Jnk1 but not jnk2 promotes the development of steatohepatitis in mice†

Schattenberg, Jörn M.; Singh, Rajat; Wang, Yongjun; Lefkowitch, Jay H.; Rigoli, Raina M.; Scherer, Philipp E.; Czaja, Mark J.

doi:10.1002/hep.20999

Cited by 365 publications

(348 citation statements)

References 45 publications

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“…Lipid accumulation in the cells can increase activity of JNK, whereas JNK promotes the development of liver steatosis (43). As expected, phosphorylation of JNK was increased in L-iNOS-Tg mice relative to WT mice (Fig.…”

Section: Volume 286 • Number 40 • October 7 2011supporting

confidence: 73%

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Shinozaki

Choi

Shimizu

et al. 2011

Journal of Biological Chemistry

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Inducible nitric-oxide synthase (iNOS), a major mediator of inflammation, plays an important role in obesity-induced insulin resistance. Inhibition of iNOS by gene disruption or pharmacological inhibitors reverses or ameliorates obesity-induced insulin resistance in skeletal muscle and liver in mice. It is unknown, however, whether increased expression of iNOS is sufficient to cause insulin resistance in vivo. To address this issue, we generated liver-specific iNOS transgenic (L-iNOS-Tg) mice, where expression of the transgene, iNOS, is regulated under mouse albumin promoter. L-iNOS-Tg mice exhibited mild hyperglycemia, hyperinsulinemia, insulin resistance, and impaired insulin-induced suppression of hepatic glucose output, as compared with wild type (WT) littermates. Insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) and -2, and Akt was significantly attenuated in liver, but not in skeletal muscle, of L-iNOS-Tg mice relative to WT mice without changes in insulin receptor phosphorylation. Moreover, liverspecific iNOS expression abrogated insulin-stimulated phosphorylation of glycogen synthase kinase-3␤, forkhead box O1, and mTOR (mammalian target of rapamycin), endogenous substrates of Akt, along with increased S-nitrosylation of Akt relative to WT mice. However, the expression of insulin receptor, IRS-1, IRS-2, Akt, glycogen synthase kinase-3␤, forkhead box O1, protein-tyrosine phosphatase-1B, PTEN (phosphatase and tensin homolog), and p85 phosphatidylinositol 3-kinase was not altered by iNOS transgene. Hyperglycemia was associated with elevated glycogen phosphorylase activity and decreased glycogen synthase activity in the liver of L-iNOS-Tg mice, whereas phosphoenolpyruvate carboxykinase, glucose-6-phosphatase, and proliferator-activated receptor ␥ coactivator-1␣ expression were not altered. These results clearly indicate that selective expression of iNOS in liver causes hepatic insulin resistance along with deranged insulin signaling, leading to hyperglycemia and hyperinsulinemia. Our data highlight a critical role for iNOS in the development of hepatic insulin resistance and hyperglycemia.The incidence of obesity and type 2 diabetes has been increasing in the United States and worldwide. Hepatic insulin resistance has a critical role in the progression of hyperglycemia in type 2 diabetes. Activation of inflammatory/stress signaling pathways have been recognized as a major culprit of hepatic insulin resistance (1, 2). These inflammatory/stress signaling pathways include the inhibitor of nuclear factor-B (IB) nuclear factor-B (NF-B), 2 c-Jun N-terminal kinase (JNK), and endoplasmic reticulum stress signaling cascades (3-7). Liver-specific activation of nuclear factor-B kinase causes hepatic insulin resistance in mice (8). Nonetheless, it remains to be determined how activation of inflammatory/stress signaling pathways induces hepatic insulin resistance.We and others have shown that the inhibition of inducible nitric-oxide synthase (iNOS, also known as NOS2) by gene disruption or pharma...

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Section: Volume 286 • Number 40 • October 7 2011supporting

confidence: 73%

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Shinozaki

Choi

Shimizu

et al. 2011

Journal of Biological Chemistry

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“…For instance, Schattenberg et al, using a methionine-and choline-deficient (MCD) diet, induced the development of steatohepatitis in mice. In this case, the development of NAFLD was driven by an activation of the JNK-cJun-AP1 signaling pathway (Schattenberg et al, 2006). In line with this study and the one showing that jnk1 plays a more prominent role in the development of insulin resistance than jnk2, Singh et al, revealed that jnk1 but not jnk2 null mice are protected from high-fat diet-induced steatosis and liver injury (Singh et al, 2009).…”

Section: Inflammation and Er Stress Induce Insulin Resistance In Metssupporting

confidence: 70%

“…In addition to its function in obesity and insulin resistance, JNK has been shown to play a major role in the development of NAFLD (Schattenberg et al, 2006;Singh et al, 2009). For instance, Schattenberg et al, using a methionine-and choline-deficient (MCD) diet, induced the development of steatohepatitis in mice.…”

Section: Inflammation and Er Stress Induce Insulin Resistance In Metsmentioning

confidence: 99%

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

Asrih

Jornayvaz

2015

Molecular and Cellular Endocrinology

278

196

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“…ROS signals to induce TNF-a and activate JNK1, both of which are implicated in hepatocellular apoptosis and development of steatohepatitis. 33 To our surprise, the activity of JNK was suppressed in the livers with combined liver injury. Current evidence suggests that JNK activation may promote cellular injury and apoptosis, but others have found that its induction may be a mechanism of cellular adaptive response to chronic stresses.…”

Section: Discussionmentioning

confidence: 78%

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

Tan

Crawford

Jaskowski

et al. 2013

Laboratory Investigation

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Endoplasmic reticulum (ER) stress is an important pathogenic mechanism for alcoholic (ALD) and nonalcoholic fatty liver disease (NAFLD). Iron overload is an important cofactor for liver injury in ALD and NAFLD, but its role in ER stress and associated stress signaling pathways is unclear. To investigate this, we developed a murine model of combined liver injury by co-feeding the mildly iron overloaded, the hemochromatosis gene-null (Hfe À / ) mouse ad libitum with ethanol and a high-fat diet (HFD) for 8 weeks. This co-feeding led to profound steatohepatitis, significant fibrosis, and increased apoptosis in the Hfe À / À mice as compared with wild-type (WT) controls. Iron overload also led to induction of unfolded protein response (XBP1 splicing, activation of IRE-1a and PERK, as well as sequestration of GRP78) and ER stress (increased CHOP protein expression) following HFD and ethanol. This is associated with a muted autophagic response including reduced LC3-I expression and impaired conjugation to LC3-II, reduced beclin-1 protein, and failure of induction of autophagy-related proteins (Atg) 3, 5, 7, and 12. As a result of the impaired autophagy, levels of the sequestosome protein p62 were most elevated in the Hfe À / À group co-fed ethanol and HFD. Iron overload reduces the activation of adenosine monophosphate protein kinase associated with ethanol and HFD feeding. We conclude that iron toxicity may modulate hepatic stress signaling pathways by impairing adaptive cellular compensatory mechanisms in alcohol-and obesity-induced liver injury.

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Jnk1 but not jnk2 promotes the development of steatohepatitis in mice†

Cited by 365 publications

References 45 publications

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Liver-specific Inducible Nitric-oxide Synthase Expression Is Sufficient to Cause Hepatic Insulin Resistance and Mild Hyperglycemia in Mice

Metabolic syndrome and nonalcoholic fatty liver disease: Is insulin resistance the link?

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

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