Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

Caleb C. Lord; Daniel Ferguson; Gwynneth Thomas; Amanda L. Brown; Rebecca C. Schugar; Amy Burrows; Anthony D. Gromovsky; Jenna Betters; Chase Neumann; Jessica Sacks; Stephanie Marshall; Russell Watts; Martina Schweiger; Richard G. Lee; Rosanne M. Crooke; Mark J. Graham; Justin D. Lathia; Takuya F. Sakaguchi; Richard Lehner; Guenter Haemmerle; Rudolf Zechner; J. Mark Brown

doi:10.1016/j.celrep.2016.06.049

Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

Caleb C. Lord, Daniel Ferguson, Gwynneth Thomas, Amanda L. Brown, Rebecca C. Schugar, Amy Burrows, Anthony D. Gromovsky, Jenna Betters, Chase Neumann, Jessica Sacks, Stephanie Marshall, Russell Watts, Martina Schweiger, Richard G. Lee, Rosanne M. Crooke, Mark J. Graham, Justin D. Lathia, Takuya F. Sakaguchi, Richard Lehner, Guenter HaemmerleRudolf Zechner, J. Mark Brown

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

37 Scopus citations

Abstract

Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

Original language	English
Pages (from-to)	939-949
Number of pages	11
Journal	Cell Reports
Volume	16
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2016.06.049
State	Published - Jul 26 2016

Keywords

lipase
neutral lipid storage disease
triacylglycerol

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10.1016/j.celrep.2016.06.049

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Lord, C. C., Ferguson, D., Thomas, G., Brown, A. L., Schugar, R. C., Burrows, A., Gromovsky, A. D., Betters, J., Neumann, C., Sacks, J., Marshall, S., Watts, R., Schweiger, M., Lee, R. G., Crooke, R. M., Graham, M. J., Lathia, J. D., Sakaguchi, T. F., Lehner, R., ... Brown, J. M. (2016). Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation. Cell Reports, 16(4), 939-949. https://doi.org/10.1016/j.celrep.2016.06.049

@article{b0340fdf54294b0ab1033f9c2eac2705,

title = "Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation",

abstract = "Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.",

keywords = "lipase, neutral lipid storage disease, triacylglycerol",

author = "Lord, {Caleb C.} and Daniel Ferguson and Gwynneth Thomas and Brown, {Amanda L.} and Schugar, {Rebecca C.} and Amy Burrows and Gromovsky, {Anthony D.} and Jenna Betters and Chase Neumann and Jessica Sacks and Stephanie Marshall and Russell Watts and Martina Schweiger and Lee, {Richard G.} and Crooke, {Rosanne M.} and Graham, {Mark J.} and Lathia, {Justin D.} and Sakaguchi, {Takuya F.} and Richard Lehner and Guenter Haemmerle and Rudolf Zechner and Brown, {J. Mark}",

note = "Publisher Copyright: {\textcopyright} 2016 The Author(s)",

year = "2016",

month = jul,

day = "26",

doi = "10.1016/j.celrep.2016.06.049",

language = "English",

volume = "16",

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journal = "Cell Reports",

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Lord, CC, Ferguson, D, Thomas, G, Brown, AL, Schugar, RC, Burrows, A, Gromovsky, AD, Betters, J, Neumann, C, Sacks, J, Marshall, S, Watts, R, Schweiger, M, Lee, RG, Crooke, RM, Graham, MJ, Lathia, JD, Sakaguchi, TF, Lehner, R, Haemmerle, G, Zechner, R & Brown, JM 2016, 'Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation', Cell Reports, vol. 16, no. 4, pp. 939-949. https://doi.org/10.1016/j.celrep.2016.06.049

TY - JOUR

T1 - Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

AU - Lord, Caleb C.

AU - Ferguson, Daniel

AU - Thomas, Gwynneth

AU - Brown, Amanda L.

AU - Schugar, Rebecca C.

AU - Burrows, Amy

AU - Gromovsky, Anthony D.

AU - Betters, Jenna

AU - Neumann, Chase

AU - Sacks, Jessica

AU - Marshall, Stephanie

AU - Watts, Russell

AU - Schweiger, Martina

AU - Lee, Richard G.

AU - Crooke, Rosanne M.

AU - Graham, Mark J.

AU - Lathia, Justin D.

AU - Sakaguchi, Takuya F.

AU - Lehner, Richard

AU - Haemmerle, Guenter

AU - Zechner, Rudolf

AU - Brown, J. Mark

PY - 2016/7/26

Y1 - 2016/7/26

N2 - Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

AB - Adipose triglyceride lipase (ATGL) and comparative gene identification 58 (CGI-58) are critical regulators of triacylglycerol (TAG) turnover. CGI-58 is thought to regulate TAG mobilization by stimulating the enzymatic activity of ATGL. However, it is not known whether this coactivation function of CGI-58 occurs in vivo. Moreover, the phenotype of human CGI-58 mutations suggests ATGL-independent functions. Through direct comparison of mice with single or double deficiency of CGI-58 and ATGL, we show here that CGI-58 knockdown causes hepatic steatosis in both the presence and absence of ATGL. CGI-58 also regulates hepatic diacylglycerol (DAG) and inflammation in an ATGL-independent manner. Interestingly, ATGL deficiency, but not CGI-58 deficiency, results in suppression of the hepatic and adipose de novo lipogenic program. Collectively, these findings show that CGI-58 regulates hepatic neutral lipid storage and inflammation in the genetic absence of ATGL, demonstrating that mechanisms driving TAG lipolysis in hepatocytes differ significantly from those in adipocytes.

KW - lipase

KW - neutral lipid storage disease

KW - triacylglycerol

UR - http://www.scopus.com/inward/record.url?scp=84992515784&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.06.049

DO - 10.1016/j.celrep.2016.06.049

M3 - Article

C2 - 27396333

AN - SCOPUS:84992515784

SN - 2639-1856

VL - 16

SP - 939

EP - 949

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

Regulation of Hepatic Triacylglycerol Metabolism by CGI-58 Does Not Require ATGL Co-activation

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Keywords

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