The level and compartmentalization of phosphatidate phosphatase-1 (lipin-1) control the assembly and secretion of hepatic VLDL

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 (1a and 1b), -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-1a or -1b 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-1a or -1b 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-1a not only abolished nuclear localization but also resulted in impaired association with microsomal membranes. Cells expressing the cytosolic lipin-1a mutant failed to promote

Estrogen-related Receptor γ (ERRγ) Is a Novel Transcriptional Regulator of Phosphatidic Acid Phosphatase, LIPIN1, and Inhibits Hepatic Insulin Signaling

“…These results are consistent with previous findings showing that hepatic LIPIN1 functions as a cytosolic PAP in the regulation of the insulin signaling cascade (4). Recent studies also demonstrated that hepatic LIPIN1 is associated with triglyceride synthesis and secretion, although the results between in vitro and in vivo conditions are somewhat inconsistent (38,39), thereby suggesting that the role of hepatic LIPIN1 appears to involve a cytosolic function related to de novo lipogenesis rather than a nuclear function related to fatty acid oxidation. However, functional differences in hepatic LIPIN1 according to its localization will require further characterization.…”

The Catalytic Efficiency of Lipin 1β Increases by Physically Interacting with the Proto-oncoprotein c-Fos

“…Lipin 1 has been found to translocate to this organelle (10,37). Furthermore, we previously found c-Fos tightly associated with the microsomal fraction (38 -40) and particularly in the same fractions as the ER in a continuous sucrose gradient (41).…”

PPAR control: it's SIRTainly as easy as PGC

“…Overexpression of lipin-1 in cultured hepatocytes leads to increased TAG synthesis (Bou Khalil et al 2009). In the nucleus, lipin-1 acts as a transcriptional coativator linked to FA oxidation (Fig.…”

“…The expression level and compartmentalization of lipin-1 controls the assembly and secretion of hepatic very lowdensity lipoprotein (VLDL; Bou Khalil et al 2009). Overexpression of lipin-1 in cultured hepatocytes leads to increased TAG synthesis (Bou Khalil et al 2009).…”