{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T17:36:48Z","timestamp":1790098608119,"version":"4.0.1"},"reference-count":59,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:sec>\n            <jats:title>Objective\u2014<\/jats:title>\n            <jats:p>\n              <jats:italic>APOA5<\/jats:italic>\n              variants are strongly associated with hypertriglyceridemia, as well as increased risks of cardiovascular disease and acute pancreatitis. Hypertriglyceridemia in apo AV dysfunction often aggravates by environmental factors such as high-carbohydrate diets or aging. To date, the molecular mechanisms by which these environmental factors induce hypertriglyceridemia are poorly defined, leaving the high-risk hypertriglyceridemia condition undertreated. Previously, we reported that LXR (liver X receptor)-SREBP (sterol regulatory element-binding protein)-1c pathway regulates large-VLDL (very low-density lipoprotein) production induced by LXR agonist. However, the pathophysiological relevance of the finding remains unknown.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results\u2014<\/jats:title>\n            <jats:p>\n              Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human\n              <jats:italic>APOA5<\/jats:italic>\n              deficiency in\n              <jats:italic>Apoa5<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice and delineate the role of SREBP-1c in vivo by generating\n              <jats:italic>Apoa5<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>;Srebp-1c<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice. The\n              <jats:italic>Apoa5<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice, which showed moderate hypertriglyceridemia on a chow diet, developed severe hypertriglyceridemia on high-carbohydrate feeding or aging as seen in patients with human apo AV deficiency. These responses were nearly completely abolished in the\n              <jats:italic>Apoa5<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              <jats:italic>;Srebp-1c<\/jats:italic>\n              <jats:sup>\u2212\/\u2212<\/jats:sup>\n              mice. Further mechanistic studies revealed that in response to these environmental factors, SREBP-1c was activated to increase triglyceride synthesis and to permit the incorporation of triglyceride into abnormally large-VLDL particles, which require apo AV for efficient clearance.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions\u2014<\/jats:title>\n            <jats:p>Severe hypertriglyceridemia develops only when genetic factors (apo AV deficiency) and environmental effects (SREBP-1c activation) coexist. We demonstrate that the regulated production of large-sized VLDL particles via SREBP-1c determines plasma triglyceride levels in apo AV deficiency. Our findings explain the long-standing enigma of the late-onset hypertriglyceridemia phenotype of apo AV deficiency and suggest a new approach to treat hypertriglyceridemia by targeting genes that mediate environmental effects.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/atvbaha.118.311931","type":"journal-article","created":{"date-parts":[[2019,1,31]],"date-time":"2019-01-31T10:02:52Z","timestamp":1548928972000},"page":"373-386","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Critical Role of SREBP-1c Large-VLDL Pathway in Environment-Induced Hypertriglyceridemia of Apo AV Deficiency"],"prefix":"10.1161","volume":"39","author":[{"given":"Mikio","family":"Takanashi","sequence":"first","affiliation":[{"name":"From the Department of Diabetes and Metabolic Diseases (Mikio Takanashi, T. Kimura, C.L., M. Tanaka, A.M., H. Yoshida, A.N., P.X., S.T., S.O., Y. Iizuka, T.G., T.Y., T. Kadowaki, H.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Kimura","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes and Metabolic Diseases (Mikio Takanashi, T. Kimura, C.L., M. Tanaka, A.M., H. Yoshida, A.N., P.X., S.T., S.O., Y. Iizuka, T.G., T.Y., T. Kadowaki, H.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chengcheng","family":"Li","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes and Metabolic Diseases (Mikio Takanashi, T. Kimura, C.L., M. Tanaka, A.M., H. Yoshida, A.N., P.X., S.T., S.O., Y. Iizuka, T.G., T.Y., T. Kadowaki, H.O.)"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Tanaka","sequence":"additional","affiliation":[{"name":"From the Department of Diabetes and Metabolic Diseases (Mikio Takanashi, T. Kimura, C.L., M. Tanaka, A.M., H. Yoshida, A.N., P.X., S.T., S.O., Y. Iizuka, T.G., T.Y., T. 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