Abstract
Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays a predominant role in the resynthesis of triacylglycerol in the small intestine, but its contribution to triacylglycerol synthesis in other tissues, such as the liver, is not clear. In this study, we identified a novel MGAT gene, which is identical with lysophosphatidylglycerol acyltransferase1 (LPGAT1). Mouse LPGAT1 is expressed in a number of tissues and most highly expressed in the liver. Hepatic LPGAT1 expression in diabetic db/db mice is higher than that in the control db/m mouse, which is consistent with increased hepatic MGAT activity in db/db mouse. To elucidate the role of LPGAT1 gene in lipid metabolism in db/db mice, we constructed an adenovirus of short hairpin RNA (shRNA) targeting LPGAT1 to selectively knockdown LPGAT1 gene expression in the liver. Hepatic MGAT activity and LPGAT1 expression in db/db mice infected with LPGAT1 shRNA adenovirus were significantly lower than those in mice infected with the control virus. Notably, treatment with LPGAT1 shRNA adenovirus caused a marked reduction in serum triacylglycerol and cholesterol levels and a significant increase in hepatic cholesterol level. These findings indicate that LPGAT1, a newly identified MGAT enzyme, plays a significant role in hepatic triacylglycerol synthesis and secretion in db/db mice.
Highlights
Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays a predominant role in the resynthesis of triacylglycerol in the small intestine, but its contribution to triacylglycerol synthesis in other tissues, such as the liver, is not clear
In our search for a new MGAT gene involved in TAG synthesis in tissues except the small intestine, we isolated a candidate gene from mouse adipose tissue cDNA library based on acyltransferase motifs
Like other MGAT enzymes, i.e., MGAT1 [10], MGAT2 [11, 13], and MGAT3 [15], lysophosphatidylglycerol acyltransferase1 (LPGAT1) enzyme appeared to prefer the sn-2-monoacylglycerol to rac-1-monoacylglycerol as acyl acceptor (Fig. 2B)
Summary
Acyl-CoA:monoacylglycerol acyltransferase (MGAT) plays a predominant role in the resynthesis of triacylglycerol in the small intestine, but its contribution to triacylglycerol synthesis in other tissues, such as the liver, is not clear. To elucidate the role of LPGAT1 gene in lipid metabolism in db/db mice, we constructed an adenovirus of short hairpin RNA (shRNA) targeting LPGAT1 to selectively knockdown LPGAT1 gene expression in the liver and determined hepatic MGAT activity, LPGAT1 expression, and serum TAG and cholesterol levels in LPGAT1 shRNA adenovirus-treated db/db mice. Enzymatic assay revealed that LPGAT1 shRNA adenovirus-induced decrease in LPGAT1 mRNA levels in db/db mice was associated with reduced hepatic MGAT and LPGAT activities (Fig. 6A, B).
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