Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Jenny D Y Chow; Robert T. Lawrence; Marin E. Healy; John E. Dominy; Jason A. Liao; David S. Breen; Frances L. Byrne; Brandon M. Kenwood; Carolin Lackner; Saeko Okutsu; Valeria R. Mas; Stephen H. Caldwell; Jose L. Tomsig; Gregory J. Cooney; Pere B. Puigserver; Nigel Turner; David E. James; Judit Villén; Kyle L. Hoehn

doi:10.1016/j.molmet.2014.02.004

Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Jenny D Y Chow, Robert T. Lawrence, Marin E. Healy, John E. Dominy, Jason A. Liao, David S. Breen, Frances L. Byrne, Brandon M. Kenwood, Carolin Lackner, Saeko Okutsu, Valeria R. Mas, Stephen H. Caldwell, Jose L. Tomsig, Gregory J. Cooney, Pere B. Puigserver, Nigel Turner, David E. James, Judit Villén, Kyle L. Hoehn

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

53 Scopus citations

Abstract

Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.

Original language	English (US)
Pages (from-to)	419-431
Number of pages	13
Journal	Molecular Metabolism
Volume	3
Issue number	4
DOIs	https://doi.org/10.1016/j.molmet.2014.02.004
State	Published - 2014
Externally published	Yes

Keywords

Acetylation
Lipid metabolism
Liver
Steatosis

ASJC Scopus subject areas

Cell Biology
Molecular Biology

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10.1016/j.molmet.2014.02.004

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Chow, J. D. Y., Lawrence, R. T., Healy, M. E., Dominy, J. E., Liao, J. A., Breen, D. S., Byrne, F. L., Kenwood, B. M., Lackner, C., Okutsu, S., Mas, V. R., Caldwell, S. H., Tomsig, J. L., Cooney, G. J., Puigserver, P. B., Turner, N., James, D. E., Villén, J., & Hoehn, K. L. (2014). Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation. Molecular Metabolism, 3(4), 419-431. https://doi.org/10.1016/j.molmet.2014.02.004

Chow, JDY, Lawrence, RT, Healy, ME, Dominy, JE, Liao, JA, Breen, DS, Byrne, FL, Kenwood, BM, Lackner, C, Okutsu, S, Mas, VR, Caldwell, SH, Tomsig, JL, Cooney, GJ, Puigserver, PB, Turner, N, James, DE, Villén, J & Hoehn, KL 2014, 'Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation', Molecular Metabolism, vol. 3, no. 4, pp. 419-431. https://doi.org/10.1016/j.molmet.2014.02.004

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title = "Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation",

abstract = "Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.",

keywords = "Acetylation, Lipid metabolism, Liver, Steatosis",

author = "Chow, {Jenny D Y} and Lawrence, {Robert T.} and Healy, {Marin E.} and Dominy, {John E.} and Liao, {Jason A.} and Breen, {David S.} and Byrne, {Frances L.} and Kenwood, {Brandon M.} and Carolin Lackner and Saeko Okutsu and Mas, {Valeria R.} and Caldwell, {Stephen H.} and Tomsig, {Jose L.} and Cooney, {Gregory J.} and Puigserver, {Pere B.} and Nigel Turner and James, {David E.} and Judit Vill{\'e}n and Hoehn, {Kyle L.}",

year = "2014",

doi = "10.1016/j.molmet.2014.02.004",

language = "English (US)",

volume = "3",

pages = "419--431",

journal = "Molecular Metabolism",

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TY - JOUR

T1 - Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

AU - Chow, Jenny D Y

AU - Lawrence, Robert T.

AU - Healy, Marin E.

AU - Dominy, John E.

AU - Liao, Jason A.

AU - Breen, David S.

AU - Byrne, Frances L.

AU - Kenwood, Brandon M.

AU - Lackner, Carolin

AU - Okutsu, Saeko

AU - Mas, Valeria R.

AU - Caldwell, Stephen H.

AU - Tomsig, Jose L.

AU - Cooney, Gregory J.

AU - Puigserver, Pere B.

AU - Turner, Nigel

AU - James, David E.

AU - Villén, Judit

AU - Hoehn, Kyle L.

PY - 2014

Y1 - 2014

N2 - Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.

AB - Lipid deposition in the liver is associated with metabolic disorders including fatty liver disease, type II diabetes, and hepatocellular cancer. The enzymes acetyl-CoA carboxylase 1 (ACC1) and ACC2 are powerful regulators of hepatic fat storage; therefore, their inhibition is expected to prevent the development of fatty liver. In this study we generated liver-specific ACC1 and ACC2 double knockout (LDKO) mice to determine how the loss of ACC activity affects liver fat metabolism and whole-body physiology. Characterization of LDKO mice revealed unexpected phenotypes of increased hepatic triglyceride and decreased fat oxidation. We also observed that chronic ACC inhibition led to hyper-acetylation of proteins in the extra-mitochondrial space. In sum, these data reveal the existence of a compensatory pathway that protects hepatic fat stores when ACC enzymes are inhibited. Furthermore, we identified an important role for ACC enzymes in the regulation of protein acetylation in the extra-mitochondrial space.

KW - Acetylation

KW - Lipid metabolism

KW - Liver

KW - Steatosis

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JO - Molecular Metabolism

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Genetic inhibition of hepatic acetyl-CoA carboxylase activity increases liver fat and alters global protein acetylation

Abstract

Keywords

ASJC Scopus subject areas

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