Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatic cirrhosis-induced Minimal hepatic encephalopathy (MHE) has been characterized for cognitive dysfunction and central nervous system (CNS) insulin resistance (IR) has been acknowledged to be closely correlated with cognitive impairment while hepatic cirrhosis has been recognized to induce IR. Thus, this study aimed to investigate whether CNS IR occurred in MHE and induced MHE, as well as the underlying mechanism. We found IR in the MHE rats, an especially decreased level of the insulin receptor (InsR), and an increased serine phosphorylation of IRS1 in CNS. PI3K/AKT pathway signaling to the phosphorylation of N-Methyl-d-Aspartate receptors (NMDA receptors, NRs, NR1/NR2B) and downstream activation of the CaMKIV/CREB pathway and final production of neurotrophic factors were triggered by insulin, but impaired in the MHE rats. Additionally, CNS IR, memory impairment, the desensitization of the PI3K/AKT/NMDA receptor (NR)/CaMKIV/CREB pathway and decreased production of BDNF/NT3 in MHE rats were improved by rosiglitazone (RSG). These results suggested that IR, which induces the deficits in the insulin-mediated PI3K/AKT/NR/CaMKIV/CREB/neurotrophin pathway and subsequent memory decline, contributes to the pathogenesis of MHE.
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PMID:Insulin Resistance Disrupts the Interaction Between AKT and the NMDA Receptor and the Inactivation of the CaMKIV/CREB Pathway in Minimal Hepatic Encephalopathy. 2921 88

Insulin resistance is a key risk factor in the progression of nonalcoholic fatty liver disease (NAFLD) and may lead to liver fibrosis. Natural killer (NK) cells are thought to exert an antifibrotic effect through their killing of activated hepatic stellate cells (HSCs). Here, we investigated how the interplay between NK cells and HSCs are modified by insulin resistance in NAFLD. Fresh peripheral blood NK cells (clusters of differentiation [CD]56dim, CD16+) were collected from 22 healthy adults and 72 patients with NAFLD not currently taking any medications and without signs of metabolic syndrome. NK cells were assessed for insulin receptor expressions and cytotoxic activity when cultured in medium with HSCs. Fibrosis severities in patients with NAFLD were correlated linearly with elevated serum proinflammatory cytokine expression and insulin resistance severity. At the same time, fibrosis severities inversely correlated with insulin receptor expressions on NK cells as well as with their cytotoxic activities determined by CD107a by flow cytometry. NK cells from donors exhibiting severe fibrosis and insulin resistance exhibited significant mammalian target of rapamycin and extracellular signal-regulated kinase depletion (through NK cell western blot quantitation), increased apoptosis, and failure to attenuate HSC activation in vitro. While exposure to insulin stimulated the cytotoxic activity of healthy NK cells, rapamycin prevented this effect and reduced NK insulin receptor expressions. Conclusion: Elevated insulin levels in F1 and F2 fibrosis enhances NK cell cytotoxic activity toward HSCs and prevents fibrosis progression by insulin receptors and downstream mammalian target of rapamycin and extracellular signal-regulated kinase pathways. At more advanced stages of insulin resistance (F3 and F4 fibrosis), impaired NK cell activity rooted in low insulin receptor expression and or low serum insulin levels could further deteriorate fibrosis and may likely lead to cirrhosis development. (Hepatology Communications 2018;2:285-298).
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PMID:Insulin signaling as a potential natural killer cell checkpoint in fatty liver disease. 2950 3


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