TY - JOUR
T1 - NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway with cholesterol uptake and lipogenesis inhibition
AU - Waku, Tsuyoshi
AU - Hagiwara, Toru
AU - Tamura, Natsuko
AU - Atsumi, Yuri
AU - Urano, Yasuomi
AU - Suzuki, Mikiko
AU - Iwami, Takuya
AU - Sato, Katsuya
AU - Yamamoto, Masayuki
AU - Noguchi, Noriko
AU - Kobayashi, Akira
N1 - Funding Information:
We thank Ms. Yue Gao, Mr. Shuto Deguchi, Ms. Mika Matsumoto, Ms. Mika Fukumoto, and Ms. Hiromi Suda for the experimental supports. The pTK-HSV-BP2 plasmid was a gift from Dr. Juro Sakai (The University of Tokyo, Tohoku University). The pCAG-GFP plasmid was a gift from Dr. Saturu Takahashi (University of Tsukuba). This work was supported in part by a grant-in-aid for Scientific Research (C) ( 19K07650 to T.W., 19K07093 to Y.U); grant-in-aid from the Harris Research Institute of Doshisha University (to T.W. and Y.U.); grant-in-aid for Scientific Research (B) ( 16H03265 , 20H04135 to A.K.); grant-in-aid for Challenging Research (Exploratory) ( 19K22826 , 21K19743 to A.K.); and grant-in-aid from the Mitsubishi Foundation (to A.K.).
Funding Information:
We thank Ms. Yue Gao, Mr. Shuto Deguchi, Ms. Mika Matsumoto, Ms. Mika Fukumoto, and Ms. Hiromi Suda for the experimental supports. The pTK-HSV-BP2 plasmid was a gift from Dr. Juro Sakai (The University of Tokyo, Tohoku University). The pCAG-GFP plasmid was a gift from Dr. Saturu Takahashi (University of Tsukuba). This work was supported in part by a grant-in-aid for Scientific Research (C) (19K07650 to T.W. 19K07093 to Y.U); grant-in-aid from the Harris Research Institute of Doshisha University (to T.W. and Y.U.); grant-in-aid for Scientific Research (B) (16H03265, 20H04135 to A.K.); grant-in-aid for Challenging Research (Exploratory) (19K22826, 21K19743 to A.K.); and grant-in-aid from the Mitsubishi Foundation (to A.K.). Conceptualization, T.W. T.H. N.T. Y.A. and Y.U.; validation and investigation, T.W. T.H. N.T. Y.A. T.I. and K.S.; generation of Nrf3-Tg mouse, M.S. M.Y. and A.K.; writing ? original draft and visualization, T.W.; writing ? review & editing, Y.U. N.N. and A.K. The authors declare no competing interests.
Publisher Copyright:
© 2021 The Author(s)
PY - 2021/10/22
Y1 - 2021/10/22
N2 - Lipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of the GGPS1 gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.
AB - Lipids, such as cholesterol and fatty acids, influence cell signaling, energy storage, and membrane formation. Cholesterol is biosynthesized through the mevalonate pathway, and aberrant metabolism causes metabolic diseases. The genetic association of a transcription factor NRF3 with obesity has been suggested, although the molecular mechanisms remain unknown. Here, we show that NRF3 upregulates gene expression in SREBP2-dependent mevalonate pathway. We further reveal that NRF3 overexpression not only reduces lanosterol, a cholesterol precursor, but also induces the expression of the GGPS1 gene encoding an enzyme in the production of GGPP from farnesyl pyrophosphate (FPP), a lanosterol precursor. NRF3 overexpression also enhances cholesterol uptake through RAB5-mediated macropinocytosis process, a bulk and fluid-phase endocytosis pathway. Moreover, we find that GGPP treatment abolishes NRF3 knockdown-mediated increase of neutral lipids. These results reveal the potential roles of NRF3 in the SREBP2-dependent mevalonate pathway for cholesterol uptake through macropinocytosis induction and for lipogenesis inhibition through GGPP production.
KW - Biochemistry
KW - Biological sciences
KW - Molecular biology
UR - http://www.scopus.com/inward/record.url?scp=85119652421&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85119652421&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2021.103180
DO - 10.1016/j.isci.2021.103180
M3 - Article
AN - SCOPUS:85119652421
SN - 2589-0042
VL - 24
JO - iScience
JF - iScience
IS - 10
M1 - 103180
ER -
