Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis

Won Mook Choi; Hee Hoon Kim; Myung Ho Kim; Resat Cinar; Hyon Seung Yi; Hyuk Soo Eun; Seok Hwan Kim; Young Jae Choi; Young Sun Lee; So Yeon Kim; Wonhyo Seo; Jun Hee Lee; Young Ri Shim; Ye Eun Kim; Keungmo Yang; Tom Ryu; Jung Hwan Hwang; Chul Ho Lee; Hueng Sik Choi; Bin Gao; Won Kim; Sang Kyum Kim; George Kunos; Won Il Jeong

doi:10.1016/j.cmet.2019.08.001

Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis

Won Mook Choi, Hee Hoon Kim, Myung Ho Kim, Resat Cinar, Hyon Seung Yi, Hyuk Soo Eun, Seok Hwan Kim, Young Jae Choi, Young Sun Lee, So Yeon Kim, Wonhyo Seo, Jun Hee Lee, Young Ri Shim, Ye Eun Kim, Keungmo Yang, Tom Ryu, Jung Hwan Hwang, Chul Ho Lee, Hueng Sik Choi, Bin GaoWon Kim, Sang Kyum Kim, George Kunos, Won Il Jeong

* New professors

Research output: Contribution to journal › Article › peer-review

57 Citations (Scopus)

Abstract

Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated reactive oxygen species (ROS) production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG, which, in turn, activates CB₁R on neighboring hepatocytes to induce de novo lipogenesis.

Original language	English
Pages (from-to)	877-889.e7
Journal	Cell Metabolism
Volume	30
Issue number	5
DOIs	https://doi.org/10.1016/j.cmet.2019.08.001
Publication status	Published - 2019 Nov 5

Bibliographical note

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MEST) (2018R1A2A1A05077608), Korea Mouse Phenotyping Project (2014M3A9D5A01073556), the Intelligent Synthetic Biology Center of Global Frontier Project (2011-0031955), and the Global Ph.D. Fellowship program (NRF-2015H1A2A1033124) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. W.M.C. H.H.K. M.H.K. H.S.Y. Y.S.L. S.Y.K. J.H.L. Y.R.S. K.Y. T.R. and W.I.J. contributed to the design and performance of animal experiments and analysis of data. W.M.C. H.H.K. and Y.E.K. constructed the AAV2/8-Slc7a11-shRNA viral construction. W.M.C. H.S.E. S.H.K. J.H.L. and W.K. contributed to the isolation of human hepatic cells from patients and analyzed the data. Y.J.C. and S.K.K. performed and analyzed sulfur-containing metabolite measurements. J.H.H. C.H.L. and H.S.C. contributed to the generation of chimeric mice. R.C. and W.S. performed measurements of endocannabinoids. B.G. G.K. and W.I.J. wrote the manuscript and provided important advice for experiments. The authors declare no competing interests.

Funding Information:
This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government ( MEST ) ( 2018R1A2A1A05077608 ), Korea Mouse Phenotyping Project ( 2014M3A9D5A01073556 ), the Intelligent Synthetic Biology Center of Global Frontier Project ( 2011-0031955 ), and the Global Ph.D. Fellowship program (NRF- 2015H1A2A1033124 ) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism , Bethesda, MD, USA.

Publisher Copyright:
© 2019 Elsevier Inc.

Keywords

2-arachidonoylglycerol
Nrf2
alcoholic liver disease
cannabinoid receptor
metabotrophic glutamate receptor 5
transsulfuration pathway
xCT

ASJC Scopus subject areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2019.08.001

Cite this

Choi, W. M., Kim, H. H., Kim, M. H., Cinar, R., Yi, H. S., Eun, H. S., Kim, S. H., Choi, Y. J., Lee, Y. S., Kim, S. Y., Seo, W., Lee, J. H., Shim, Y. R., Kim, Y. E., Yang, K., Ryu, T., Hwang, J. H., Lee, C. H., Choi, H. S., ... Jeong, W. I. (2019). Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis. Cell Metabolism, 30(5), 877-889.e7. https://doi.org/10.1016/j.cmet.2019.08.001

Choi, WM, Kim, HH, Kim, MH, Cinar, R, Yi, HS, Eun, HS, Kim, SH, Choi, YJ, Lee, YS, Kim, SY, Seo, W, Lee, JH, Shim, YR, Kim, YE, Yang, K, Ryu, T, Hwang, JH, Lee, CH, Choi, HS, Gao, B, Kim, W, Kim, SK, Kunos, G & Jeong, WI 2019, 'Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis', Cell Metabolism, vol. 30, no. 5, pp. 877-889.e7. https://doi.org/10.1016/j.cmet.2019.08.001

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title = "Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis",

abstract = "Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated reactive oxygen species (ROS) production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG, which, in turn, activates CB1R on neighboring hepatocytes to induce de novo lipogenesis.",

keywords = "2-arachidonoylglycerol, Nrf2, alcoholic liver disease, cannabinoid receptor, metabotrophic glutamate receptor 5, transsulfuration pathway, xCT",

author = "Choi, {Won Mook} and Kim, {Hee Hoon} and Kim, {Myung Ho} and Resat Cinar and Yi, {Hyon Seung} and Eun, {Hyuk Soo} and Kim, {Seok Hwan} and Choi, {Young Jae} and Lee, {Young Sun} and Kim, {So Yeon} and Wonhyo Seo and Lee, {Jun Hee} and Shim, {Young Ri} and Kim, {Ye Eun} and Keungmo Yang and Tom Ryu and Hwang, {Jung Hwan} and Lee, {Chul Ho} and Choi, {Hueng Sik} and Bin Gao and Won Kim and Kim, {Sang Kyum} and George Kunos and Jeong, {Won Il}",

note = "Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MEST) (2018R1A2A1A05077608), Korea Mouse Phenotyping Project (2014M3A9D5A01073556), the Intelligent Synthetic Biology Center of Global Frontier Project (2011-0031955), and the Global Ph.D. Fellowship program (NRF-2015H1A2A1033124) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. W.M.C. H.H.K. M.H.K. H.S.Y. Y.S.L. S.Y.K. J.H.L. Y.R.S. K.Y. T.R. and W.I.J. contributed to the design and performance of animal experiments and analysis of data. W.M.C. H.H.K. and Y.E.K. constructed the AAV2/8-Slc7a11-shRNA viral construction. W.M.C. H.S.E. S.H.K. J.H.L. and W.K. contributed to the isolation of human hepatic cells from patients and analyzed the data. Y.J.C. and S.K.K. performed and analyzed sulfur-containing metabolite measurements. J.H.H. C.H.L. and H.S.C. contributed to the generation of chimeric mice. R.C. and W.S. performed measurements of endocannabinoids. B.G. G.K. and W.I.J. wrote the manuscript and provided important advice for experiments. The authors declare no competing interests. Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government ( MEST ) ( 2018R1A2A1A05077608 ), Korea Mouse Phenotyping Project ( 2014M3A9D5A01073556 ), the Intelligent Synthetic Biology Center of Global Frontier Project ( 2011-0031955 ), and the Global Ph.D. Fellowship program (NRF- 2015H1A2A1033124 ) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism , Bethesda, MD, USA. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",

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T1 - Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis

AU - Choi, Won Mook

AU - Kim, Hee Hoon

AU - Kim, Myung Ho

AU - Cinar, Resat

AU - Yi, Hyon Seung

AU - Eun, Hyuk Soo

AU - Kim, Seok Hwan

AU - Choi, Young Jae

AU - Lee, Young Sun

AU - Kim, So Yeon

AU - Seo, Wonhyo

AU - Lee, Jun Hee

AU - Shim, Young Ri

AU - Kim, Ye Eun

AU - Yang, Keungmo

AU - Ryu, Tom

AU - Hwang, Jung Hwan

AU - Lee, Chul Ho

AU - Choi, Hueng Sik

AU - Gao, Bin

AU - Kim, Won

AU - Kim, Sang Kyum

AU - Kunos, George

AU - Jeong, Won Il

N1 - Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government (MEST) (2018R1A2A1A05077608), Korea Mouse Phenotyping Project (2014M3A9D5A01073556), the Intelligent Synthetic Biology Center of Global Frontier Project (2011-0031955), and the Global Ph.D. Fellowship program (NRF-2015H1A2A1033124) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, USA. W.M.C. H.H.K. M.H.K. H.S.Y. Y.S.L. S.Y.K. J.H.L. Y.R.S. K.Y. T.R. and W.I.J. contributed to the design and performance of animal experiments and analysis of data. W.M.C. H.H.K. and Y.E.K. constructed the AAV2/8-Slc7a11-shRNA viral construction. W.M.C. H.S.E. S.H.K. J.H.L. and W.K. contributed to the isolation of human hepatic cells from patients and analyzed the data. Y.J.C. and S.K.K. performed and analyzed sulfur-containing metabolite measurements. J.H.H. C.H.L. and H.S.C. contributed to the generation of chimeric mice. R.C. and W.S. performed measurements of endocannabinoids. B.G. G.K. and W.I.J. wrote the manuscript and provided important advice for experiments. The authors declare no competing interests. Funding Information: This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korea government ( MEST ) ( 2018R1A2A1A05077608 ), Korea Mouse Phenotyping Project ( 2014M3A9D5A01073556 ), the Intelligent Synthetic Biology Center of Global Frontier Project ( 2011-0031955 ), and the Global Ph.D. Fellowship program (NRF- 2015H1A2A1033124 ) through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and future Planning and by intramural research funds of the National Institute on Alcohol Abuse and Alcoholism , Bethesda, MD, USA. Publisher Copyright: © 2019 Elsevier Inc.

PY - 2019/11/5

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N2 - Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated reactive oxygen species (ROS) production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG, which, in turn, activates CB1R on neighboring hepatocytes to induce de novo lipogenesis.

AB - Choi et al. show that chronic alcohol consumption induces CYP2E1-mediated reactive oxygen species (ROS) production by hepatocytes, which is compensated by GSH generation through xCT-mediated uptake of cystine. The parallel release of glutamate stimulates mGluR5 on hepatic stellate cells (HSCs) to produce 2-AG, which, in turn, activates CB1R on neighboring hepatocytes to induce de novo lipogenesis.

KW - 2-arachidonoylglycerol

KW - Nrf2

KW - alcoholic liver disease

KW - cannabinoid receptor

KW - metabotrophic glutamate receptor 5

KW - transsulfuration pathway

KW - xCT

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AN - SCOPUS:85074145373

SN - 1550-4131

VL - 30

SP - 877-889.e7

JO - Cell Metabolism

JF - Cell Metabolism

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ER -

Glutamate Signaling in Hepatic Stellate Cells Drives Alcoholic Steatosis

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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