TY - JOUR
T1 - Critical Role of SREBP-1c Large-VLDL pathway in environment-induced hypertriglyceridemia of apo AV deficiency
AU - Takanashi, Mikio
AU - Kimura, Takeshi
AU - Li, Chengcheng
AU - Tanaka, Masaki
AU - Matsuhashi, Ako
AU - Yoshida, Hiroki
AU - Noda, Akari
AU - Xu, Pengfei
AU - Takase, Satoru
AU - Okazaki, Sachiko
AU - Iizuka, Yoko
AU - Kumagai, Hidetoshi
AU - Ikeda, Yuichi
AU - Gotoda, Takanari
AU - Takahashi, Manabu
AU - Yagyu, Hiroaki
AU - Ishibashi, Shun
AU - Yamauchi, Toshimasa
AU - Kadowaki, Takashi
AU - Liang, Guosheng
AU - Okazaki, Hiroaki
N1 - Funding Information:
This work was supported in part by National Institutes of Health grant HL-20948 (G. Liang); Banyu Life Science Foundation International (H. Okazaki); Health, Labour and Welfare Sciences Research Grant for Research on Rare and Intractable Diseases (H. Okazaki); and Japan Society for the Promotion of Science KAKENHI (Grants-in-Aid for Scientific Research) Grant Numbers JP17K09858 (Grant-in-Aid for Scientific Research (C) to H. Okazaki) and JP23890039 (Grant-in-Aid for Research Activity Start-up to H. Okazaki).
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/3/1
Y1 - 2019/3/1
N2 - Objective - APOA5 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. Approach and Results - Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5-/- mice and delineate the role of SREBP-1c in vivo by generating Apoa5-/-;Srebp-1c-/- mice. The Apoa5-/- 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 Apoa5-/-;Srebp-1c-/- 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. Conclusions - 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.
AB - Objective - APOA5 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. Approach and Results - Here, we reconstitute the environment-induced hypertriglyceridemia phenotype of human APOA5 deficiency in Apoa5-/- mice and delineate the role of SREBP-1c in vivo by generating Apoa5-/-;Srebp-1c-/- mice. The Apoa5-/- 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 Apoa5-/-;Srebp-1c-/- 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. Conclusions - 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.
KW - carbohydrate
KW - diet
KW - hypertriglyceridemia
KW - phenotype
KW - sterol regulatory element-binding protein
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U2 - 10.1161/ATVBAHA.118.311931
DO - 10.1161/ATVBAHA.118.311931
M3 - Article
C2 - 30700132
AN - SCOPUS:85062424330
SN - 1079-5642
VL - 39
SP - 373
EP - 386
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 3
ER -