Human 1-Acylglycerol-3-phosphate O-Acyltransferase isoforms 1 and 2: Biochemical characterization and inability to rescue hepatic steatosis in Agpat2 -/- gene lipodystrophic mice

Anil K. Agarwal, Suja Sukumaran, Víctor A. Cortés, Katie Tunison, Dario Mizrachi, Shireesha Sankella, Robert D. Gerard, Jay D. Horton, Abhimanyu Garg

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Abstract

Loss-of-function mutations in 1-acylglycerol-3-phosphate O-acyltransferase (AGPAT) 2 in humans and mice result in loss of both the white and brown adipose tissues from birth. AGPAT2 generates precursors for the synthesis of glycerophospholipids and triacylglycerols. Loss of adipose tissue, or lipodystrophy, results in hyperinsulinemia, diabetes mellitus, and severe hepatic steatosis. Here, we analyzed biochemical properties of human AGPAT2 and its close homolog, AGPAT1, and we studied their role in liver by transducing their expression via recombinant adenoviruses in Agpat2 -/- mice. The in vitro substrate specificities of AGPAT1 and AGPAT2 are quite similar for lysophosphatidic acid and acyl-CoA. Protein homology modeling of both the AGPATs with glycerol-3-phosphate acyltransferase 1 (GPAT1) revealed that they have similar tertiary protein structure, which is consistent with their similar substrate specificities. When co-expressed, both isoforms co-localize to the endoplasmic reticulum. Despite such similarities, restoring AGPAT activity in liver by overexpression of either AGPAT1 or AGPAT2 in Agpat2 -/- mice failed to ameliorate the hepatic steatosis. From these studies, we suggest that the role of AGPAT1 or AGPAT2 in liver lipogenesis is minimal and that accumulation of liver fat is primarily a consequence of insulin resistance and loss of adipose tissue in Agpat2 -/- mice.

Original languageEnglish (US)
Pages (from-to)37676-37691
Number of pages16
JournalJournal of Biological Chemistry
Volume286
Issue number43
DOIs
StatePublished - Oct 28 2011

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1-Acylglycerol-3-Phosphate O-Acyltransferase
Liver
Protein Isoforms
Genes
Tissue
Glycerophospholipids
Substrate Specificity
Acyltransferases
Acyl Coenzyme A
Adipose Tissue
Substrates
Medical problems
Lipodystrophy
White Adipose Tissue
Lipogenesis
Triglycerides
Proteins
Brown Adipose Tissue
Fats
Hyperinsulinism

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Human 1-Acylglycerol-3-phosphate O-Acyltransferase isoforms 1 and 2 : Biochemical characterization and inability to rescue hepatic steatosis in Agpat2 -/- gene lipodystrophic mice. / Agarwal, Anil K.; Sukumaran, Suja; Cortés, Víctor A.; Tunison, Katie; Mizrachi, Dario; Sankella, Shireesha; Gerard, Robert D.; Horton, Jay D.; Garg, Abhimanyu.

In: Journal of Biological Chemistry, Vol. 286, No. 43, 28.10.2011, p. 37676-37691.

Research output: Contribution to journalArticle

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