NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action

Sheng, Liang; Zhou, Yang; Chen, Zheng; Ren, Decheng; Cho, Kae Won; Jiang, Lin; Shen, Hong; Sasaki, Yoshiyuki; Rui, Liangyou

doi:10.1038/nm.2756

Cited by 93 publications

(102 citation statements)

References 37 publications

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“…Although both are activated by TNF-α, they were reported to have opposite activities in the regulation of the cAMP signaling pathway. NIK upregulated the pathway by direct phosphorylation of the CREB protein in a study of glucagon signaling in liver (26). IKKε downregulated the pathway through induction of PDE3B activity in a study of IKKε in adipocytes (27) in which IKKε was found to phosphorylate the PDE3B protein.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

Zhao

et al. 2015

Diabetes

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The transcription factor nuclear factor-κB (NF-κB) mediates inflammation and stress signals in cells. To test NF-κB in the control of hepatic insulin sensitivity, we inactivated NF-κB in the livers of C57BL/6 mice through deletion of the p65 gene, which was achieved by crossing floxed-p65 and Alb-cre mice to generate L-p65-knockout (KO) mice. KO mice did not exhibit any alterations in growth, reproduction, and body weight while on a chow diet. However, the mice on a high-fat diet (HFD) exhibited an improvement in systemic insulin sensitivity. Hepatic insulin sensitivity was enhanced as indicated by increased pyruvate tolerance, Akt phosphorylation, and decreased gene expression in hepatic gluconeogenesis. In the liver, a decrease in intracellular cAMP was observed with decreased CREB phosphorylation. Cyclic nucleotide phosphodiesterase-3B (PDE3B), a cAMP-degrading enzyme, was increased in mRNA and protein as a result of the absence of NF-κB activity. NF-κB was found to inhibit PDE3B transcription through three DNA-binding sites in the gene promoter in response to tumor necrosis factor-α. Body composition, food intake, energy expenditure, and systemic and hepatic inflammation were not significantly altered in KO mice on HFD. These data suggest that NF-κB inhibits hepatic insulin sensitivity by upregulating cAMP through suppression of PDE3B gene transcription.

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Section: Discussionmentioning

confidence: 99%

Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

Zhao

et al. 2015

Diabetes

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“…However, chronic inflammation in the liver causes insulin resistance, leading to increased HGP (79). Liver inflammation also increases the ability of glucagon to stimulate HGP (36, 234). …”

Section: Liver Glucose Metabolismmentioning

confidence: 99%

Energy Metabolism in the Liver

Rui

2014

Comprehensive Physiology

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The liver is an essential metabolic organ, and its metabolic activity is tightly controlled by insulin and other metabolic hormones. Glucose is metabolized into pyruvate through glycolysis in the cytoplasm, and pyruvate is completely oxidized to generate ATP through the TCA cycle and oxidative phosphorylation in the mitochondria. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long-chain fatty acids are incorporated into triacylglycerol, phospholipids, and cholesterol esters in hepatocytes, and these complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as VLDL particles. In the fasted state, the liver secretes glucose through both breakdown of glycogen (glycogenolysis) and de novo glucose synthesis (gluconeogenesis). During pronged fasting, hepatic gluconeogenesis is the primary source of endogenous glucose production. Fasting also promotes lipolysis in adipose tissue to release nonesterified fatty acids which are converted into ketone bodies in the liver though mitochondrial β oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver metabolic processes are tightly regulated by neuronal and hormonal systems. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis, but suppresses gluconeogenesis; glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC-1α, and CRTC2, control the expression of the enzymes which catalyze the rate-limiting steps of liver metabolic processes, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases (NAFLD).

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“…Since inflammation promotes insulin resistance, a driving force for type 2 diabetes, the H-lipid subpopulation is also likely to contribute the pathogenesis of type 2 diabetes by stimulating the production of proinflammatory cytokines. These cytokines may increase the ability of the L-lipid subpopulation to produce glucose by increasing insulin resistance and/or by increasing the hyperglycemic response to glucagon as we recently reported (23).…”

Section: Discussionmentioning

confidence: 68%

Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice

Sheng

Jiang

Rui

2013

American Journal of Physiology-Endocrinology and Metabolism

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Sheng L, Jiang B, Rui L. Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice. Am J Physiol Endocrinol Metab 305: E1115-E1123, 2013. First published August 27, 2013 doi:10.1152/ajpendo.00401.2013The liver is an essential metabolic organ. In addition to metabolizing glucose and lipids, hepatocytes also secrete various cytokines that modulate both hepatocyte metabolism and liver inflammation. Hepatocyte injury and death and liver inflammation are the major contributors to liver diseases, including nonalcoholic steatohepatitis (NASH). Anatomic locations have a profound effect on hepatocyte metabolism, and liver zonation describes the metabolic heterogeneity of hepatocytes along the portovenous axis. However, it is unclear whether hepatocyte heterogeneity is affected by intrinsic factors and whether dietary fat, a risk factor for NASH, has distinct detrimental effects on different hepatocyte subpopulations. Here, we showed that mouse livers contained both high-lipid and low-lipid subpopulations of hepatocytes. The high-lipid subpopulation was more susceptible to injury and apoptosis and produced more proinflamatrory cytokines after treatment with endotoxin and saturated fatty acids. Dietary fat consumption further increased fatty acid uptake, intracellular lipid levels, hepatocyte injury and death, and the expression of proinflammatory cytokines in the high-lipid subpopulation. In contrast, dietary fat slightly increased lipid levels, cell death, and expression of proinflammatory cytokines in the low-lipid subpopulation. The lowlipid subpopulation produced more glucose. Fat consumption further activated the gluconeogenic program in the low-lipid, but not the high-lipid, subpopulations. These data suggest that intracellular lipid content is a key intrinsic determinant for hepatocyte heterogeneity of metabolic, inflammatory, and survival states.

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NF-κB–inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action

Cited by 93 publications

References 37 publications

Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

Inactivation of NF-κB p65 (RelA) in Liver Improves Insulin Sensitivity and Inhibits cAMP/PKA Pathway

Energy Metabolism in the Liver

Intracellular lipid content is a key intrinsic determinant for hepatocyte viability and metabolic and inflammatory states in mice

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