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author:("Liang, hanau")
1.  Methionine sulfoxide reductase A affects insulin resistance by protecting insulin receptor function 
Oxidative stress plays a significant role in the development of insulin resistance; however, the cellular targets of oxidation that cause insulin resistance have yet to be fully elucidated. Methionine sulfoxide reductases (Msr) reduce oxidized methionine residues, thereby repairing and protecting proteins from oxidation. Recently, several genome-wide analyses have found human obesity to be strongly correlated with polymorphisms near the methionine sulfoxide reductase A (MsrA) locus. In this study, we tested whether modulation of MsrA expression significantly alters the development of obesity and/or insulin resistance in mice. We show that mice lacking MsrA (MsrA−/−) are prone to the development of high fat diet-induced insulin resistance and a reduced physiological insulin response compared to high fat-fed wild type mice. We also show that oxidative stress in C2C12 cell cultures reduces both insulin-stimulated phosphorylation and autophosphorylation of the insulin receptor. Tissues from high fat-fed mice show similar reduction in insulin receptor function and the lack of MsrA further diminishes these functions. Together, these data demonstrate for the first time that MsrA plays a role in the regulation of glucose homeostasis. In addition, these data support a novel hypothesis that obesity-induced insulin resistance is caused in part by reduced function of insulin signaling proteins arising from protein oxidation.
doi:10.1016/j.freeradbiomed.2012.10.544
PMCID: PMC3578155  PMID: 23089224
oxidative stress; methionine sulfoxide; diabetes; obesity; glucose homeostasis
2.  Effect of Lipopolysaccharide on Inflammation and Insulin Action in Human Muscle 
PLoS ONE  2013;8(5):e63983.
Accumulating evidence from animal studies suggest that chronic elevation of circulating intestinal-generated lipopolysaccharide (LPS) (i.e., metabolic endotoxemia) could play a role in the pathogenesis of insulin resistance. However, the effect of LPS in human muscle is unclear. Moreover, it is unknown whether blockade/down regulation of toll-like receptor (TLR)4 can prevent the effect of LPS on insulin action and glucose metabolism in human muscle cells. In the present study we compared plasma LPS concentration in insulin resistant [obese non-diabetic and obese type 2 diabetic (T2DM)] subjects versus lean individuals. In addition, we employed a primary human skeletal muscle cell culture system to investigate the effect of LPS on glucose metabolism and whether these effects are mediated via TLR4. Obese non-diabetic and T2DM subjects had significantly elevated plasma LPS and LPS binding protein (LBP) concentrations. Plasma LPS (r = −0.46, P = 0.005) and LBP (r = −0.49, P = 0.005) concentrations negatively correlated with muscle insulin sensitivity (M). In human myotubes, LPS increased JNK phosphorylation and MCP-1 and IL-6 gene expression. This inflammatory response led to reduced insulin-stimulated IRS-1, Akt and AS160 phosphorylation and impaired glucose transport. Both pharmacologic blockade of TLR4 with TAK-242, and TLR4 gene silencing, suppressed the inflammatory response and insulin resistance caused by LPS in human muscle cells. Taken together, these findings suggest that elevations in plasma LPS concentration found in obese and T2DM subjects could play a role in the pathogenesis of insulin resistance and that antagonists of TLR4 may improve insulin action in these individuals.
doi:10.1371/journal.pone.0063983
PMCID: PMC3660322  PMID: 23704966
3.  TAK-242, a small-molecule inhibitor of Toll-like receptor 4 signalling, unveils similarities and differences in lipopolysaccharide- and lipidinduced inflammation and insulin resistance in muscle cells 
Bioscience Reports  2012;33(1):e00004.
Emerging evidence suggests that TLR (Toll-like receptor) 4 and downstream pathways [MAPKs (mitogen-activated protein kinases) and NF-κB (nuclear factor κB)] play an important role in the pathogenesis of insulin resistance. LPS (lipopolysaccharide) and saturated NEFA (non-esterified fatty acids) activate TLR4, and plasma concentrations of these TLR4 ligands are elevated in obesity and Type 2 diabetes. Our goals were to define the role of TLR4 on the insulin resistance caused by LPS and saturated NEFA, and to dissect the independent contribution of LPS and NEFA to the activation of TLR4-driven pathways by employing TAK-242, a specific inhibitor of TLR4. LPS caused robust activation of the MAPK and NF-κB pathways in L6 myotubes, along with impaired insulin signalling and glucose transport. TAK-242 completely prevented the inflammatory response (MAPK and NF-κB activation) caused by LPS, and, in turn, improved LPS-induced insulin resistance. Similar to LPS, stearate strongly activated MAPKs, although stimulation of the NF-κB axis was modest. As seen with LPS, the inflammatory response caused by stearate was accompanied by impaired insulin action. TAK-242 also blunted stearate-induced inflammation; yet, the protective effect conferred by TAK-242 was partial and observed only on MAPKs. Consequently, the insulin resistance caused by stearate was only partially improved by TAK-242. In summary, TAK-242 provides complete and partial protection against LPS- and NEFA-induced inflammation and insulin resistance, respectively. Thus, LPS-induced insulin resistance depends entirely on TLR4, whereas NEFA works through TLR4-dependent and -independent mechanisms to impair insulin action.
doi:10.1042/BSR20120098
PMCID: PMC3522475  PMID: 23050932
endotoxin; mitogen-activated protein kinase (MAPK); nuclear factor κB (NF-κB); saturated non-esterified fatty acid (NEFA); Toll-like receptor 4 (TLR4).; AP-1, activator protein-1; 2-DG, 2-deoxy-D[1,2-3H]glucose; DAG, diacylglycerol; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GSK, glycogen synthase kinase; IκB, inhibitory κB; IKK, IκB kinase; IL, interleukin; iNOS, inducible nitric oxide synthase; IRAK, IL-1-receptor-associated kinase; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharide; MAPK, mitogen-activated protein kinase; MCP1, monocyte chemoattractant protein-1; MEMα, minimum essential medium α; MyD88, myeloid differentiation factor 88; NEFA, non-esterified fatty acid(s); NF-κB, nuclear factor κB; NOD2, nucleotide-binding oligomerization domain-2; PKC, protein kinase C; RT–PCR, reverse transcription–PCR; TIR, Toll/IL-1 receptor; TIRAP, TIR domain-containing adaptor protein; TLR, Toll-like receptor; TNF, tumour necrosis factor; TRAF-6, TNF-receptor-associated factor-6
4.  Overexpression of Mn Superoxide Dismutase Does Not Increase Life Span in Mice 
Genetic manipulations of Mn superoxide dismutase (MnSOD), SOD2 expression have demonstrated that altering the level of MnSOD activity is critical for cellular function and life span in invertebrates. In mammals, Sod2 homozygous knockout mice die shortly after birth, and alterations of MnSOD levels are correlated with changes in oxidative damage and in the generation of mitochondrial reactive oxygen species. In this study, we directly tested the effects of overexpressing MnSOD in young (4–6 months) and old (26–28 months) mice on mitochondrial function, levels of oxidative damage or stress, life span, and end-of-life pathology. Our data show that an approximately twofold overexpression of MnSOD throughout life in mice resulted in decreased lipid peroxidation, increased resistance against paraquat-induced oxidative stress, and decreased age-related decline in mitochondrial ATP production. However, this change in MnSOD expression did not alter either life span or age-related pathology.
doi:10.1093/gerona/glp100
PMCID: PMC2759571  PMID: 19633237
Oxidative damage; Mn superoxide dismutase; Pathology; Aging
5.  Glutathione Peroxidase 4 Differentially Regulates the Release of Apoptogenic Proteins from Mitochondria 
Free radical biology & medicine  2009;47(3):312-320.
Glutathione peroxidase 4 (Gpx4) is a unique antioxidant enzyme that repairs oxidative damage to biomembranes. In the present study, we examined the effect of Gpx4 on the release of various apoptogenic proteins from mitochondria using transgenic mice overexpressing Gpx4 [Tg(GPX4+/0)] and mice deficient in Gpx4 (Gpx4+/− mice). Diquat exposure triggered apoptosis that occurred through intrinsic pathway and resulted in the mitochondrial release of cytochrome c (cyt. c), Smac/DIABLO, and Omi/HtrA2 in the liver of wild-type (Wt) mice. Liver apoptosis and cyt. c release were suppressed in Tg(GPX4+/0) mice but exacerbated in Gpx4+/− mice; however, neither the Tg(GPX4+/0) nor the Gpx4+/− mice showed any alterations in the levels of Smac/DIABLO or Omi/HtrA2 released from mitochondria. Submitochondrial fractionation data showed that Smac/DIABLO and Omi/HtrA2 existed primarily in the intermembrane space and matrix, while cyt. c and Gpx4 were both associated with inner membrane. In addition, diquat exposure induced cardiolipin peroxidation in the liver of Wt mice; the levels of cardiolipin peroxidation were reduced in Tg(GPX4+/0) mice but elevated in Gpx4+/− mice. These data suggest that Gpx4 differentially regulates apoptogenic protein release due to its inner membrane location in mitochondria and its ability to repair cardiolipin peroxidation.
doi:10.1016/j.freeradbiomed.2009.05.012
PMCID: PMC2773016  PMID: 19447173
Gpx4; Phospholipid hydroperoxide glutathione peroxidase 4; Apoptosis; Cardiolipin; Lipid peroxidation; Oxidative stress

Results 1-5 (5)