Liver-specific deletion of Agpat5 protects against liquid sucrose-induced hyperinsulinemia and glucose intolerance.

Agpat5 (1-acylglycerol-3-phosphate O-acyltransferase 5) is a broadly expressed lipid regulatory enzyme involved in glycerophospholipid metabolism. Multiple genetic studies in mice and humans have identified that Agpat5 is associated with plasma insulin, cholesterol, and alanine aminotransferase levels. Despite the strong genetic evidence on Agpat5, no study has investigated its liver-specific role in physiology. Here, we conducted a series of metabolic studies under four distinct dietary conditions to assess the impact of liver-specific Agpat5 deletion on plasma insulin levels, glucose tolerance, plasma cholesterol levels, and hepatic steatosis. Liver-specific deletion of Agpat5 did not affect plasma insulin levels, glucose tolerance, plasma cholesterol levels, or hepatic steatosis in mice fed a chow diet, high-fat diet, or Western diet. However, when mice consumed a chow diet combined with liquid sucrose, liver-specific deletion of Agpat5 resulted in significantly decreased plasma insulin levels and improved glucose tolerance without alterations in body weight or fat mass. Using global lipidomics, we identified that Agpat5 specifically modulated levels of phosphatidylglycerol and cardiolipin within the livers of mice consuming liquid sucrose. Overall, our findings indicate a liver-specific role of Agpat5 in contributing to hyperinsulinemia and glucose tolerance in the absence of body weight changes when consuming liquid sucrose.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Brian W. Parks reports financial support was provided by National Heart Lung and Blood Institute. Judith A. Simcox reports financial support was provided by Howard Hughes Medical Institute. Judith A. Simcox reports financial support was provided by Juvenile Diabetes Research Foundation Limited. Judith A. Simcox reports financial support was provided by National Institute of Diabetes and Digestive and Kidney Diseases. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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