Abstract
Acylglycerophosphate acyltransferase 4 (AGPAT4)/lysophosphatidic acid acyltransferase delta catalyzes the formation of phosphatidic acid (PA), a precursor of triacyl-glycerol (TAG). We investigated the effect of Agpat4 gene ablation on white adipose tissue (WAT) after finding consistent expression across depots. Epididymal WAT mass was 40% larger in male Agpat4-/- mice than wild-type littermates, but unchanged in perirenal, retroperitoneal, and inguinal WAT and subscapular brown adipose tissue. Metabolic changes were identified in epididymal WAT that were not evident in perirenal WAT, which was analyzed for comparison. The total epididymal TAG content doubled, increasing adipocyte cell size without changing markers of differentiation. Enzymes involved in de novo lipogenesis and complex lipid synthesis downstream of phosphatidic acid production were also unchanged. However, total epididymal TAG hydrolase activity was reduced, and there were significant decreases in total ATGL and reduced phosphorylation of hormone-sensitive lipase at the S563 and S660 PKA-activation sites. Analysis of Agpats 1, 2, 3, and 5, as well as Gpats 1, 2, 3, and 4, demonstrated compensatory upregulation in perirenal WAT that did not occur in epididymal WAT. Our findings therefore indicate depot-specific differences in the redundancy of Agpat4 and highlight the molecular and metabolic heterogeneity of individual visceral depots.
Highlights
Acylglycerophosphate acyltransferase 4 (AGPAT4)/ lysophosphatidic acid acyltransferase delta catalyzes the for mation of phosphatidic acid (PA), a precursor of triacyl glycerol (TAG)
Multiple tissues were analyzed for Agpat4 expression in wild-type mice using RT-PCR (Fig. 1A), and Agpat4 expression was analyzed in several adipose depots, including perirenal, epididymal, retroperitoneal, and inguinal white adipose tissue (WAT) depots, as well as the subscapular brown adipose tissue (BAT) depot (Fig. 1B)
In male Agpat4 / mice (absence of Agpat4 transcript demonstrated by RT-PCR in epididymal WAT and perirenal WAT, Fig. 1C), body weights did not differ significantly (Fig. 1D), and no statistically significant differences were seen in weights of perirenal, retroperitoneal, or inguinal WAT or subscapular BAT compared with wild-type littermates (Fig. 1E)
Summary
Acylglycerophosphate acyltransferase 4 (AGPAT4)/ lysophosphatidic acid acyltransferase delta catalyzes the for mation of phosphatidic acid (PA), a precursor of triacyl glycerol (TAG). True AGPAT/LPAATs function in the second committed step of the Kennedy pathway for the de novo biosynthesis of glycerophospholipids and triacylglycerol (TAG) by catalyzing the acyl-CoA-dependent formation of phosphatidic acid (PA) using lysophosphatidic acid (LPA) as the preferred acyl acceptor [3]. Functional characterization of these enzymes has, narrowed the group of true AGPATs/LPAATs that prefer LPA to only 5 of the 11 isoforms (AGPATs 1, 2, 3, 4, and 5), with the rest primarily utilizing a different lysophospholipid acylacceptor, or glycerol-3-phosphate [2].
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