Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine
Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolip...
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Frontiers Media S.A.
2022-08-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.935362/full |
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| author | Piao-Piao Huang Piao-Piao Huang Wen-Qiang Zhu Wen-Qiang Zhu Jing-Mei Xiao Yi-Qi Zhang Rong Li Yang Yang Yang Yang Li Shen Li Shen Fei Luo Fei Luo Fei Luo Wen Dai Wen Dai Wen Dai Ping-An Lian Ping-An Lian Ya-Xin Tang Ya-Xin Tang Juan-Li Ran Xian-Sheng Huang Xian-Sheng Huang |
| author_facet | Piao-Piao Huang Piao-Piao Huang Wen-Qiang Zhu Wen-Qiang Zhu Jing-Mei Xiao Yi-Qi Zhang Rong Li Yang Yang Yang Yang Li Shen Li Shen Fei Luo Fei Luo Fei Luo Wen Dai Wen Dai Wen Dai Ping-An Lian Ping-An Lian Ya-Xin Tang Ya-Xin Tang Juan-Li Ran Xian-Sheng Huang Xian-Sheng Huang |
| author_sort | Piao-Piao Huang |
| collection | DOAJ |
| description | Long-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5. |
| first_indexed | 2024-04-12T06:40:12Z |
| format | Article |
| id | doaj.art-395d520572324f13b710e82125328ec3 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-12T06:40:12Z |
| publishDate | 2022-08-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Pharmacology |
| spelling | doaj.art-395d520572324f13b710e82125328ec32022-12-22T03:43:45ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-08-011310.3389/fphar.2022.935362935362Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapinePiao-Piao Huang0Piao-Piao Huang1Wen-Qiang Zhu2Wen-Qiang Zhu3Jing-Mei Xiao4Yi-Qi Zhang5Rong Li6Yang Yang7Yang Yang8Li Shen9Li Shen10Fei Luo11Fei Luo12Fei Luo13Wen Dai14Wen Dai15Wen Dai16Ping-An Lian17Ping-An Lian18Ya-Xin Tang19Ya-Xin Tang20Juan-Li Ran21Xian-Sheng Huang22Xian-Sheng Huang23Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaNational Clinical Research Center for Mental Disorders, and Department of Psychiatry, The Second Xiangya Hospital of Central South University, Changsha, Hunan, ChinaDepartment of Critical Care Medicine, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, ChinaDepartment of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Molecular Genetics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, United StatesDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Medicine, Columbia University Medical Center, New York, NY, United StatesDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Stomatology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaDepartment of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaResearch Institute of Blood Lipid and Atherosclerosis, The Second Xiangya Hospital, Central South University, Changsha, Hunan, ChinaLong-term use of olanzapine, an antipsychotic drug, induces hypertriglyceridemia, resulting in a higher risk of cardiovascular disease. However, the effects and underlying mechanisms of short-term use of olanzapine on circulating triglyceride levels remain poorly understood. Here, the role of apolipoprotein A5 (apoA5), a regulator of triglyceride metabolism, was investigated in olanzapine-induced hypertriglyceridemia. Our multi-center clinical study recruited 36 schizophrenia patients who received short-term (8 weeks) of olanzapine. Besides, female C57BL/6J mice were treated with olanzapine (3 mg/kg/day versus 6 mg/kg/day) for 6 weeks. We demonstrated that short-term use of olanzapine increased plasma triglyceride and decreased plasma apoA5 levels in the patients and mice, with a negative correlation between the two factors. However, no obesity was observed in the patients and mice. Interestingly, olanzapine increased hepatic apoA5 protein in the mice, without significant changes in hepatic Apoa5 mRNA. Consistently, in vitro studies indicated that olanzapine increased medium triglyceride levels and decreased medium apoA5 levels in a dose-dependent manner in human HepG2 cells and primary mouse hepatocytes. Whereas the olanzapine treatment increased hepatic apoA5 protein in vitro, without effects on hepatic APOA5 mRNA. Of note, olanzapine increased the co-localization between apoA5 protein and accumulated lipid droplets in hepatocytes, as opposed to at the hepatocellular plasma membrane, in mouse liver as demonstrated by fluorescence staining. Therefore, our study indicated that short-term use of olanzapine induced hypertriglyceridemia due to defects of sorting and secretion of hepatic apoA5.https://www.frontiersin.org/articles/10.3389/fphar.2022.935362/fullolanzapinehypertriglyceridemiaapolipoprotein A5sortingsecretion |
| spellingShingle | Piao-Piao Huang Piao-Piao Huang Wen-Qiang Zhu Wen-Qiang Zhu Jing-Mei Xiao Yi-Qi Zhang Rong Li Yang Yang Yang Yang Li Shen Li Shen Fei Luo Fei Luo Fei Luo Wen Dai Wen Dai Wen Dai Ping-An Lian Ping-An Lian Ya-Xin Tang Ya-Xin Tang Juan-Li Ran Xian-Sheng Huang Xian-Sheng Huang Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine Frontiers in Pharmacology olanzapine hypertriglyceridemia apolipoprotein A5 sorting secretion |
| title | Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine |
| title_full | Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine |
| title_fullStr | Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine |
| title_full_unstemmed | Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine |
| title_short | Alterations in sorting and secretion of hepatic apoA5 induce hypertriglyceridemia due to short-term use of olanzapine |
| title_sort | alterations in sorting and secretion of hepatic apoa5 induce hypertriglyceridemia due to short term use of olanzapine |
| topic | olanzapine hypertriglyceridemia apolipoprotein A5 sorting secretion |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.935362/full |
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