Mechanism of anti-lipolytic action of acipimox in isolated rat adipocytes
Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acip...
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| Veröffentlicht in: | Diabetologia 1996, Vol.39 (1), p.45-53 |
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| creator | CHRISTIE, A. W MCCORMICK, D. K. T EMMISON, N KRAEMER, F. B ALBERTI, K. G. M. M YEAMAN, S. J |
| description | Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 mumol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p < 0.05) decreased by 100 mumol/l acipimox, whereas, in the absence of adenosine deaminase, 100 mumol/l acipimox showed no significant (p > 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p < 0.05) reductions occurring at and above, 0.5 mumol/l and 10 mumol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p < 0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p < 0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes. |
| doi_str_mv | 10.1007/BF00400412 |
| format | Article |
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W ; MCCORMICK, D. K. T ; EMMISON, N ; KRAEMER, F. B ; ALBERTI, K. G. M. M ; YEAMAN, S. J</creator><creatorcontrib>CHRISTIE, A. W ; MCCORMICK, D. K. T ; EMMISON, N ; KRAEMER, F. B ; ALBERTI, K. G. M. M ; YEAMAN, S. J</creatorcontrib><description>Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 mumol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p < 0.05) decreased by 100 mumol/l acipimox, whereas, in the absence of adenosine deaminase, 100 mumol/l acipimox showed no significant (p > 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p < 0.05) reductions occurring at and above, 0.5 mumol/l and 10 mumol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p < 0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p < 0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes.</description><identifier>ISSN: 0012-186X</identifier><identifier>EISSN: 1432-0428</identifier><identifier>DOI: 10.1007/BF00400412</identifier><identifier>PMID: 8720602</identifier><language>eng</language><publisher>Berlin: Springer</publisher><subject>Adenosine Deaminase - pharmacology ; Adipocytes - drug effects ; Adipocytes - metabolism ; Animals ; Biological and medical sciences ; Cells, Cultured ; Cyclic AMP - metabolism ; Cyclic AMP-Dependent Protein Kinases - metabolism ; General and cellular metabolism. Vitamins ; Glycerol - metabolism ; Hypolipidemic Agents - pharmacology ; Isoproterenol - pharmacology ; Kinetics ; Lipase - metabolism ; Lipolysis - drug effects ; Male ; Medical sciences ; Pharmacology. 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W</creatorcontrib><creatorcontrib>MCCORMICK, D. K. T</creatorcontrib><creatorcontrib>EMMISON, N</creatorcontrib><creatorcontrib>KRAEMER, F. B</creatorcontrib><creatorcontrib>ALBERTI, K. G. M. M</creatorcontrib><creatorcontrib>YEAMAN, S. J</creatorcontrib><title>Mechanism of anti-lipolytic action of acipimox in isolated rat adipocytes</title><title>Diabetologia</title><addtitle>Diabetologia</addtitle><description>Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 mumol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p < 0.05) decreased by 100 mumol/l acipimox, whereas, in the absence of adenosine deaminase, 100 mumol/l acipimox showed no significant (p > 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p < 0.05) reductions occurring at and above, 0.5 mumol/l and 10 mumol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p < 0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p < 0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes.</description><subject>Adenosine Deaminase - pharmacology</subject><subject>Adipocytes - drug effects</subject><subject>Adipocytes - metabolism</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic AMP-Dependent Protein Kinases - metabolism</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Glycerol - metabolism</subject><subject>Hypolipidemic Agents - pharmacology</subject><subject>Isoproterenol - pharmacology</subject><subject>Kinetics</subject><subject>Lipase - metabolism</subject><subject>Lipolysis - drug effects</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Pharmacology. Drug treatments</subject><subject>Pyrazines - pharmacology</subject><subject>Rats</subject><subject>Rats, Wistar</subject><subject>Subcellular Fractions - metabolism</subject><issn>0012-186X</issn><issn>1432-0428</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkE1Lw0AURQdRaq1u3AtZiAsh-uYjM5OlFquFihsFd-FlMsGRJFMzU7D_3mhD5V14i3O4i0vIOYUbCqBu7xcAYghlB2RKBWcpCKYPyRSAspRq-X5MTkL4BACeCTkhE60YSGBTsny25gM7F9rE1wl20aWNW_tmG51J0ETnuz9g3Nq1_jtxXeKCbzDaKukxJlgNttlGG07JUY1NsGfjn5G3xcPr_CldvTwu53er1HBKY1rTWjNDDWPK5CrjuaY1cszyUmrELNNZrphWSloj89IYQUusJBeohIQKOJ-Rq13vuvdfGxti0bpgbNNgZ_0mFEozyfVwM3K9E03vQ-htXax712K_LSgUv7sV_7sN8sXYuilbW-3VcaiBX44cg8Gm7rEzLuw1lkuhWc5_AJRTc18</recordid><startdate>1996</startdate><enddate>1996</enddate><creator>CHRISTIE, A. W</creator><creator>MCCORMICK, D. K. T</creator><creator>EMMISON, N</creator><creator>KRAEMER, F. B</creator><creator>ALBERTI, K. G. M. 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J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c311t-f1f82c1c227c9753981fa3a59b68aa55859728776ec69bcc41bad634a7460d033</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Adenosine Deaminase - pharmacology</topic><topic>Adipocytes - drug effects</topic><topic>Adipocytes - metabolism</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic AMP-Dependent Protein Kinases - metabolism</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Glycerol - metabolism</topic><topic>Hypolipidemic Agents - pharmacology</topic><topic>Isoproterenol - pharmacology</topic><topic>Kinetics</topic><topic>Lipase - metabolism</topic><topic>Lipolysis - drug effects</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Pharmacology. Drug treatments</topic><topic>Pyrazines - pharmacology</topic><topic>Rats</topic><topic>Rats, Wistar</topic><topic>Subcellular Fractions - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>CHRISTIE, A. W</creatorcontrib><creatorcontrib>MCCORMICK, D. K. T</creatorcontrib><creatorcontrib>EMMISON, N</creatorcontrib><creatorcontrib>KRAEMER, F. B</creatorcontrib><creatorcontrib>ALBERTI, K. G. M. M</creatorcontrib><creatorcontrib>YEAMAN, S. J</creatorcontrib><collection>Pascal-Francis</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><jtitle>Diabetologia</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>CHRISTIE, A. W</au><au>MCCORMICK, D. K. T</au><au>EMMISON, N</au><au>KRAEMER, F. B</au><au>ALBERTI, K. G. M. M</au><au>YEAMAN, S. J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Mechanism of anti-lipolytic action of acipimox in isolated rat adipocytes</atitle><jtitle>Diabetologia</jtitle><addtitle>Diabetologia</addtitle><date>1996</date><risdate>1996</risdate><volume>39</volume><issue>1</issue><spage>45</spage><epage>53</epage><pages>45-53</pages><issn>0012-186X</issn><eissn>1432-0428</eissn><abstract>Acipimox is commonly used to treat hypertriglyceridaemia in non-insulin-dependent diabetic patients, but its precise mechanism of action has yet to be elucidated. We examined the in vitro effects of acipimox on the lipolytic regulatory cascade in epididymal adipocytes isolated from Wistar rats. Acipimox inhibited the lipolytic rate stimulated by adenosine deaminase (1 U/ml) in a concentration-dependent manner, reaching a near-basal value at 10 mumol/l acipimox. Lipolysis activated by sub-maximal levels of isoproterenol in combination with adenosine deaminase (20 mU/ml) was significantly (p < 0.05) decreased by 100 mumol/l acipimox, whereas, in the absence of adenosine deaminase, 100 mumol/l acipimox showed no significant (p > 0.05) inhibition. These findings suggested that the anti-lipolytic mechanism regulated by adenosine may also be regulated by acipimox. Acipimox diminished the intracellular cyclic AMP level produced by 25 nmol/l isoproterenol in the presence of adenosine deaminase (20 mU/ml) in a concentration-dependent manner. At the same level of stimulation, acipimox inhibited the cyclic AMP-dependent protein kinase activity ratio and lipolytic rate over the same concentration range, with significant (p < 0.05) reductions occurring at and above, 0.5 mumol/l and 10 mumol/l acipimox, respectively. Western blotting showed that upon lipolytic stimulation (1 U/ml adenosine deaminase; 100 nmol/l isoproterenol) a threefold increase in the lipolytic rate was accompanied by a significant (p < 0.05) rise in hormone-sensitive lipase associated with the lipid fraction. Acipimox (1 mmol/l) and insulin (1 nmol/l) re-distributed hormone-sensitive lipase back to the cytosol, with a corresponding significant (p < 0.05) loss from the fat cake fraction of adipocyte homogenates. In conclusion, the anti-lipolytic action of acipimox is mediated through suppression of intracellular cyclic AMP levels, with the subsequent decrease in cyclic AMP-dependent protein kinase activity, leading to the reduced association of hormone-sensitive lipase with triacylglycerol substrate in the lipid droplet of adipocytes.</abstract><cop>Berlin</cop><pub>Springer</pub><pmid>8720602</pmid><doi>10.1007/BF00400412</doi><tpages>9</tpages></addata></record> |
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| ispartof | Diabetologia, 1996, Vol.39 (1), p.45-53 |
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| subjects | Adenosine Deaminase - pharmacology Adipocytes - drug effects Adipocytes - metabolism Animals Biological and medical sciences Cells, Cultured Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - metabolism General and cellular metabolism. Vitamins Glycerol - metabolism Hypolipidemic Agents - pharmacology Isoproterenol - pharmacology Kinetics Lipase - metabolism Lipolysis - drug effects Male Medical sciences Pharmacology. Drug treatments Pyrazines - pharmacology Rats Rats, Wistar Subcellular Fractions - metabolism |
| title | Mechanism of anti-lipolytic action of acipimox in isolated rat adipocytes |
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