Disease relevance of AGPAT2

• Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes [1].
• Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil [2].
• Our study shows that LPAAT-beta is upregulated in ovarian cancer and is more prevalent in poorly differentiated tumours [3].
• Antitumor activity of lysophosphatidic acid acyltransferase-beta inhibitors, a novel class of agents, in multiple myeloma [4].
• CONCLUSION: These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias [5].

Psychiatry related information on AGPAT2

• In our subjects, there did not appear to be any distinguishing clinical characteristics between CGL subjects with AGPAT2 or Gng3lg mutations with the exception of mental retardation in carriers of Gng3lg [6].

High impact information on AGPAT2

• AGPAT2 mRNA is highly expressed in adipose tissue [7].
• We conclude that mutations in AGPAT2 may cause congenital generalized lipodystrophy by inhibiting triacylglycerol synthesis and storage in adipocytes [7].
• AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34 [7].
• The AGPAT2 enzyme catalyzes the acylation of lysophosphatidic acid to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids [7].
• Here, we report a genome screen of nine BSCL families from two geographical clusters (in Lebanon and Norway) [8].

Chemical compound and disease context of AGPAT2

• AGPAT2 is a key enzyme involved in triglyceride and phospholipid biosynthesis and, thus, the discovery of AGPAT2 mutations has heightened interest in the biochemical pathways of triglyceride synthesis and their implications in human physiology and in the pathophysiology of obesity, lipodystrophies and other adipose tissue disorders [9].
• Congenital generalized lipodystrophy or Berardinelli-Seip syndrome, autosomal recessive, is characterized by a complete early lipoatrophy and severe insulin resistance and results, in most cases, from mutations either in the seipin gene of unknown function or AGPAT2 encoding an enzyme involved in triacylglycerol synthesis [10].

Biological context of AGPAT2

• The AGPAT2 catalyses the acylation of the lysophosphatidic acid at the sn-2 position to form phosphatidic acid, a key intermediate in the biosynthesis of triacylglycerol and glycerophospholipids [11].
• The LPAAT-alpha gene is located on chromosome 6p21.3, an area within the class III region of the major hiscompatibility complex (MHC) and the LPAAT-beta gene is mapped to chromosome 9q34 [12].
• Therefore, we genotyped 45 pedigrees with CGL for AGPAT2 and BSCL2 loci and compared the phenotypes in the various subtypes [13].
• In contrast, all 10 BSCL subjects from two families living in the southeastern region were found to a have a homozygous 1036-bp deletion including exons 3 and 4 of AGPAT2 [2].
• Linkage studies in humans have revealed that AGPAT2 contributes to glycerolipid synthesis and plays an important role in regulating lipid metabolism [14].

Anatomical context of AGPAT2

• LPAAT-alpha mRNA is uniformly expressed throughout most tissues with the highest level found in skeletal muscle; whereas LPAAT-beta is differentially expressed, with the highest level found in heart and liver, and negligible level in brain and placenta [12].
• Lysophosphatidic acid acyltransferase beta mRNA was found in all cell lines and ovarian tumours examined [3].
• Our data therefore demonstrate for the first time that inhibiting LPAAT-beta induces cytotoxicity in MM cells in the bone marrow milieu, providing the framework for clinical trials of these novel agents in MM [4].
• The fact that lysoPM could traverse cell membranes permitted additional characterization of LPAAT-beta activity in cells: PC-3 and DU145 cells converted exogenously added lysoPM and (14)C-labeled 18:1 into (14)C-labeled phosphatidylmethanol (PM) [15].
• Given that PA is a cofactor in a number of signaling cascades that are constitutively active in tumors, we evaluated the role of PA produced by LPAAT-beta in Xenopus oocyte meiotic maturation assays and an isoform-specific inhibitor of LPAAT-beta in mammalian cell assays [16].

Associations of AGPAT2 with chemical compounds

• The unexpected finding, that levels of several phospholipid species, including phosphatidic acid (PA), are elevated in TAG-depleted adipocytes with AGPAT2 knockdown, suggests that impaired AGPAT2 activity affects availability of PA for TAG synthesis but not overall PA synthesis nor utilization of PA for phospholipid synthesis [17].
• The enzymatic activities of the wild type AGPAT2 and mutants were determined in cell lysates of overexpressing Chinese hamster ovary cells by measuring the conversion of [(3)H]LPA to [(3)H]PA in the presence of oleoyl-coenzyme A [18].
• LPAAT-beta increases both linoleate and linolenate incorporation into PA, which is also reduced by LSF [19].
• Dexamethasone and immunomodulatory derivatives of thalidomide (IMiDs), but not proteasome inhibitor PS-341, augmented MM cell apoptosis triggered by LPAAT-beta inhibitors [4].
• The data presented here suggest that PA produced by LPAAT-beta plays an important role in signaling pathways critical to tumor cell survival [16].

Other interactions of AGPAT2

• We conclude that CGL patients with Seipin mutations have a more severe lack of body fat, which affects both metabolically active and mechanical adipose tissue, compared with patients with mutations in the AGPAT2 gene [1].

Analytical, diagnostic and therapeutic context of AGPAT2

• We investigated the expression of LPAAT-beta by reverse transcriptase-polymerase chain reaction and immunohistochemistry in 10 ovarian cell lines as well as in a cohort of 106 ovarian tumours and normal ovaries [3].
• Furthermore, LPAAT-beta expression was positively associated with higher tumour grade (P=0.044), higher mitotic index (P<0.0001) and tumour stage (P=0.032) [3].
• Expression of LPAAT-beta was significantly linked to reduced overall survival time (P=0.024) as well as to shorter progression-free survival time (P=0.012) in patients younger than 60 years [3].

References