Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism
Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead mo...
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| Veröffentlicht in: | Nutrition, metabolism, and cardiovascular diseases metabolism, and cardiovascular diseases, 2021-07, Vol.31 (8), p.2490-2506 |
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| creator | Srivastava, Rai Ajit K. Hurley, Timothy R. Oniciu, Daniela Adeli, Khosrow Newton, Roger S. |
| description | Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.
Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.
In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (−34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (−71% and −64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose–response efficacy.
Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
•Lead molecule identified using De novo lipogenesis.•Central moiety and carbon chain length influenced lipogenesis.•It showed antihyperlipidemic, anti-lipogenic, and liver lipid lowering activities.•Efficacy associated with down-regulation of DGAT2 and inducing LPL, CPT1-a, PLIN1 and PDK4.•Lead molecule can be beneficial in the treatment of fatty liver disease. |
| doi_str_mv | 10.1016/j.numecd.2021.05.024 |
| format | Article |
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Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.
In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (−34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (−71% and −64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose–response efficacy.
Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
•Lead molecule identified using De novo lipogenesis.•Central moiety and carbon chain length influenced lipogenesis.•It showed antihyperlipidemic, anti-lipogenic, and liver lipid lowering activities.•Efficacy associated with down-regulation of DGAT2 and inducing LPL, CPT1-a, PLIN1 and PDK4.•Lead molecule can be beneficial in the treatment of fatty liver disease.</description><identifier>ISSN: 0939-4753</identifier><identifier>EISSN: 1590-3729</identifier><identifier>DOI: 10.1016/j.numecd.2021.05.024</identifier><identifier>PMID: 34172319</identifier><language>eng</language><publisher>Netherlands: Elsevier B.V</publisher><subject>Adipogenesis ; Animals ; ATP citrate Lyase ; Carnitine O-Palmitoyltransferase - metabolism ; Cells, Cultured ; Cholesterol - biosynthesis ; Cholesterol - blood ; Diacyl glycerol acyl transferase ; Dicarboxylic Acids - pharmacology ; Diet, High-Fat ; Disease Models, Animal ; Fatty acid oxidation ; Fatty Acids - biosynthesis ; Fatty Acids - blood ; Fatty Acids - pharmacology ; Hamster ; Hepatocytes - drug effects ; Hepatocytes - enzymology ; Humans ; Hyperlipidemias - blood ; Hyperlipidemias - drug therapy ; Hyperlipidemias - enzymology ; Hypolipidemic Agents - pharmacology ; Lipogenesis ; Lipogenesis - drug effects ; Lipoprotein Lipase - metabolism ; Male ; Mesocricetus ; Perilipin-1 - metabolism ; Perilipin1 ; Protein Kinases - metabolism ; Pyruvate dehydrogenase kinase 4 ; Rabbits ; Rats ; Rats, Wistar</subject><ispartof>Nutrition, metabolism, and cardiovascular diseases, 2021-07, Vol.31 (8), p.2490-2506</ispartof><rights>2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University</rights><rights>Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c362t-1a95cf1b20ec0c8856e764c4e2f8b69621c6ba1e36564a38b8d19a7ce15860a13</citedby><cites>FETCH-LOGICAL-c362t-1a95cf1b20ec0c8856e764c4e2f8b69621c6ba1e36564a38b8d19a7ce15860a13</cites><orcidid>0000-0002-9597-1154</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.numecd.2021.05.024$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34172319$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Srivastava, Rai Ajit K.</creatorcontrib><creatorcontrib>Hurley, Timothy R.</creatorcontrib><creatorcontrib>Oniciu, Daniela</creatorcontrib><creatorcontrib>Adeli, Khosrow</creatorcontrib><creatorcontrib>Newton, Roger S.</creatorcontrib><title>Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism</title><title>Nutrition, metabolism, and cardiovascular diseases</title><addtitle>Nutr Metab Cardiovasc Dis</addtitle><description>Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.
Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.
In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (−34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (−71% and −64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose–response efficacy.
Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
•Lead molecule identified using De novo lipogenesis.•Central moiety and carbon chain length influenced lipogenesis.•It showed antihyperlipidemic, anti-lipogenic, and liver lipid lowering activities.•Efficacy associated with down-regulation of DGAT2 and inducing LPL, CPT1-a, PLIN1 and PDK4.•Lead molecule can be beneficial in the treatment of fatty liver disease.</description><subject>Adipogenesis</subject><subject>Animals</subject><subject>ATP citrate Lyase</subject><subject>Carnitine O-Palmitoyltransferase - metabolism</subject><subject>Cells, Cultured</subject><subject>Cholesterol - biosynthesis</subject><subject>Cholesterol - blood</subject><subject>Diacyl glycerol acyl transferase</subject><subject>Dicarboxylic Acids - pharmacology</subject><subject>Diet, High-Fat</subject><subject>Disease Models, Animal</subject><subject>Fatty acid oxidation</subject><subject>Fatty Acids - biosynthesis</subject><subject>Fatty Acids - blood</subject><subject>Fatty Acids - pharmacology</subject><subject>Hamster</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - enzymology</subject><subject>Humans</subject><subject>Hyperlipidemias - blood</subject><subject>Hyperlipidemias - drug therapy</subject><subject>Hyperlipidemias - enzymology</subject><subject>Hypolipidemic Agents - pharmacology</subject><subject>Lipogenesis</subject><subject>Lipogenesis - drug effects</subject><subject>Lipoprotein Lipase - metabolism</subject><subject>Male</subject><subject>Mesocricetus</subject><subject>Perilipin-1 - metabolism</subject><subject>Perilipin1</subject><subject>Protein Kinases - metabolism</subject><subject>Pyruvate dehydrogenase kinase 4</subject><subject>Rabbits</subject><subject>Rats</subject><subject>Rats, Wistar</subject><issn>0939-4753</issn><issn>1590-3729</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kc1u1DAUhSMEokPhDRDykk1S_8ROwgIJlUKRKrGBteXYN41Hjh3sZNTwWDwIe94GT6cgsWFl2fruOdfnFMVLgiuCibjYV36dQJuKYkoqzCtM60fFjvAOl6yh3eNihzvWlXXD2VnxLKU9xqzBrH5anLGaNJSRblf8em-TDgeIGwoDUl65cLtCOl588OXPHyjcWWO_q94BcsHflnpU1iNjtYp9uNuc1WhQy7Ihpa1JSCVkVuWQ9aPt7RLivdY_hDdIj8FBWiAGh9LmlxGSTW_Q1TBkXX2_iwOVuTDNYc0D2XLcZojOztbAlE1HNR0FEopwAOVS3vcADuVIRuVtmp4XT4b8DC8ezvPi64erL5fX5c3nj58u392Umgm6lER1XA-kpxg01m3LBTSi1jXQoe1FJyjRolcEmOCiVqztW0M61WggvBVYEXZevD7pzjF8y9EtcsqRgnPKQ1iTpLzmvGtpIzJan1AdQ0oRBjlHO6m4SYLlsVS5l6dS5bFUibnMpeaxVw8Oaz-B-Tv0p8UMvD0BkP95sBBl0ha8BmMj6EWaYP_v8BsZFLvT</recordid><startdate>20210722</startdate><enddate>20210722</enddate><creator>Srivastava, Rai Ajit K.</creator><creator>Hurley, Timothy R.</creator><creator>Oniciu, Daniela</creator><creator>Adeli, Khosrow</creator><creator>Newton, Roger S.</creator><general>Elsevier B.V</general><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><orcidid>https://orcid.org/0000-0002-9597-1154</orcidid></search><sort><creationdate>20210722</creationdate><title>Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism</title><author>Srivastava, Rai Ajit K. ; Hurley, Timothy R. ; Oniciu, Daniela ; Adeli, Khosrow ; Newton, Roger S.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c362t-1a95cf1b20ec0c8856e764c4e2f8b69621c6ba1e36564a38b8d19a7ce15860a13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>Adipogenesis</topic><topic>Animals</topic><topic>ATP citrate Lyase</topic><topic>Carnitine O-Palmitoyltransferase - metabolism</topic><topic>Cells, Cultured</topic><topic>Cholesterol - biosynthesis</topic><topic>Cholesterol - blood</topic><topic>Diacyl glycerol acyl transferase</topic><topic>Dicarboxylic Acids - pharmacology</topic><topic>Diet, High-Fat</topic><topic>Disease Models, Animal</topic><topic>Fatty acid oxidation</topic><topic>Fatty Acids - biosynthesis</topic><topic>Fatty Acids - blood</topic><topic>Fatty Acids - pharmacology</topic><topic>Hamster</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - enzymology</topic><topic>Humans</topic><topic>Hyperlipidemias - blood</topic><topic>Hyperlipidemias - drug therapy</topic><topic>Hyperlipidemias - enzymology</topic><topic>Hypolipidemic Agents - pharmacology</topic><topic>Lipogenesis</topic><topic>Lipogenesis - drug effects</topic><topic>Lipoprotein Lipase - metabolism</topic><topic>Male</topic><topic>Mesocricetus</topic><topic>Perilipin-1 - metabolism</topic><topic>Perilipin1</topic><topic>Protein Kinases - metabolism</topic><topic>Pyruvate dehydrogenase kinase 4</topic><topic>Rabbits</topic><topic>Rats</topic><topic>Rats, Wistar</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Srivastava, Rai Ajit K.</creatorcontrib><creatorcontrib>Hurley, Timothy R.</creatorcontrib><creatorcontrib>Oniciu, Daniela</creatorcontrib><creatorcontrib>Adeli, Khosrow</creatorcontrib><creatorcontrib>Newton, Roger S.</creatorcontrib><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>Nutrition, metabolism, and cardiovascular diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Srivastava, Rai Ajit K.</au><au>Hurley, Timothy R.</au><au>Oniciu, Daniela</au><au>Adeli, Khosrow</au><au>Newton, Roger S.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism</atitle><jtitle>Nutrition, metabolism, and cardiovascular diseases</jtitle><addtitle>Nutr Metab Cardiovasc Dis</addtitle><date>2021-07-22</date><risdate>2021</risdate><volume>31</volume><issue>8</issue><spage>2490</spage><epage>2506</epage><pages>2490-2506</pages><issn>0939-4753</issn><eissn>1590-3729</eissn><abstract>Cholesterol and triglycerides are risk factors for developing cardiovascular disease. Therefore, appropriate cells and assays are required to discover and develop dual cholesterol and fatty acid inhibitors. A predictive hyperlipidemic animal model is needed to evaluate mechanism of action of lead molecule for therapeutic indications.
Primary hepatocytes from rat, hamster, rabbit, and humans were compared for suitability to screen compounds by de novo lipogenesis (DNL) using14C-acetate. Hyperlipidemic hamsters were used to evaluate efficacy and mode of action.
In rat hepatocytes DNL assay, both the central moiety and carbon chain length influenced the potency of lipogenesis inhibition. In hyperlipidemic hamsters, ETC-1002 decreased plasma cholesterol and triglycerides by 41% and 49% at the 30 mg/kg dose. Concomitant decreases in non-esterified fatty acids (−34%) and increases in ketone bodies (20%) were associated with induction of hepatic CPT1-α. Reductions in proatherogenic VLDL-C and LDL-C (−71% and −64%) occurred partly through down-regulation of DGAT2 and up-regulation of LPL and PDK4. Activation of PLIN1 and PDK4 dampened adipogenesis and showed inverse correlation with adipose mass. Hepatic concentrations of cholesteryl ester and TG decreased by 67% and 64%, respectively. Body weight decreased with concomitant decreases in epididymal fat. Plasma and liver concentrations of ETC-1002 agreed with the observed dose–response efficacy.
Taken together, ETC-1002 reduced proatherogenic lipoproteins, hepatic lipids and adipose tissues in hyperlipidemic hamsters via induction of LPL, CPT1-α, PDK4, and PLIN1, and downregulation of DGAT2. These characteristics may be useful in the treatment of fatty livers that causes non-alcoholic steatohepatitis.
•Lead molecule identified using De novo lipogenesis.•Central moiety and carbon chain length influenced lipogenesis.•It showed antihyperlipidemic, anti-lipogenic, and liver lipid lowering activities.•Efficacy associated with down-regulation of DGAT2 and inducing LPL, CPT1-a, PLIN1 and PDK4.•Lead molecule can be beneficial in the treatment of fatty liver disease.</abstract><cop>Netherlands</cop><pub>Elsevier B.V</pub><pmid>34172319</pmid><doi>10.1016/j.numecd.2021.05.024</doi><tpages>17</tpages><orcidid>https://orcid.org/0000-0002-9597-1154</orcidid></addata></record> |
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| ispartof | Nutrition, metabolism, and cardiovascular diseases, 2021-07, Vol.31 (8), p.2490-2506 |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete |
| subjects | Adipogenesis Animals ATP citrate Lyase Carnitine O-Palmitoyltransferase - metabolism Cells, Cultured Cholesterol - biosynthesis Cholesterol - blood Diacyl glycerol acyl transferase Dicarboxylic Acids - pharmacology Diet, High-Fat Disease Models, Animal Fatty acid oxidation Fatty Acids - biosynthesis Fatty Acids - blood Fatty Acids - pharmacology Hamster Hepatocytes - drug effects Hepatocytes - enzymology Humans Hyperlipidemias - blood Hyperlipidemias - drug therapy Hyperlipidemias - enzymology Hypolipidemic Agents - pharmacology Lipogenesis Lipogenesis - drug effects Lipoprotein Lipase - metabolism Male Mesocricetus Perilipin-1 - metabolism Perilipin1 Protein Kinases - metabolism Pyruvate dehydrogenase kinase 4 Rabbits Rats Rats, Wistar |
| title | Discovery of analogues of non-β oxidizable long-chain dicarboxylic fatty acids as dual inhibitors of fatty acids and cholesterol synthesis: Efficacy of lead compound in hyperlipidemic hamsters reveals novel mechanism |
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