Phosphatase and tensin homolog (PTEN) regulates hepatic lipogenesis, microsomal triglyceride transfer protein, and the secretion of apolipoprotein B-containing lipoproteins

Abstract

HepaticapolipoproteinB(apoB)lipoproteinproductionismetabolicallyregulatedviathephosphoinositide 3-kinase cascade; however, the role of the key negative regulator of this pathway, the tumor suppressor phosphatase with tensin homology (PTEN), is unknown. Here, we demonstrate that hepatic protein levels of apoB100 and microsomal triglyceride transfer protein (MTP) are significantly down-regulated (73% and 36%, respectively) in the liver of PTEN liver-specific knockout (KO) mice, and this is accompanied by increased triglyceride (TG) accumulation and lipogenic gene expression, and reduced hepatic apoB secretion in freshly isolated hepatocytes. MTP protein mass and lipid transfer activity were also significantly reduced in liver of PTEN KO mice. Overexpression of the dominant negative mutant PTEN C/S124 (adenovirus expressing PTEN C/S mutant [AdPTENC/S]) possessing constitutive phospoinositide 3-kinase activity in HepG2 cells led to significant reductions in both secreted apoB100 and cellular MTP mass (76% and 34%, respectively), and increased messenger RNA (mRNA) levels of sterol regulatory element binding protein 1c (SREBP-1c), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). Reduced apoB100 secretion induced by AdPTENC/S was associated with increased degradation of newly-synthesized cellular apoB100, in a lactacystin-sensitive manner, suggesting enhanced proteasomal degradation. AdPTENC/S also reduced apoB-lipoprotein production in McA-RH7777 and primary hamster hepatocytes. Our findings suggest a link between PTEN expression and hepatic production of apoB-containing lipoproteins. We postulate that perturbations in PTEN not only may influence hepatic insulin signaling and hepatic lipogenesis, but also may alter hepatic apoB-lipoprotein production and the MTP stability. On loss of PTEN activity, increased lipid substrate availability in the face of reduced hepatic lipoprotein production capacity can rapidly lead to hepatosteatosis and fatty liver.

Hepatic PTEN deficiency improves muscle insulin sensitivity and decreases adiposity in mice

“…Based on our results, steatosis development arises not only from an increased de novo lipogenesis and decreased VLDL export as shown by Qiu et al [26], but also from an increased FA uptake, as suggested by the significant upregulation of several FA transporters. This is linked with substantial changes in hepatic glucose metabolism, including enhanced glycolysis (whose products are essentially used for de novo lipogenesis), as well as decreased gluconeogenesis.…”

Selective Hepatic Insulin Resistance, VLDL Overproduction, and Hypertriglyceridemia

“…Liver-specific deletion of PTP-1B improves hepatic insulin signaling, enhances insulin suppression of hepatic gluconeogenesis, and lowers circulating levels of TG and cholesterol. 58 Evidence that generation of PIP3 is necessary for insulinmediated suppression of VLDL is provided by recent studies of phosphatase and tensin homolog PTEN, 59 a lipid phosphatase that catalyzes removal of the 3′ phosphate of phosphoinositides. Data suggest that loss of PTEN and associated increases in cellular PIP3 result in suppressed VLDL secretion.…”

“…Data suggest that loss of PTEN and associated increases in cellular PIP3 result in suppressed VLDL secretion. 59 In HepG2 cells expressing dominant negative PTEN, there is a 50% lowering of cellular and secreted B100. 59 Overexpression of PTEN renders cells unresponsive to insulin suggesting that rapid elimination of PIP3 by PTEN negates suppression.…”

“…59 In HepG2 cells expressing dominant negative PTEN, there is a 50% lowering of cellular and secreted B100. 59 Overexpression of PTEN renders cells unresponsive to insulin suggesting that rapid elimination of PIP3 by PTEN negates suppression. Congruent results were shown in McArdle RH-7777 cells where expression of PTEN enhances secretion of VLDL, whereas expression of dominant negative PTEN suppresses secretion of VLDL supporting the role of PIP3 in modulating VLDL secretion.…”

“…Congruent results were shown in McArdle RH-7777 cells where expression of PTEN enhances secretion of VLDL, whereas expression of dominant negative PTEN suppresses secretion of VLDL supporting the role of PIP3 in modulating VLDL secretion. 59 Although liver-specific disruption of PTEN improves glucose tolerance and reduces plasma FA in vivo, PTEN deletion also results in increased DNL, hepatomegaly, hepatic steatosis, and increased glycogen synthesis because of hyperphosphorylation of AKT. 60 In one model, plasma VLDL apoB levels and apoB secretion by hepatocytes were reduced.…”