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Abstract
Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). PAP-1 activity is encoded by members of the lipin family, including lipin-1 (1alpha and 1beta), -2, and -3. We determined the effect of lipin-1 expression on the assembly and secretion of very low density lipoproteins (VLDL) using McA-RH7777 cells. Expression of lipin-1alpha or -1beta increased the synthesis and secretion of [(3)H]glycerol-labeled lipids under either basal- or oleate-supplemented conditions. In the presence of oleate, the increased TAG secretion was mainly associated with VLDL(1) (S(f) > 100) and VLDL(2) (S(f) 20-100). Expression of lipin-1alpha or -1beta increased secretion efficiency and decreased intracellular degradation of [(35)S]apolipoprotein B-100 (apoB100). Knockdown of lipin-1 using specific short interfering RNA decreased secretion of [(3)H]glycerolipids and [(35)S]apoB100 even though total PAP-1 activity was not decreased, owing to the presence of lipin-2 and -3 in the cells. Deletion of the nuclear localization signal sequences within lipin-1alpha not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1alpha mutant failed to promote [(35)S]apoB100 synthesis or secretion, and showed compromised stimulation in [(3)H]TAG synthesis and secretion. Thus, alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion.
Highlights
Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG)
We have previously shown that TAG synthesis, apoB synthesis and stability, and very low density lipoproteins (VLDL) secretion in primary rat hepatocytes were all increased by the glucocorticoid dexamethasone, whereas insulin counteracted these effects [30,31,32]
Transfection of lipin-1a or -1b plasmids into McA-RH7777 cells resulted in expression of the respective lipin-1 isoforms, which were readily detectable in cell lysate with the anti-V5 antibody (Fig. 1A, left panel)
Summary
Phosphatidate phosphatase-1 (PAP-1) converts phosphatidate to diacylglycerol and plays a key role in the biosynthesis of phospholipids and triacylglycerol (TAG). Alteration in hepatic expression of lipin-1 and its compartmentalization control VLDL assembly/secretion.—Bou Khalil, M., M. Yao. The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL. Formation of hepatic VLDL requires the active synthesis of various lipid constituents (e.g., TAG, cholesterol, cholesteryl esters, and phospholipids) that are assembled together with the large, hydrophobic apolipoprotein B100 (apoB100) [1,2,3], and the assembly process is initiated during or immediately after translation and translocation of apoB100 across the endoplasmic reticulum (ER) membranes [4]. A key enzyme involved in the de novo biosynthesis of TAG and phospholipids is phosphatidate phosphatase-1 (PAP-1), which converts of phosphatidate (PA) to diacylglycerol (DAG) [14, 15]. Increased PAP-1 activity under stress or other aberrant metabolic conditions (such as starvation, diabetes, and post-alcohol consumption) augments the capacity to sequester an increased FA supply to the liver as TAG [14]
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