Lipidomic Analyses of Female Mice Lacking Hepatic Lipase and Endothelial Lipase Indicate Selective Modulation of Plasma Lipid Species

Abstract

Hepatic lipase (HL) and endothelial lipase (EL) share overlapping and complementary roles in lipoprotein metabolism. The deletion of HL and EL alleles in mice raises plasma total cholesterol and phospholipid concentrations. However, the influence of HL and EL in vivo on individual molecular species from each class of lipid is not known. We hypothesized that the loss of HL, EL or both in vivo may affect select molecular species from each class of lipids. To test this hypothesis, we performed lipidomic analyses on plasma and livers from fasted female wild-type, HL-knockout, EL-knockout, and HL/EL-double knockout mice. Overall, the loss of HL, EL, or both, resulted in minimal changes to hepatic lipids; however, select species of CE were surprisingly reduced in the livers of mice only lacking EL. The loss of HL, EL, or both, reduced the plasma concentrations for select molecular species of triacylglycerol, diacylglycerol, and free fatty acid. On the other hand, the loss of HL, EL, or both, raised the plasma concentrations for select molecular species of phosphatidylcholine, cholesteryl ester, diacylglycerol, sphingomyelin, ceramide, plasmanylcholine, and plasmenylcholine. The increased plasma concentration of select ether phospholipids was evident in the absence of EL, thus suggesting that EL might exhibit a phospholipase A2 activity. Using recombinant EL, we showed that it could hydrolyse the artificial phospholipase A2 substrate 4-nitro-3-(octanoyloxy)benzoic acid. In summary, our study shows for the first time the influence of HL and EL on individual molecular species of several classes of lipids in vivo using lipidomic methods.

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins

“…EL possesses a substrate preference for lipolysis of phospholipids bearing long-chain polyunsaturated FAs in the sn-2 position of HDL-phosphatidylcholine (PC) [ 32 – 34 ]. To further understand the consequences of EL deficiency on impaired postprandial TRL clearance in the HFD-fed state, we performed lipidomics of plasma TG and phospholipids from HFD fed Lipg -/- vs WT mice after fasting and post-OFTT ( Fig 6A–6D , S1 and S2 Tables ).…”

Regulation of hepatic lipase activity by sphingomyelin in plasma lipoproteins

“…However this order of preference may not be applicable to the physiological conditions where the PC species not only occur in varying concentrations, but also compete with each other. In another study [33], the molecular species composition was investigated in HL deficient mice, the rationale being that the species preferred by HL would accumulate in the absence of the enzyme. These studies revealed that 36:4 PC (presumably16:0–20:4 and 18:2–18:2), and 36:2 PC (presumably 18:0–18:2 and 18:1–18:1) accumulated in the HL-deficient mice, suggesting preference of the enzyme for these PC species.…”

Brain Natriuretic Peptide Stimulates Lipid Metabolism through Its Receptor NPR1 and the Glycerolipid Metabolism Pathway in Chicken Adipocytes

“…28,29 LIPG, a member of a family of triglyceride lipase genes, has a key role in the intravascular remodeling of lipoproteins 30 and plasma levels of DG. 31 Taken together, it was hypothesized that BNP binds with NPR1 and upregulates its expression in membranes. Then, it activates AGPAT1 and AGPAT2 and regulates triglyceride hydrolysis.…”

“…AGPAT2 contributes to glycerolipid synthesis and has an important role in the regulation of lipid metabolism . DGKG comprises a family of enzymes that phosphorylate the second messenger diacylglycerol (DG) to phosphatidic acid. , LIPG, a member of a family of triglyceride lipase genes, has a key role in the intravascular remodeling of lipoproteins and plasma levels of DG . Taken together, it was hypothesized that BNP binds with NPR1 and upregulates its expression in membranes.…”