Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

Víctor A. Cortés; David E. Curtis; Suja Sukumaran; Xinli Shao; Vinay Parameswara; Shirya Rashid; Amy R. Smith; Jimin Ren; Victoria Esser; Robert E. Hammer; Anil K. Agarwal; Jay D. Horton; Abhimanyu Garg

doi:10.1016/j.cmet.2009.01.002

Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

Víctor A. Cortés, David E. Curtis, Suja Sukumaran, Xinli Shao, Vinay Parameswara, Shirya Rashid, Amy R. Smith, Jimin Ren, Victoria Esser, Robert E. Hammer, Anil K. Agarwal, Jay D. Horton, Abhimanyu Garg

Résultat de recherche: Article › examen par les pairs

197 Citations (Scopus)

Résumé

Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2^-/- mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ∼4-fold in Agpat2^-/- mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2^-/- mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ∼50% in Agpat2^-/- mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2^-/- mice.

Langue d'origine	English
Pages (de-à)	165-176
Nombre de pages	12
Journal	Cell Metabolism
Volume	9
Numéro de publication	2
DOI	https://doi.org/10.1016/j.cmet.2009.01.002
Statut de publication	Published - févr. 4 2009
Publié à l'externe	Oui

Note bibliographique

Funding Information:
We thank Norma Anderson, Scott Clark, Ruth Giselle, Lauren Koob, Daniel Smith, and Judy Sanchez for technical assistance and Beverley Adams-Huet for statistical analysis. This work was supported by the National Institutes of Health grants R01-DK54387, HL20948, PL1 DK081182, and HL092550; the Southwestern Medical Foundation; and the Perot Family Foundation. V.A.C. is supported by a postdoctoral fellowship from Pontificia Universidad Católica de Chile and a Presidential Fellowship from the Government of Chile. D.E.C. was supported by the UT Southwestern Physician Scientist Training Program.

ASJC Scopus Subject Areas

Physiology
Molecular Biology
Cell Biology

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10.1016/j.cmet.2009.01.002

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Cortés, V. A., Curtis, D. E., Sukumaran, S., Shao, X., Parameswara, V., Rashid, S., Smith, A. R., Ren, J., Esser, V., Hammer, R. E., Agarwal, A. K., Horton, J. D., & Garg, A. (2009). Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy. Cell Metabolism, 9(2), 165-176. https://doi.org/10.1016/j.cmet.2009.01.002

Cortés, VA, Curtis, DE, Sukumaran, S, Shao, X, Parameswara, V, Rashid, S, Smith, AR, Ren, J, Esser, V, Hammer, RE, Agarwal, AK, Horton, JD & Garg, A 2009, 'Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy', Cell Metabolism, vol. 9, n° 2, pp. 165-176. https://doi.org/10.1016/j.cmet.2009.01.002

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title = "Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy",

abstract = "Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2-/- mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ∼4-fold in Agpat2-/- mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2-/- mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ∼50% in Agpat2-/- mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2-/- mice.",

author = "Cort{\'e}s, {V{\'i}ctor A.} and Curtis, {David E.} and Suja Sukumaran and Xinli Shao and Vinay Parameswara and Shirya Rashid and Smith, {Amy R.} and Jimin Ren and Victoria Esser and Hammer, {Robert E.} and Agarwal, {Anil K.} and Horton, {Jay D.} and Abhimanyu Garg",

note = "Funding Information: We thank Norma Anderson, Scott Clark, Ruth Giselle, Lauren Koob, Daniel Smith, and Judy Sanchez for technical assistance and Beverley Adams-Huet for statistical analysis. This work was supported by the National Institutes of Health grants R01-DK54387, HL20948, PL1 DK081182, and HL092550; the Southwestern Medical Foundation; and the Perot Family Foundation. V.A.C. is supported by a postdoctoral fellowship from Pontificia Universidad Cat{\'o}lica de Chile and a Presidential Fellowship from the Government of Chile. D.E.C. was supported by the UT Southwestern Physician Scientist Training Program. ",

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AU - Cortés, Víctor A.

AU - Curtis, David E.

AU - Sukumaran, Suja

AU - Shao, Xinli

AU - Parameswara, Vinay

AU - Rashid, Shirya

AU - Smith, Amy R.

AU - Ren, Jimin

AU - Esser, Victoria

AU - Hammer, Robert E.

AU - Agarwal, Anil K.

AU - Horton, Jay D.

AU - Garg, Abhimanyu

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N2 - Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2-/- mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ∼4-fold in Agpat2-/- mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2-/- mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ∼50% in Agpat2-/- mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2-/- mice.

AB - Mutations in 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) cause congenital generalized lipodystrophy. To understand the molecular mechanisms underlying the metabolic complications associated with AGPAT2 deficiency, Agpat2 null mice were generated. Agpat2-/- mice develop severe lipodystrophy affecting both white and brown adipose tissue, extreme insulin resistance, diabetes, and hepatic steatosis. The expression of lipogenic genes and rates of de novo fatty acid biosynthesis were increased ∼4-fold in Agpat2-/- mouse livers. The mRNA and protein levels of monoacylglycerol acyltransferase isoform 1 were markedly increased in the livers of Agpat2-/- mice, suggesting that the alternative monoacylglycerol pathway for triglyceride biosynthesis is activated in the absence of AGPAT2. Feeding a fat-free diet reduced liver triglycerides by ∼50% in Agpat2-/- mice. These observations suggest that both dietary fat and hepatic triglyceride biosynthesis via a monoacylglycerol pathway may contribute to hepatic steatosis in Agpat2-/- mice.

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Molecular Mechanisms of Hepatic Steatosis and Insulin Resistance in the AGPAT2-Deficient Mouse Model of Congenital Generalized Lipodystrophy

Résumé

Note bibliographique

ASJC Scopus Subject Areas

ODD de l’ONU

Accès au document

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