Alterations in Hepatic Metabolism in fld Mice Reveal a Role for Lipin 1 in Regulating VLDL-Triacylglyceride Secretion

Abstract

Objective-Lipin 1 controls fatty acid metabolism in the nucleus as a transcriptional regulator and in the cytosol as an enzyme catalyzing the penultimate step in phosphoglycerol triacylglyceride (TAG) synthesis. We sought to evaluate the effects of lipin 1 on hepatic TAG synthesis and secretion by gain-of-function and loss-of-function approaches. Methods and Results-Rates of TAG synthesis were not impaired in hepatocytes isolated from adult lipin 1-deficient (fld) mice and were actually increased in 14-day-old fld mice. Additionally, compared to littermate controls, VLDL-TAG secretion rates were markedly increased in fld mice of both ages. Lipin 1 overexpression did not alter TAG synthesis rates but significantly suppressed VLDL-TAG secretion. The lipin 1-mediated suppression of VLDL-TAG secretion was linked to the peptide motif mediating its transcriptional-regulatory effects. However, the expression of candidate genes required for VLDL assembly and secretion was unaltered by lipin 1 activation or deficiency. Finally, the hepatic expression of lipin 1 was diminished in obese insulin-resistant mice, whereas adenoviral-mediated overexpression of lipin 1 in liver of these mice inhibits VLDL-TAG secretion and improves hepatic insulin signaling. Conclusions-Collectively, these studies reveal new and unexpected effects of lipin 1 on hepatic TAG metabolism and obesity-related hepatic insulin resistance.

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.…”

A Conserved Serine Residue Is Required for the Phosphatidate Phosphatase Activity but Not the Transcriptional Coactivator Functions of Lipin-1 and Lipin-2

“…Consistent with its tissue distribution, lipin-1 contributes the majority of PAP activity in adipose tissue and muscle (6,7). Lipin-1 is also expressed in peripheral nerve, where it is required for normal Schwann cell function (14), and in liver, where it plays a role in response to fasting and in hepatic lipoprotein secretion (5,8,15,16). Mutations in human LPIN1 have recently been detected and cause recurrent acute myoglobinuria in childhood (17), indicating a critical role for lipin-1 in human muscle function.…”

Insulin Resistance and Metabolic Derangements in Obese Mice Are Ameliorated by a Novel Peroxisome Proliferator-activated Receptor γ-sparing Thiazolidinedione

“…Plasma insulin was measured using the Linco rat/mouse insulin ELISA kits. For determination of plasma radioactivity of [3- Cell Culture Studies-Primary cultures of mouse hepatocytes were prepared as described (29). For isolation of hepatocytes from DIO mice, mice that had been fed a high fat diet for 12 weeks were used.…”

“…Plasma insulin and adiponectin concentrations were determined by commercially available ELISAs from Crystal Chemical Co. and Linco Research Inc., respectively. Hepatic triglyceride content was determined using a colorimetric assay as previously described (29).…”