Hepatic Phosphoserine Aminotransferase 1 Regulates Insulin Sensitivity in Mice via Tribbles Homolog 3

Yu, Junjie; Xiao, Fei; Guo, Yinlong; Deng, Jiali; Liu, Bin; Zhang, Qian; Li, Kai; Wang, Chunxia; Chen, Shanghai; Guo, Feifan

doi:10.2337/db14-1368

Cited by 34 publications

(29 citation statements)

References 47 publications

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“…Adenovirus expressing TRB3 (Ad-TRB3) was purchased from Hanbio (Shanghai, China). Adenovirus expressing scrambled or short hairpin RNA for mouse TRB3 was generated as reported previously (50). Viruses were diluted in PBS and administered at a dose of 1.5 ϫ 10 7 plaque-forming units/well in a 12-well plate or through tail vein injection using 5 ϫ 10 8 plaque-forming units/mouse.…”

Section: Methodsmentioning

confidence: 99%

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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Although numerous biological functions of the activating transcription factor 4 (ATF4) have been identified, a direct effect of ATF4 on alcoholic liver steatosis has not been described previously. The aim of our current study is to investigate the role of ATF4 in alcoholic liver steatosis and elucidate the underlying mechanisms. Here, we showed that the expression of ATF4 is induced by ethanol in hepatocytes in vitro and in vivo, and liverspecific ATF4 knock-out mice are resistant to ethanol-induced liver steatosis, associated with stimulated hepatic AMP-activated protein kinase (AMPK) activity. Furthermore, adenovirus-mediated AMPK knockdown significantly reversed the suppressive effects of ATF4 deficiency on ethanol-induced liver steatosis in mice. In addition, ethanol-fed ATF4 knock-out mice exhibit AMPK-dependent inhibition of fatty acid synthase and stimulation of carnitine palmitoyltransferase 1 (CPT1) in the liver. Moreover, hepatic Tribbles homolog 3 (TRB3) expression was stimulated by ethanol in an ATF4-dependent manner, and adenovirus-mediated TRB3 knockdown blocked ATF4-dependent ethanol-induced AMPK inhibition and triglyceride accumulation in AML-12 cells. Finally, TRB3 directly interacted with AMPK to suppress its phosphorylation. Taken together, these results identify the ATF4-TRB3-AMPK axis as a novel pathway responsible for ethanol-induced liver steatosis.People consuming excessive amounts of alcohol for prolonged periods suffer from alcoholic liver disease, which encompasses fatty liver, hepatic inflammation and necrosis, progressive fibrosis, and hepatocellular carcinoma (1). Alcoholic fatty liver is the early stage of alcoholic liver disease, characterized by increased accumulation of fat in the liver, which is usually caused by increased free fatty acid (FFA) 4 uptake, augmented de novo lipogenesis, decreased ␤-oxidation, and/or impaired triglyceride (TG) export (2). Studies have identified some important regulators for ethanol-induced liver steatosis, including sirtuin 1 (SIRT1) (3), sterol regulatory element-binding protein 1 (SREBP-1) (4), peroxisome proliferator-activated receptor ␥ coactivator 1-␣ (PGC-1␣) (5), and 5Ј-adenosine monophosphate-activated protein kinase (AMPK) (6 -8).Among them, AMPK is one of the most important regulators (6 -8). AMPK is a heterotrimeric complex consisting of a catalytic ␣ subunit and two regulatory ␤/␥ subunits. It acts as a key metabolic "switch" by phosphorylating target enzymes involved in lipid metabolism, such as acetyl-CoA carboxylase (ACC) (9). Malonyl-CoA, the product of ACC, is both a precursor for fatty acid biosynthesis and a potent inhibitor of ␤-oxidation at the step regulated by carnitine palmitoyltransferase I (10). AMPK activity is suppressed under ethanol exposure (6) and activation of AMPK by its activator (5-aminoimidazole-4-carboxamide 1-␤-D-ribofuranoside) or metformin prevents ethanol-induced liver steatosis (11, 12). However, the molecular mechanisms underlying ethanol suppression of AMPK activity remain largely unknown. Activating...

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Section: Methodsmentioning

confidence: 99%

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Li¹,

Xiao²,

et al. 2016

Journal of Biological Chemistry

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“…PSAT1 has some important metabolic functions such as PSAT1 deficiency results in intractable seizures and acquired microcephaly [8], and reduced expression in diabetic mice [36]. However, there was no previous information regarding PSAT1 expression and function in endothelial migration.…”

Section: Discussionmentioning

confidence: 99%

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

Lee¹,

Park²,

Shin³

2016

Journal of Life Science

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Cilostazol is known to be a selective inhibitor of phosphodiesterase III and is generally used to treat stroke. Our previous findings showed that cilostazol enhanced capillary density through angiogenesis after focal cerebral ischemia. Angiogenesis is an important physiological process for promoting revascularization to overcome tissue ischemia. It is a multistep process consisting of endothelial cell proliferation, migration, and tubular structure formation. Here, we examined the modulatory effect of cilostazol at each step of the angiogenic mechanism by using human brain microvascular endothelial cells (HBMECs). We found that cilostazol increased the migration of HBMECs in a dose-dependent manner. However, it did not enhance HBMEC proliferation and capillary-like tube formation. We used a cDNA microarray to analyze the mechanisms of cilostazol in cell migration. We picked five candidate genes that were potentially related to cell migration, and we confirmed the gene expression levels by real-time PCR. The genes phosphoserine aminotransferase 1 (PSAT1) and CCAAT/enhancer binding protein β (C/EBPβ) were up-regulated. The genes tissue factor pathway inhibitor 2 (TFPI2), retinoic acid receptor responder 1 (RARRES1), and RARRES3 were down-regulated. Our observations suggest that cilostazol can promote angiogenesis by promoting endothelial migration. Understanding the cilostazol-modulated regulatory mechanisms in brain endothelial cells may help stimulate blood vessel formation for the treatment of ischemic diseases.

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“…The siRNA sequence specific for mouse NR2F2 was 59-ACUGGCCAUAUAUGGCAAUUCAAUAUAUUGAAUU GCCAUAUAUGGCAGU-39. Mouse primary hepatocytes were prepared by collagenase perfusion (17), and Hep1-6 and 293T cells (Cell Centre, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences) were maintained in DMEM as described previously (17). Primary hepatocytes were transfected with NR2F2-expressing plasmid by Effectene Transfection Reagent (Qiagen, Hilden, Germany) or NR2F2 siRNA by X-tremeGENE siRNA Transfection Reagent (Roche Diagnostics, Mannheim, Germany).…”

Section: Plasmid Construction and Cell Treatmentsmentioning

confidence: 99%

“…The Ad-peroxisome proliferator-activated receptor a (AdPPARa) was provided by Y. Liu (Institute for Nutritional Sciences, Shanghai, China). Purified high-titer stocks of amplified recombinant adenoviruses (17) were diluted in PBS and administered at a dose of 1 3 10 7 plaque-forming units/well in 12-well plates or injected at a dose of 1 3 10 9 plaque-forming units/mice through the tail vein for a single injection. Glucose output and glycogen content were determined as described previously (17).…”

Section: Generation and Administration Of Recombinant Adenovirusesmentioning

confidence: 99%

A Novel Function of Hepatic FOG2 in Insulin Sensitivity and Lipid Metabolism Through PPARα

Guo

Deng

et al. 2016

Diabetes

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Friend of GATA 2 (FOG2) is a transcriptional cofactor involved mostly in cardiac function. The aim of this study was to investigate the role of hepatic FOG2 in insulin sensitivity and lipid accumulation. FOG2 overexpression by adenovirus-expressing FOG2 (Ad-FOG2) significantly attenuates insulin signaling in hepatocytes in vitro. Opposite effects were observed when FOG2 was knocked down through adenovirus-expressing small hairpin RNA for FOG2 (Ad-shFOG2). Furthermore, FOG2 knockdown by Ad-shFOG2 ameliorated insulin resistance in leptin receptor-mutated (db/db) mice, and FOG2 overexpression by Ad-FOG2 attenuated insulin sensitivity in C57BL/6J wild-type (WT) mice. In addition, Ad-FOG2 reduced, whereas Ad-shFOG2 promoted, hepatic triglyceride (TG) accumulation in WT mice under fed or fasted conditions, which was associated with increased or decreased hepatic peroxisome proliferator-activated receptor a (PPARa) expression, respectively. Moreover, the improved insulin sensitivity and increased hepatic TG accumulation by Ad-shFOG2 were largely reversed by adenovirusexpressing PPARa (Ad-PPARa) in WT mice. Finally, we generated FOG2 liver-specific knockout mice and found that they exhibit enhanced insulin sensitivity and elevated hepatic TG accumulation, which were also reversed by AdPPARa. Taken together, the results demonstrate a novel function of hepatic FOG2 in insulin sensitivity and lipid metabolism through PPARa.Insulin resistance is a risk factor for type 2 diabetes (T2D), and dysregulated hepatic lipid metabolism is the major cause of nonalcoholic fatty liver disease. Many studies have demonstrated a relationship between T2D and nonalcoholic fatty liver disease. For example, insulin resistance has been shown to accompany liver steatosis (1-3). On the other hand, improved insulin sensitivity sometimes is not enough to ameliorate disrupted lipid metabolism (4-6). These results suggest a complex relationship between the regulation of insulin sensitivity and hepatic lipid metabolism. Because the liver is critical in the regulation of glucose and lipid metabolism, the function of many genes expressed in the liver needs to be explored.Friend of GATA 2 (FOG2, also known as ZFPM2) was first cloned from mouse embryonic brain (7) and heart (8). FOG2 is expressed in many tissues (8,9) and functions as a coregulator of the transcriptional factor GATA family (7,8). Studies have shown that FOG2 is involved in the regulation of many physiological processes, including coronary vascular development and heart morphology (10-12). However, some studies have implied a possible role of FOG2 in the regulation of insulin signaling and lipid metabolism such that FOG2 can bind to the regulatory unit p85 of phosphatidylinositol 3-kinase (PI3K) and attenuate phosphorylation of protein kinase B (AKT), the major component of insulin signaling in various cell types (13). Furthermore, FOG2 expression is increased in liver of insulin-resistant mice induced by interleukin-6 injection or with mutation in leptin receptor (db/db) (14). Moreover, ...

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Hepatic Phosphoserine Aminotransferase 1 Regulates Insulin Sensitivity in Mice via Tribbles Homolog 3

Cited by 34 publications

References 47 publications

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Liver-specific Gene Inactivation of the Transcription Factor ATF4 Alleviates Alcoholic Liver Steatosis in Mice

Cilostazol Promotes the Migration of Brain Microvascular Endothelial Cells

A Novel Function of Hepatic FOG2 in Insulin Sensitivity and Lipid Metabolism Through PPARα

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