate for peroxisomal β-oxidation, and 10,12-tricosadiynoic acid, a specific inhibitor for peroxisomal β-oxidation, to specifically induce and suppress peroxisomal β-oxidation. Our results suggested that induction of peroxisomal β-oxidation increased liver cholesterol biosynthesis in streptozotocin-induced diabetic mice. We found that excessive oxidation of fatty acids by peroxisomes generated considerable free acetate in the liver, which was used as a precursor for cholesterol biosynthesis. In addition, we show that specific inhibition of peroxisomal β-oxidation decreased cholesterol biosynthesis by reducing acetate formation in the liver in diabetic mice, demonstrating a crosstalk between peroxisomal β-oxidation and cholesterol biosynthesis. Based on these results, we propose that induction of peroxisomal β-oxidation serves as a mechanism for a fatty acid-induced upregulation in cholesterol biosynthesis and also plays a role in diabetes-induced hypercholesterolemia. Although diabetes normally causes an elevation of cholesterol biosynthesis and induces hypercholesterolemia in animals and human, the mechanism linking diabetes to the dysregulation of cholesterol biosynthesis in the liver is not fully understood. As liver peroxisomal β-oxidation is induced in the diabetic state and peroxisomal oxidation of fatty acids generates free acetate, we hypothesized that peroxisomal β-oxidation might play a role in liver cholesterol biosynthesis in diabetes. Here, we used erucic acid, a specific substrate for peroxisomal β-oxidation, and 10,12-tricosadiynoic acid, a specific inhibitor for peroxisomal β-oxidation, to specifically induce and suppress peroxisomal β-oxidation. Our results suggested that induction of peroxisomal β-oxidation increased liver cholesterol biosynthesis in streptozotocin-induced diabetic mice. We found that excessive oxidation of fatty acids by peroxisomes generated considerable free acetate in the liver, which was used as a precursor for cholesterol biosynthesis. In addition, we show that specific inhibition of peroxisomal β-oxidation decreased cholesterol biosynthesis by reducing acetate formation in the liver in diabetic mice, demonstrating a crosstalk between peroxisomal β-oxidation and cholesterol biosynthesis. Based on these results, we propose that induction of peroxisomal β-oxidation serves as a mechanism for a fatty acid-induced upregulation in cholesterol biosynthesis and also plays a role in diabetes-induced hypercholesterolemia. Numerous reports demonstrated that uncontrolled diabetes is associated with hypercholesterolemia, which greatly increases the risk of atherosclerosis and related cardiovascular diseases (1Cassader M. Ruiu G. Gambino R. Alemanno N. Veglia F. Pagano G. Hypercholesterolemia in non-insulin-dependent diabetes mellitus: Different effect of simvastatin on VLDL and LDL cholesterol level.Atherosclerosis. 1993; 99: 47-53Google Scholar, 2Haffner S.M. Diabetes, hyperlipidemia, and coronary artery disease.Am. J. Cardiol. 1999; 83: 17F-21FGoogle Scholar, 3Grant G.R. Wakabayashi S. Yamamoto R. Matsutomo R. Takebayashi K. Inukai T. Comparison of hyperglycemia, hypertension, and hypercholesterolemia management in patients with type 2 diabetes.Am. J. Med. 2002; 112: 603-609Google Scholar). However, the mechanisms by which diabetes cause elevation in plasma cholesterol level are not fully demonstrated. As liver cholesterol biosynthesis is enhanced in the diabetic animals (4Hotta S. Chaikoff I.L. Mechanism of increased hepatic cholesterogenesis in diabetes: Its relation to carbohydrate utilization.J. Biol. Chem. 1954; 206: 835-844Google Scholar, 5Kwong L.K. Feingold K.R. Peric-Golia L. Le T. Karkas J.D. Alberts A.W. Wilson D.E. Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.Diabetes. 1991; 40: 1630-1639Google Scholar), the dysregulated cholesterol biosynthesis might play a role in diabetes-induced hypercholesterolemia. It is well-known that free fatty acid (FFA) stimulates hepatic cholesterol biosynthesis (6Nilsson A. Sundler R. Akesson B. Effect of different albumin-bound fatty acids on fatty acid and cholesterol biosynthesis in rat hepatocytes.FEBS Lett. 1974; 45: 282-285Google Scholar, 7Gu Y. Yin J. Saturated fatty acids promote cholesterol biosynthesis: Effects and mechanisms.Obes. Med. 2020; 18: 100201Google Scholar, 8Schafer H.F. Kattermann R. Fatty acid modulation of HepG2 cell cholesterol biosynthesis and esterification.Clin. Biochem. 1992; 25: 325-330Google Scholar), and liver-FFAs increased significantly under the condition of diabetes. Therefore, the increased supply of fatty acids might lead to elevated cholesterol synthesis and very low density lipoprotein-cholesterol (VLDL-C) secretion in the diabetic animals. To explore the potential roles of fatty acids in cholesterol biosynthesis and hyperlipidemia in diabetes, we focused on peroxisomal β-oxidation, a fatty acid oxidation (FAO) system that acted on long-chain fatty acids (9Reddy J.K. Hashimoto T. Peroxisomal β-oxidation and peroxisome proliferator–activated receptor α: An adaptive metabolic system.Annu. Rev. Nutr. 2001; 21: 193-230Google Scholar). Although the crosstalk between peroxisomal β-oxidation and cholesterol biosynthesis is not established so far, we noted that peroxisomal FAO is induced in the liver of diabetic animals (10Asayama K. Sandhir R. Sheikh F.G. Hayashibe H. Nakane T. Singh I. Increased peroxisomal fatty acid beta-oxidation and enhanced expression of peroxisome proliferator-activated receptor-alpha in diabetic rat liver.Mol. Cell. Biochem. 1999; 194: 227-234Google Scholar, 11Horie S. Ishii H. Suga T. Changes in peroxisomal fatty acid oxidation in the diabetic rat liver.J. Biochem. 1981; 90: 1691-1696Google Scholar, 12Thomas H. Schladt L. Knehr M. Oesch F. Effect of diabetes and starvation on the activity of rat liver epoxide hydrolases, glutathione S-transferases and peroxisomal β-oxidation.Biochem. Pharmacol. 1989; 38: 4291-4297Google Scholar, 13Asayama K. Yokota S. Kato K. Peroxisomal oxidases in various tissues of diabetic rats.Diabetes Res. Clin. Pract. 1991; 11: 89-94Google Scholar), and peroxisomal β-oxidation generated free acetate as the ultimate product (14Leighton F. Bergseth S. Rørtveit T. Christiansen E.N. Bremer J. Free acetate production by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation.J. Biol. Chem. 1989; 264: 10347-10350Google Scholar, 15Hovik R. Brodal B. Bartlett K. Osmundsen H. Metabolism of acetyl-CoA by isolated peroxisomal fractions: Formation of acetate and acetoacetyl-CoA.J. Lipid Res. 1991; 32: 993-999Google Scholar, 16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar). It was reported that cholesterol biosynthesis from acetate is increased in the liver of diabetic animals (17Brady R.O. Gurin S. Biosynthesis of labeled fatty acids and cholesterol in experimental diabetes.J. Biol. Chem. 1950; 187: 589-596Google Scholar, 18Hotta S. Chaikoff I.L. Cholesterol synthesis from acetate in the diabetic liver.J. Biol. Chem. 1952; 198: 895-899Google Scholar, 19Van Bruggen J.T. Yamada P. Hutchens T.T. West E.S. Lipogenesis of the intact alloxan-diabetic rat.J. Biol. Chem. 1954; 209: 635-640Google Scholar), and [1-14C]-acetate incorporation into cholesterol by liver slices was much greater in animals fed erucic acid than in those fed palmitic, stearic, oleic, or linoleic acid (20Carroll K.K. Effect of erucic acid on incorporation of acetate-1-C14 into cholesterol and faty acids.Can. J. Biochem. Physiol. 1959; 37: 803-810Google Scholar). Furthermore, direct measurement of cholesterol synthesis from [1-14C]-lignoceric acid suggested that the acetyl-CoA generated from peroxisomal β-oxidation was preferentially used for biosynthesis of cholesterol (21Hashimoto F. Ishikawa T. Hamada S. Hayashi H. Effect of gemfibrozil on lipid biosynthesis from acetyl-CoA derived from peroxisomal beta-oxidation.Biochem. Pharmacol. 1995; 49: 1213-1221Google Scholar). We hypothesized that peroxisomal oxidation of endogenous fatty acids might play a role in liver cholesterol biosynthesis and induce elevation in plasma cholesterol in the diabetic animals. Erucic acid (C22:1) as a specific substrate for peroxisomal β-oxidation was used to induce peroxisomal β-oxidation flux (16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar, 22Bremer J. Norum K.R. Metabolism of very long-chain monounsaturated fatty acids (22:1) and the adaptation to their presence in the diet.J. Lipid Res. 1982; 196: 149-159Google Scholar), and 10,12-tricosadiynoic acid (TDYA), a specific inhibitor for peroxisomal β-oxidation, was applied to suppress peroxisomal β-oxidation (23Zeng J. Deng S. Wang Y. Li P. Tang L. Pang Y. Specific inhibition of acyl-CoA oxidase-1 by an acetylenic acid improves hepatic lipid and reactive oxygen species (ROS) metabolism in fed a diet.J. Biol. Chem. Scholar). the role and potential mechanism of peroxisomal β-oxidation in liver cholesterol biosynthesis in diabetic mice. of the in peroxisomal β-oxidation in of the diabetic Peroxisomal β-oxidation increased significantly in the liver of the diabetic by was elevated in the increased significantly in the diabetic fatty acids are to endogenous for peroxisome receptor excessive hepatic of fatty acids in diabetic in of peroxisome receptor and of the in peroxisomal β-oxidation (9Reddy J.K. Hashimoto T. Peroxisomal β-oxidation and peroxisome proliferator–activated receptor α: An adaptive metabolic system.Annu. Rev. Nutr. 2001; 21: 193-230Google Scholar, Christiansen E.N. Norum K.R. of the effect of on peroxisomal β-oxidation in rat J. 1982; 206: Scholar). long-chain acyl-CoA increased in the diabetic which for peroxisomal β-oxidation. To the role of peroxisomal β-oxidation in cholesterol erucic acid (C22:1) was to diabetic to fatty acid flux peroxisomal β-oxidation and acid a fatty acid that is preferentially in was used as a to mitochondrial FAO was also in cholesterol biosynthesis. results that peroxisomal of of β-oxidation, was increased by the of and by was for a for peroxisomal β-oxidation, was also significantly increased in liver as by cholesterol increased significantly by of as by of effect on cholesterol level was not significantly of or and low density lipoprotein-cholesterol increased by the of and and cholesterol level also increased of and by was for of acid a in cholesterol increased by in as by and was in as a of liver cholesterol biosynthesis was also significantly elevated in which was by and of in cholesterol increased by in was in results that peroxisomal β-oxidation than mitochondrial FAO cholesterol biosynthesis in the liver of the diabetic mice, which in increased secretion and might play a role in diabetes-induced hypercholesterolemia. To of peroxisomal FAO might cholesterol the diabetic fed a with erucic acid and a with was used as a 10,12-tricosadiynoic acid was to specifically suppress peroxisomal β-oxidation. Peroxisomal β-oxidation was induced in of the diabetic to the as enhanced by and by was by increased significantly in the diabetic fed as by the of and in the results suggested that increased substrate flux peroxisomal β-oxidation in the diabetic mice. and plasma of increased by as significantly by in the and cholesterol was significantly in the diabetic and increased by diabetic as by the with effect on liver cholesterol level in the diabetic mice. low density lipoprotein-cholesterol secretion was also and the results that secretion increased significantly in diabetic as enhanced by and by In the significantly increased secretion in diabetic mice, which was by the of results suggested that the in cholesterol biosynthesis as induced by peroxisomal β-oxidation VLDL secretion in the diabetic mice, of peroxisomal β-oxidation cholesterol synthesis and VLDL which was in with reports that the of cholesterol biosynthesis by VLDL secretion in animals and G. T. T. M. I. K. M. S. Effect of on in Scholar, Effects of on J. Cardiol. Scholar). level of low density lipoprotein-cholesterol increased in the diabetic fed as decreased by cholesterol was significantly in the diabetic fed to the of decreased cholesterol level in the diabetic and plasma and of erucic acid or not cause of the plasma or in the diabetic mice, as in Therefore, the results suggested that to the diabetic enhanced peroxisomal FAO and significantly increased liver cholesterol which in increased secretion and elevated cholesterol as by of a specific inhibitor for peroxisomal β-oxidation. in cholesterol biosynthesis to the enhanced cholesterol biosynthesis as by or was to in the and not significantly the and the activity of the in cholesterol was also significantly in the diabetic with or activity was increased in the diabetic to the was with or Furthermore, liver activity was not significantly the results that the increased biosynthesis of cholesterol in liver as induced by peroxisomal β-oxidation as was not to in the in cholesterol biosynthesis. acetyl-CoA in liver increased in the diabetic elevated by the of or and by was not significantly the activity was in mice, in the diabetic with or acetyl-CoA activity decreased significantly in the diabetic and in the diabetic with or liver malonyl-CoA was in the diabetic of or results suggested that the increased formation of acetyl-CoA as by the enhanced peroxisomal β-oxidation was not of in or malonyl-CoA formation in the liver of the diabetic mice. As peroxisomal β-oxidation generates free acetate as the ultimate product (14Leighton F. Bergseth S. Rørtveit T. Christiansen E.N. Bremer J. Free acetate production by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation.J. Biol. Chem. 1989; 264: 10347-10350Google Scholar, 15Hovik R. Brodal B. Bartlett K. Osmundsen H. Metabolism of acetyl-CoA by isolated peroxisomal fractions: Formation of acetate and acetoacetyl-CoA.J. Lipid Res. 1991; 32: 993-999Google Scholar, 16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar), the elevated acetyl-CoA in the was from the enhanced of free acetate from peroxisomal β-oxidation in the diabetic with or acetate was significantly in the diabetic as elevated in the diabetic with and and diabetic and by the with that peroxisomal metabolism of fatty acids acetate the liver acetyl-CoA activity was not significantly by the diabetic with or expression of peroxisomal acetyl-CoA was in of the diabetic as elevated by diabetic Peroxisomal and and the results that activity was induced in the diabetic and the activity of was much than that of of liver peroxisomes from diabetic with acetyl-CoA to of acetate the of was that acetate than was the ultimate product of fatty acids to peroxisomal β-oxidation in the liver of diabetic mice. of isolated with increased acetate as by with of isolated with acetate as as increased as by of or a specific inhibitor for Therefore, to the activity in liver peroxisomes of the diabetic mice, of the acetyl-CoA generated in peroxisomal β-oxidation was to free acetate and to acetyl-CoA formation and cholesterol biosynthesis. reported to induce cholesterol biosynthesis in animals (4Hotta S. Chaikoff I.L. Mechanism of increased hepatic cholesterogenesis in diabetes: Its relation to carbohydrate utilization.J. Biol. Chem. 1954; 206: 835-844Google Scholar, 5Kwong L.K. Feingold K.R. Peric-Golia L. Le T. Karkas J.D. Alberts A.W. Wilson D.E. Intestinal and hepatic cholesterogenesis in hypercholesterolemic dyslipidemia of experimental diabetes in dogs.Diabetes. 1991; 40: 1630-1639Google Scholar), the mechanism by which dysregulated and fatty acid metabolism in diabetes to increased cholesterol biosynthesis is not demonstrated an role of peroxisomal β-oxidation in cholesterol biosynthesis. mechanism was in in plasma in diabetes results in increased of fatty acids in liver and induces peroxisomal β-oxidation. peroxisomal metabolism of fatty acids stimulates acetate into the and increased of a precursor for cholesterol biosynthesis. demonstrated a between peroxisomal β-oxidation and cholesterol biosynthesis. Peroxisomal β-oxidation system for than fatty acyl-CoA system in rat liver by a S. A. Scholar), the roles of peroxisomal FAO in liver lipid are not fully Our a between peroxisomal β-oxidation and mitochondrial fatty acid oxidation and suggested that induction of peroxisomal β-oxidation mitochondrial FAO by stimulating liver malonyl-CoA formation in fed a which of and (16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar). However, peroxisomal FAO might play a role in cholesterol biosynthesis is not In results suggested that peroxisomal β-oxidation cholesterol biosynthesis and elevated plasma cholesterol level under the condition of diabetes, as by specific inhibition of peroxisomal β-oxidation. As peroxisomal β-oxidation plays a role in metabolism of long-chain fatty acids (9Reddy J.K. Hashimoto T. Peroxisomal β-oxidation and peroxisome proliferator–activated receptor α: An adaptive metabolic system.Annu. Rev. Nutr. 2001; 21: 193-230Google Scholar), the of endogenous fatty acids in liver and the of peroxisomes to liver FAO by J. of the peroxisomal and mitochondrial beta-oxidation in isolated rat Scholar, R. of peroxisomal and mitochondrial fatty acid oxidation in rat hepatocytes J. 1991; Scholar, oxidation in rat for production by J. Biochem. Scholar). It was that peroxisomal β-oxidation for that of FAO under might significantly elevated under diabetic condition liver peroxisomal β-oxidation is induced in diabetes and much might β-oxidation in of the acetyl-CoA generated in peroxisomal β-oxidation used for cholesterol biosynthesis. Therefore, we propose that of the of peroxisomal β-oxidation is to biosynthesis of cholesterol under the condition of diabetes and in peroxisomal β-oxidation is induced and fatty acid synthesis is with peroxisomal β-oxidation in diabetic or animals or specific for mitochondrial FAO to the role of peroxisomal β-oxidation in cholesterol biosynthesis. mechanism by which elevated fatty acids oxidation in diabetes causes an in cholesterol biosynthesis is As fatty acid synthesis is in the liver of the diabetic the in liver cholesterol biosynthesis is not significantly S. Chaikoff I.L. Cholesterol synthesis from acetate in the diabetic liver.J. Biol. Chem. 1952; 198: 895-899Google Scholar, 19Van Bruggen J.T. Yamada P. Hutchens T.T. West E.S. Lipogenesis of the intact alloxan-diabetic rat.J. Biol. Chem. 1954; 209: 635-640Google Scholar). Therefore, the supply of acetyl-CoA a in cholesterol biosynthesis. It is that are of the acetyl-CoA for biosynthesis of is and is from acetate generated by FAO J. Fatty acid oxidation in relation to cholesterol biosynthesis in Scholar, A. between the metabolism of linoleic and for cholesterol synthesis and oxidation to Scholar). As liver level and are in diabetes, the acetyl-CoA that used for cholesterol biosynthesis is not from and from the acetate in FAO as liver FAO is enhanced in the diabetic animals J.D. of hepatic fatty acid oxidation and Rev. Biochem. 49: Scholar). acetate is increased in liver of or diabetic animals G. acetate in relation to lipid 21: Scholar, and of acetate in J. 1974; Scholar), which that the acetate from FAO used for cholesterol biosynthesis. To the of acetate, we noted the well-known that the acetyl-CoA generated in mitochondrial FAO is used for formation or in acid J.D. of hepatic fatty acid oxidation and Rev. Biochem. 49: Scholar). It was reported that mitochondrial FAO not free acetate (16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar, and of acetate in J. 1974; Scholar), as in that to isolated in acetate level that the increased acetate as by FAO was generated It was reported that peroxisomal β-oxidation generated free acetate as the ultimate product (14Leighton F. Bergseth S. Rørtveit T. Christiansen E.N. Bremer J. Free acetate production by rat hepatocytes during peroxisomal fatty acid and dicarboxylic acid oxidation.J. Biol. Chem. 1989; 264: 10347-10350Google Scholar, 15Hovik R. Brodal B. Bartlett K. Osmundsen H. Metabolism of acetyl-CoA by isolated peroxisomal fractions: Formation of acetate and acetoacetyl-CoA.J. Lipid Res. 1991; 32: 993-999Google results that peroxisomal oxidation of erucic acid as as generated free acetate as the as by the of a specific inhibitor for peroxisomal β-oxidation (16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar). Therefore, the increased formation of acetate in the diabetic liver was to the enhanced peroxisomal FAO As peroxisomes are not to acetyl-CoA J.K. Peroxisomal and Scholar), are for from peroxisome to the is to acetyl-CoA to acetate peroxisomal the is to the acetyl-CoA to of acyl-CoA and as in peroxisomal lipid Lipid Res. Scholar). It is that in liver and of the acetyl-CoA generated in peroxisomal β-oxidation is to acetate, in and the acetyl-CoA is to for in and acyl-CoA in for of β-oxidation of Scholar, of and in rat Biol. Chem. Scholar). formation of acetate from acetyl-CoA was to level expression and activity of in rat the the activity of was very low in rat liver, expression and activity in and J.K. Peroxisomal and Scholar). free acetate in liver to of a specific acetyl-CoA in liver T. J. Ishikawa M. K. Yamamoto T.T. a mitochondrial in the oxidation of Biol. Chem. 2001; Scholar). acetate that from peroxisomal β-oxidation of long-chain fatty acids used for biosynthesis of direct measurement of cholesterol synthesis from substrate for peroxisomal β-oxidation suggested that the generated from peroxisomal β-oxidation was preferentially used for biosynthesis of cholesterol (21Hashimoto F. Ishikawa T. Hamada S. Hayashi H. Effect of gemfibrozil on lipid biosynthesis from acetyl-CoA derived from peroxisomal beta-oxidation.Biochem. Pharmacol. 1995; 49: 1213-1221Google Scholar), which was in with It was reported the metabolism of in liver generated acetate and cholesterol synthesis and to elevation in liver and plasma cholesterol level of on lipid Lipid Res. 18: Scholar). demonstrated a mechanism for diabetes-induced in cholesterol biosynthesis and hypercholesterolemia in and in results suggested that induction of peroxisomal β-oxidation enhanced liver cholesterol biosynthesis in the diabetic mice, specific inhibition of peroxisomal β-oxidation cholesterol biosynthesis and plasma cholesterol However, that in the role of peroxisomal β-oxidation in cholesterol biosynthesis was a specific inhibitor for peroxisomal β-oxidation, the of not fully Therefore, to liver peroxisomal β-oxidation in diabetic animals are to results and the mechanism acyl-CoA oxidase-1 generated A. Chen X. M. Chen Y. Zhang X. B. derived from hepatic peroxisomal β-oxidation and Cell. 2020; Scholar). results also potential role of As erucic acid is preferentially by peroxisomal β-oxidation system (16Chen X. Shang L. Deng S. Li P. Chen K. Gao T. Zhang X. Chen Z. Zeng J. Peroxisomal oxidation of erucic acid suppresses mitochondrial fatty acid oxidation by stimulating malonyl-CoA formation in the rat liver.J. Biol. Chem. 2020; 295: 10168-10179Google Scholar), excessive of in diabetic patients might metabolism of very long-chain fatty acid by which cholesterol biosynthesis and and to hypercholesterolemia. erucic acid as is in and P. A. and in Scholar), and the in diabetes are than in in and risk and their in Scholar). Although the between and hypercholesterolemia is not established so far, we that of might the risk of hypercholesterolemia in the diabetic patients and low erucic acid or as the of in which might liver and by reducing the from peroxisomal β-oxidation and reducing cholesterol biosynthesis. acid acid acid, and from acid and erucic acid (C22:1) from of acid by a acyl-CoA and by as J. between the of fatty Biochem. Scholar). used of or from by by and by by used in erucic animals in with free to and under and of and of was induced by of to the of the the level was by a and and the with for the of peroxisomal β-oxidation on cholesterol erucic acid or acid by to diabetic for the of peroxisomal β-oxidation, was to the diabetic of erucic the of induction of peroxisomal β-oxidation on cholesterol the diabetic to or for was to suppress peroxisomal β-oxidation. and diabetic fed the the from the and and in the by the of of and the of mitochondrial was isolated by a to the Osmundsen H. of peroxisomal β-oxidation in rat liver by J. Scholar, J.K. of peroxisomes in peroxisomes are J. Physiol. Physiol. Scholar). mitochondrial was on of a of 2 and for on a with a the for activity with and for to the of the mitochondrial was for to and for to and for and the 2 of as P. P. F. J. and of in hepatocytes isolated from J. Scholar). was by and to than under an of in To cholesterol or to the erucic acid or acid or acetate, and to the for the was by the of activity of was by the in to A. G. S. of cholesterol biosynthesis in of and in liver and Lipid Res. Scholar). and activity was to the by the in to of the in and mitochondrial for cholesterogenesis and Biol. Chem. Scholar). system and activity was by a from activity was by of the with and of the by a and of of metabolism in rat J. Scholar). of and of activity was as A. G. S. of cholesterol biosynthesis in of and in liver and Lipid Res. Scholar). with and by with and by Peroxisomal β-oxidation was in liver by acyl-CoA in the presence of as by of peroxisomal β-oxidation of fatty 1981; Scholar), with as the plasma and liver A. G. A. in type 2 diabetes: of metabolic 2001; Scholar). Free was to and in was into and by to free and was by was by with Y. R. L. X. of and in Scholar). the of was in for the was by and on and density T. and of plasma density in a Lipid Res. 21: Scholar). a was increased to for LDL and VLDL to and and for on Cholesterol was to the was from liver tissues with was with was in a 2 acyl-CoA and and and and peroxisomal and and and expression to the was a on and liver cholesterol by a from and to the from or the from and to the of and in of and metabolic J. Scholar), the of acetyl-CoA and from the and was by the of and of lipid and J. Physiol. 1959; 37: and a and secretion was by the as F. Y. R. H. secretion of very low density by Clin. Scholar). with and and VLDL was isolated from by density liver and secretion from the of the and as acetate, and to the malonyl-CoA was by as of by Scholar). and peroxisomal acetyl-CoA was acetyl-CoA and was activity was as T. J. Ishikawa M. K. Yamamoto T.T. a mitochondrial in the oxidation of Biol. Chem. 2001; Scholar). and peroxisomal was by a by and in and Scholar). was by for peroxisomal acetyl-CoA to the of Y. K. F. of and acetyl-CoA in from and Comparison of the and peroxisomal Biochem. Scholar). isolated peroxisomes with of and the was for and the activity was Peroxisomal was by the of formation of from acetyl-CoA Y. K. F. of and acetyl-CoA in from and Comparison of the and peroxisomal Biochem. Scholar, K. of an acyl-CoA that as a of peroxisomal lipid Biol. Chem. 2002; Scholar). Peroxisomal activity was as with as a substrate Peroxisomal and 1981; Scholar). are as to for the of was with or by was are the that of with the of was by the of P. R. from of and and of in X. Y. H. S. T. and L. S. X. Y. H. and J. Z. X. Y. and S. J. Z. J. Z. J. Z. J. Z. and J. Z. J. Z.

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