Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S]
Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2020-08-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520434893 |
| _version_ | 1818898486627663872 |
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| author | Yan Q. Chen Thomas G. Pottanat Robert W. Siegel Mariam Ehsani Yue-Wei Qian Eugene Y. Zhen Ajit Regmi William C. Roell Haihong Guo M. Jane Luo Ruth E. Gimeno Ferdinand van't Hooft Robert J. Konrad |
| author_facet | Yan Q. Chen Thomas G. Pottanat Robert W. Siegel Mariam Ehsani Yue-Wei Qian Eugene Y. Zhen Ajit Regmi William C. Roell Haihong Guo M. Jane Luo Ruth E. Gimeno Ferdinand van't Hooft Robert J. Konrad |
| author_sort | Yan Q. Chen |
| collection | DOAJ |
| description | Angiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome. |
| first_indexed | 2024-12-19T19:32:50Z |
| format | Article |
| id | doaj.art-c72ea3f26d074f9c9c33cf92743a0709 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-19T19:32:50Z |
| publishDate | 2020-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-c72ea3f26d074f9c9c33cf92743a07092022-12-21T20:08:33ZengElsevierJournal of Lipid Research0022-22752020-08-0161812031220Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S]Yan Q. Chen0Thomas G. Pottanat1Robert W. Siegel2Mariam Ehsani3Yue-Wei Qian4Eugene Y. Zhen5Ajit Regmi6William C. Roell7Haihong Guo8M. Jane Luo9Ruth E. Gimeno10Ferdinand van't Hooft11Robert J. Konrad12Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INLilly Research Laboratories, Eli Lilly and Company, Indianapolis, INDivision of Cardiovascular Medicine, Department of Medicine Solna, Karolinska Institutet Karolinska University Hospital Solna, Stockholm, SwedenTo whom correspondence should be addressed konrad_robert@lilly.com; Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN; To whom correspondence should be addressed konrad_robert@lilly.comAngiopoietin-like protein (ANGPTL)8 has been implicated in metabolic syndrome and reported to regulate adipose FA uptake through unknown mechanisms. Here, we studied how complex formation of ANGPTL8 with ANGPTL3 or ANGPTL4 varies with feeding to regulate LPL. In human serum, ANGPTL3/8 and ANGPTL4/8 complexes both increased postprandially, correlated negatively with HDL, and correlated positively with all other metabolic syndrome markers. ANGPTL3/8 also correlated positively with LDL-C and blocked LPL-facilitated hepatocyte VLDL-C uptake. LPL-inhibitory activity of ANGPTL3/8 was >100-fold more potent than that of ANGPTL3, and LPL-inhibitory activity of ANGPTL4/8 was >100-fold less potent than that of ANGPTL4. Quantitative analyses of inhibitory activities and competition experiments among the complexes suggested a model in which localized ANGPTL4/8 blocks the LPL-inhibitory activity of both circulating ANGPTL3/8 and localized ANGPTL4, allowing lipid sequestration into fat rather than muscle during the fed state. Supporting this model, insulin increased ANGPTL3/8 secretion from hepatocytes and ANGPTL4/8 secretion from adipocytes. These results suggest that low ANGPTL8 levels during fasting enable ANGPTL4-mediated LPL inhibition in fat tissue to minimize adipose FA uptake. During feeding, increased ANGPTL8 increases ANGPTL3 inhibition of LPL in muscle via circulating ANGPTL3/8, while decreasing ANGPTL4 inhibition of LPL in adipose tissue through localized ANGPTL4/8, thereby increasing FA uptake into adipose tissue. Excessive caloric intake may shift this system toward the latter conditions, possibly predisposing to metabolic syndrome.http://www.sciencedirect.com/science/article/pii/S0022227520434893lipoprotein lipaseadipose tissuemuscletriglyceridesmetabolic syndromeangiopoietin-like protein 3 |
| spellingShingle | Yan Q. Chen Thomas G. Pottanat Robert W. Siegel Mariam Ehsani Yue-Wei Qian Eugene Y. Zhen Ajit Regmi William C. Roell Haihong Guo M. Jane Luo Ruth E. Gimeno Ferdinand van't Hooft Robert J. Konrad Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] Journal of Lipid Research lipoprotein lipase adipose tissue muscle triglycerides metabolic syndrome angiopoietin-like protein 3 |
| title | Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] |
| title_full | Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] |
| title_fullStr | Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] |
| title_full_unstemmed | Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] |
| title_short | Angiopoietin-like protein 8 differentially regulates ANGPTL3 and ANGPTL4 during postprandial partitioning of fatty acids[S] |
| title_sort | angiopoietin like protein 8 differentially regulates angptl3 and angptl4 during postprandial partitioning of fatty acids s |
| topic | lipoprotein lipase adipose tissue muscle triglycerides metabolic syndrome angiopoietin-like protein 3 |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520434893 |
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