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Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation

Glucagon and N,(6)O(2)-dibutyryl cyclic adenosine 3‘,5‘-cyclic monophosphate (Bt(2)cAMP) inhibit fatty acid synthesis from acetate by more than 90% and prevent citrate formation in chick hepatocytes metabolizing glucose. With substrates that enter glycolysis at or below triose-phosphates, e.g., fruc...

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Published in:Journal of lipid research 1979-11, Vol.20 (8), p.974-985
Main Authors: Clarke, S D, Watkins, P A, Lane, M D
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description Glucagon and N,(6)O(2)-dibutyryl cyclic adenosine 3‘,5‘-cyclic monophosphate (Bt(2)cAMP) inhibit fatty acid synthesis from acetate by more than 90% and prevent citrate formation in chick hepatocytes metabolizing glucose. With substrates that enter glycolysis at or below triose-phosphates, e.g., fructose, lactate, or pyruvate, Bt(2)cAMP has no effect on the citrate level and its inhibitory effect on fatty acid synthesis is substantially reversed. Because acetyl-CoA carboxylase requires a tricarboxylic acid activator for activity, it is proposed that regulation of fatty acid synthesis by Bt(2)cAMP is due, in part, to changes in the citrate level. Reduced citrate formation appears to result from a cAMP-induced inhibition of glycolysis. Bt(2)cAMP inhibits (14)CO(2) production from [1-(14)C]-, [6-(14)C]-, and [U-(14)C]glucose and has little effect on (14)CO(2) formation from [1-(14)C]- or [2-(14)C]pyruvate or from [1-(14)C]fructose. [(14)C]Lactate formation from glucose is depressed 50% by Bt(2)cAMP. In the presence of an inhibitor of mitochondrial pyruvate transport lactate accumulation is enhanced, but continues to be lowered 50% by Bt(2)cAMP. The activity of phosphofructokinase is greatly decreased in Bt(2)cAMP-treated cells while the activities of pyruvate kinase and acetyl-CoA carboxylase are unaffected. It appears that decreased glycolytic flux and decreased citrate formation result from depressed phosphofructokinase activity. Fatty acid synthesis from [(14)C]acetate is partially inhibited by Bt(2)cAMP in the presence of fructose, lactate, and pyruvate despite a high citrate level. Incorporation of [(14)C]fructose, [(14)C]pyruvate, or [(14)C]lactate into fatty acids is similarly depressed by Bt(2)cAMP. Synthesis of cholesterol from [(14)C]acetate or [2-(14)C]pyruvate is unaffected by Bt(2)cAMP. These results implicate a second site of inhibition of fatty acid synthesis by Bt(2)cAMP that involves the utilization, but not the production, of cytoplasmic acetyl-CoA.-Clarke, S. D., P. A. Watkins, and M. D. Lane. Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation.
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With substrates that enter glycolysis at or below triose-phosphates, e.g., fructose, lactate, or pyruvate, Bt(2)cAMP has no effect on the citrate level and its inhibitory effect on fatty acid synthesis is substantially reversed. Because acetyl-CoA carboxylase requires a tricarboxylic acid activator for activity, it is proposed that regulation of fatty acid synthesis by Bt(2)cAMP is due, in part, to changes in the citrate level. Reduced citrate formation appears to result from a cAMP-induced inhibition of glycolysis. Bt(2)cAMP inhibits (14)CO(2) production from [1-(14)C]-, [6-(14)C]-, and [U-(14)C]glucose and has little effect on (14)CO(2) formation from [1-(14)C]- or [2-(14)C]pyruvate or from [1-(14)C]fructose. [(14)C]Lactate formation from glucose is depressed 50% by Bt(2)cAMP. In the presence of an inhibitor of mitochondrial pyruvate transport lactate accumulation is enhanced, but continues to be lowered 50% by Bt(2)cAMP. The activity of phosphofructokinase is greatly decreased in Bt(2)cAMP-treated cells while the activities of pyruvate kinase and acetyl-CoA carboxylase are unaffected. It appears that decreased glycolytic flux and decreased citrate formation result from depressed phosphofructokinase activity. Fatty acid synthesis from [(14)C]acetate is partially inhibited by Bt(2)cAMP in the presence of fructose, lactate, and pyruvate despite a high citrate level. Incorporation of [(14)C]fructose, [(14)C]pyruvate, or [(14)C]lactate into fatty acids is similarly depressed by Bt(2)cAMP. Synthesis of cholesterol from [(14)C]acetate or [2-(14)C]pyruvate is unaffected by Bt(2)cAMP. These results implicate a second site of inhibition of fatty acid synthesis by Bt(2)cAMP that involves the utilization, but not the production, of cytoplasmic acetyl-CoA.-Clarke, S. D., P. A. Watkins, and M. D. Lane. 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The activity of phosphofructokinase is greatly decreased in Bt(2)cAMP-treated cells while the activities of pyruvate kinase and acetyl-CoA carboxylase are unaffected. It appears that decreased glycolytic flux and decreased citrate formation result from depressed phosphofructokinase activity. Fatty acid synthesis from [(14)C]acetate is partially inhibited by Bt(2)cAMP in the presence of fructose, lactate, and pyruvate despite a high citrate level. Incorporation of [(14)C]fructose, [(14)C]pyruvate, or [(14)C]lactate into fatty acids is similarly depressed by Bt(2)cAMP. Synthesis of cholesterol from [(14)C]acetate or [2-(14)C]pyruvate is unaffected by Bt(2)cAMP. These results implicate a second site of inhibition of fatty acid synthesis by Bt(2)cAMP that involves the utilization, but not the production, of cytoplasmic acetyl-CoA.-Clarke, S. D., P. A. Watkins, and M. D. Lane. Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation.</description><subject>Animals</subject><subject>Bucladesine - pharmacology</subject><subject>Chickens</subject><subject>Cholesterol - biosynthesis</subject><subject>Citrates - metabolism</subject><subject>Cyclic AMP - physiology</subject><subject>Fatty Acids - biosynthesis</subject><subject>Female</subject><subject>Fructose - metabolism</subject><subject>Glucagon - pharmacology</subject><subject>Glucose - metabolism</subject><subject>Glycolysis - drug effects</subject><subject>Lactates - metabolism</subject><subject>Liver - drug effects</subject><subject>Liver - metabolism</subject><subject>Male</subject><subject>Phosphofructokinase-1 - metabolism</subject><subject>Pyruvate Kinase - metabolism</subject><issn>0022-2275</issn><issn>1539-7262</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1979</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNqFUcuO1DAQtBCvYeEPQPIJwSFgO4mdcEGjFY-VFoEEnC27YzO9ZOLB9qyUA_-OM1nNFV8sV3VXu6sIecHZG864fPudMSEqIVT7SrDXdV9O1d4jG97WfaWEFPfJ5lzymDxJ6YYx3jSSPyIPRc2E7Dbk7xaO2VEIU45hpMFTb3KeqQEcaJqnvHMJE7UzhRlGBLr98o3iRAtOYYfwm4546yIFN47v6CGkhHZ0NGERLWI47dBixjAtL8AcTSF8iHuzgE_JA2_G5J7d3Rfk58cPPy4_V9dfP11dbq8raHqVK9UZ2whgNW89SAedNeX3tem5sdABc7xTbDBSlq1tPTRMeCs6qRxXBoT39QW5WnWHYG70IeLexFkHg_oEhPhLm5gRRqetlMDNwGXrfSNUY5Q1nesH67uWd40oWi9XrUMMf44uZb3HtKxvJheOSaumX1yXpbBdCyEWW6Lz58Gc6SVBfUpQL_FowfQpQd2Wvud3A45274Zz1xpZod-vtCuG3aKLOgG6CdyA0UEuG-F_BvwDr1Kr3w</recordid><startdate>197911</startdate><enddate>197911</enddate><creator>Clarke, S D</creator><creator>Watkins, P A</creator><creator>Lane, M D</creator><general>Elsevier Inc</general><general>Elsevier</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>DOA</scope></search><sort><creationdate>197911</creationdate><title>Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation</title><author>Clarke, S D ; Watkins, P A ; Lane, M D</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c497t-78ab42c0315fc6ec8ba0263a91abc8c0e1870da66726b3d402fb2867e17ac2ff3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1979</creationdate><topic>Animals</topic><topic>Bucladesine - pharmacology</topic><topic>Chickens</topic><topic>Cholesterol - biosynthesis</topic><topic>Citrates - metabolism</topic><topic>Cyclic AMP - physiology</topic><topic>Fatty Acids - biosynthesis</topic><topic>Female</topic><topic>Fructose - metabolism</topic><topic>Glucagon - pharmacology</topic><topic>Glucose - metabolism</topic><topic>Glycolysis - drug effects</topic><topic>Lactates - metabolism</topic><topic>Liver - drug effects</topic><topic>Liver - metabolism</topic><topic>Male</topic><topic>Phosphofructokinase-1 - metabolism</topic><topic>Pyruvate Kinase - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Clarke, S D</creatorcontrib><creatorcontrib>Watkins, P A</creatorcontrib><creatorcontrib>Lane, M D</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>Journal of lipid research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Clarke, S D</au><au>Watkins, P A</au><au>Lane, M D</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation</atitle><jtitle>Journal of lipid research</jtitle><addtitle>J Lipid Res</addtitle><date>1979-11</date><risdate>1979</risdate><volume>20</volume><issue>8</issue><spage>974</spage><epage>985</epage><pages>974-985</pages><issn>0022-2275</issn><eissn>1539-7262</eissn><abstract>Glucagon and N,(6)O(2)-dibutyryl cyclic adenosine 3‘,5‘-cyclic monophosphate (Bt(2)cAMP) inhibit fatty acid synthesis from acetate by more than 90% and prevent citrate formation in chick hepatocytes metabolizing glucose. With substrates that enter glycolysis at or below triose-phosphates, e.g., fructose, lactate, or pyruvate, Bt(2)cAMP has no effect on the citrate level and its inhibitory effect on fatty acid synthesis is substantially reversed. Because acetyl-CoA carboxylase requires a tricarboxylic acid activator for activity, it is proposed that regulation of fatty acid synthesis by Bt(2)cAMP is due, in part, to changes in the citrate level. Reduced citrate formation appears to result from a cAMP-induced inhibition of glycolysis. Bt(2)cAMP inhibits (14)CO(2) production from [1-(14)C]-, [6-(14)C]-, and [U-(14)C]glucose and has little effect on (14)CO(2) formation from [1-(14)C]- or [2-(14)C]pyruvate or from [1-(14)C]fructose. [(14)C]Lactate formation from glucose is depressed 50% by Bt(2)cAMP. In the presence of an inhibitor of mitochondrial pyruvate transport lactate accumulation is enhanced, but continues to be lowered 50% by Bt(2)cAMP. The activity of phosphofructokinase is greatly decreased in Bt(2)cAMP-treated cells while the activities of pyruvate kinase and acetyl-CoA carboxylase are unaffected. It appears that decreased glycolytic flux and decreased citrate formation result from depressed phosphofructokinase activity. Fatty acid synthesis from [(14)C]acetate is partially inhibited by Bt(2)cAMP in the presence of fructose, lactate, and pyruvate despite a high citrate level. Incorporation of [(14)C]fructose, [(14)C]pyruvate, or [(14)C]lactate into fatty acids is similarly depressed by Bt(2)cAMP. Synthesis of cholesterol from [(14)C]acetate or [2-(14)C]pyruvate is unaffected by Bt(2)cAMP. These results implicate a second site of inhibition of fatty acid synthesis by Bt(2)cAMP that involves the utilization, but not the production, of cytoplasmic acetyl-CoA.-Clarke, S. D., P. A. Watkins, and M. D. Lane. 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subjects Animals
Bucladesine - pharmacology
Chickens
Cholesterol - biosynthesis
Citrates - metabolism
Cyclic AMP - physiology
Fatty Acids - biosynthesis
Female
Fructose - metabolism
Glucagon - pharmacology
Glucose - metabolism
Glycolysis - drug effects
Lactates - metabolism
Liver - drug effects
Liver - metabolism
Male
Phosphofructokinase-1 - metabolism
Pyruvate Kinase - metabolism
title Acute control of fatty acid synthesis by cyclic AMP in the chick liver cell: possible site of inhibition of citrate formation
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