scholarly journals Diacylglycerol Activation of Protein Kinase Cε and Hepatic Insulin Resistance

2012 ◽  
Vol 15 (5) ◽  
pp. 574-584 ◽  
Author(s):  
François R. Jornayvaz ◽  
Gerald I. Shulman
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Hepatic Insulin Resistance

scholarly journals Hepatic Mitogen-Activated Protein Kinase Phosphatase 1 Selectively Regulates Glucose Metabolism and Energy Homeostasis

2014 ◽  
Vol 35 (1) ◽  
pp. 26-40 ◽  
Author(s):  
Ahmed Lawan ◽  
Lei Zhang ◽  
Florian Gatzke ◽  
Kisuk Min ◽  
Michael J. Jurczak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Glucose Metabolism ◽  
Energy Homeostasis ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Fibroblast Growth Factor 21 ◽  
High Fat ◽  
Mitogen Activated Protein ◽  
Fat Feeding

The liver plays a critical role in glucose metabolism and communicates with peripheral tissues to maintain energy homeostasis. Obesity and insulin resistance are highly associated with nonalcoholic fatty liver disease (NAFLD). However, the precise molecular details of NAFLD remain incomplete. The p38 mitogen-activated protein kinase (MAPK) and c-Jun NH2-terminal kinase (JNK) regulate liver metabolism. However, the physiological contribution of MAPK phosphatase 1 (MKP-1) as a nuclear antagonist of both p38 MAPK and JNK in the liver is unknown. Here we show that hepatic MKP-1 becomes overexpressed following high-fat feeding. Liver-specific deletion of MKP-1 enhances gluconeogenesis and causes hepatic insulin resistance in chow-fed mice while selectively conferring protection from hepatosteatosis upon high-fat feeding. Further, hepatic MKP-1 regulates both interleukin-6 (IL-6) and fibroblast growth factor 21 (FGF21). Mice lacking hepatic MKP-1 exhibit reduced circulating IL-6 and FGF21 levels that were associated with impaired skeletal muscle mitochondrial oxidation and susceptibility to diet-induced obesity. Hence, hepatic MKP-1 serves as a selective regulator of MAPK-dependent signals that contributes to the maintenance of glucose homeostasis and peripheral tissue energy balance. These results also demonstrate that hepatic MKP-1 overexpression in obesity is causally linked to the promotion of hepatosteatosis.

205-OR: Hepatic Protein Kinase C-e Is Necessary and Sufficient in Mediating Lipid-Induced Hepatic Insulin Resistance

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 205-OR
Author(s):  
KUN LYU ◽  
DONGYAN ZHANG ◽  
MARIO KAHN ◽  
MARCOS R.S. RODRIGUES ◽  
SANDRO HIRABARA ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase C ◽  
Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Kinase C ◽  
Necessary And Sufficient

Abstract 552: Aberrant Expression of MicroRNA-378a Induces Hepatic Insulin Resistance via Activation of ER Stress and the dsRNA Activated Protein Kinase PKR

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Xiao Cheng ◽  
Yongyan Song ◽  
Qiaozhu Su
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Er Stress ◽  
Target Genes ◽  
Rna Binding ◽  
Mrna Level ◽  
Hepatic Insulin Resistance ◽  
Stress Signaling ◽  
Aberrant Expression ◽  
Mitochondrial Fatty Acid

microRNAs(miRNAs) are noncoding RNAs with a length of 19 to 25 nt that are involved in posttranscriptional gene regulation by binding to the 3’-untranslated regions (3’-UTR) of target mRNA and impacting diverse cellular processes, including cell differentiation, energy metabolism and chronic inflammation. MicroRNA-378a (miR-378a) has been reported to be involved in adipose tissue browning and cancer development. However, its role in cellular stress signaling and hepatic insulin resistance has not yet been investigated. Here we reported that expression of hepatic miR-378a was upregulated by metabolic inflammatory inducers, such as high fructose feeding, bacterial lipopolysaccharide (LPS) and inflammatory cytokine TNFα. The elevated miR-378a subsequently targeted the 3’-UTR of PPARα which compromised mitochondrial fatty acid β-oxidation and induced mitochondrial and ER stress. miR-378a was further found to directly interacted with the dsRNA binding motifs within the dsRNA activated protein kinase PKR and activated the kinase to sustain the inflammatory stress and blunt the insulin signaling in hepatocytes. Genetic depletion of miR-378a rescued hepatocytes from mitochondrial and ER stress, systemic inflammation and insulin resistance induced by fructose and LPS. Conclusion: This study, for the first time, demonstrates that miR-378a is involved in mediating the metabolic inflammatory response in the onset of insulin resistance. This study further unveils a novel finding that miR-378a is capable of directly interacting with and activating a protein kinase PKR to sustain the stress signaling between mitochondria and ER. This discovery greatly broadens the physiological function of miR-378a by demonstrating that, in addition to regulate its target genes on the mRNA level, miRNA-378a is able to interact with RNA binding protein(s) and exerts its regulatory effect directly on the protein levels. Results from this study may provide rationale for using miR-378a as a pharmaceutical target in the treatment of insulin resistance.

scholarly journals Activation of dsRNA-Dependent Protein Kinase R by MicroRNA-378 Sustains Metabolic Inflammation in Hepatic Insulin Resistance

2021 ◽  
Author(s):  
Hao Wang ◽  
Yongyan Song ◽  
Yuxin Wu ◽  
Virender Kumar ◽  
Ram I Mahato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Er Stress ◽  
Rna Binding ◽  
Hepatic Insulin Resistance ◽  
Protein Kinase R ◽  
Dependent Protein Kinase ◽  
Metabolic Inflammation ◽  
Mitochondrial Fatty Acid ◽  
Dependent Protein

<a>MicroRNAs (miRNAs) are noncoding small RNAs that regulate various pathophysiological cellular processes. Here we reported that expression of the miR-378 family was significantly induced by metabolic inflammatory inducers, a high-fructose diet, and inflammatory cytokine TNF</a>a. Hepatic miRNA profiling revealed that expression of miR-378a was highly upregulated which, in turn, targeted the 3’-UTR of PPARa mRNA, impaired mitochondrial fatty acid b-oxidation and induced mitochondrial and ER stress. More importantly, the upregulated miR-378a can directly bind to and activate the dsRNA-dependent protein kinase R (PKR) to sustain the metabolic stress. <i>In vivo</i>, genetic depletion of miR-378a prevented PKR activation, ameliorated inflammatory stress and insulin resistance. Counterbalancing the upregulated miR-378a using nanoparticles encapsulated with an anti-miR-378a oligonucleotide restored PPARa activity, inhibited PKR activation and ER stress, and improved insulin sensitivity in the fructose-fed mice. <i>Conclusion: </i>Our study delineated a novel mechanism of miRNA-378a in the pathogenesis of metabolic inflammation and insulin resistance through targeting metabolic signaling at both mRNA (e.g., PPARa) and protein (e.g., PKR) molecules. This novel finding of functional interaction between miRNAs (e.g., miR-378a) and cellular RNA binding protein(s) (e.g., PKR) is biologically significant as it greatly broadens the potential targets of miRNAs in cellular pathophysiological processes.

scholarly journals Serum- and glucocorticoid-induced kinase drives hepatic insulin resistance by directly inhibiting AMP-activated protein kinase

Cell Reports ◽  
2021 ◽  
Vol 37 (1) ◽  
pp. 109785
Author(s):  
Ben Zhou ◽  
Yuyao Zhang ◽  
Sainan Li ◽  
Lianfeng Wu ◽  
Geza Fejes-Toth ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Amp Activated Protein Kinase

scholarly journals 4-Phenylbutyric acid improves free fatty acid-induced hepatic insulin resistance in vivo

2021 ◽  
Vol 10 (8) ◽  
pp. 861-872
Author(s):  
Sandra Pereira ◽  
Jessy Moore ◽  
Jia-Xu Li ◽  
Wen Qin Yu ◽  
Husam Ghanim ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Protein Kinase ◽  
Er Stress ◽  
Mitogen Activated Protein Kinase ◽  
Hepatic Insulin Resistance ◽  
Initiation Factor ◽  
Fibroblast Growth Factor 21 ◽  
Chemical Chaperone ◽  
Fetuin A ◽  
Phenylbutyric Acid

Plasma free fatty acids (FFAs) are elevated in obesity and can induce insulin resistance via endoplasmic reticulum (ER) stress. However, it is unknown whether hepatic insulin resistance caused by the elevation of plasma FFAs is alleviated by chemical chaperones. Rats received one of the following i.v. treatments for 48 h: saline, intralipid plus heparin (IH), IH plus the chemical chaperone 4-phenylbutyric acid (PBA), or PBA alone and a hyperinsulinemic-euglycemic clamp was performed during the last 2 h. PBA co-infusion normalized IH-induced peripheral insulin resistance, similar to our previous findings with an antioxidant and an IκBα kinase β (IKKβ) inhibitor. Different from our previous results with the antioxidant and IKKβ inhibitor, PBA also improved IH-induced hepatic insulin resistance in parallel with activation of Akt. Unexpectedly, IH did not induce markers of ER stress in the liver, but PBA prevented IH-induced elevation of phosphorylated eukaryotic initiation factor-2α protein in adipose tissue. PBA tended to decrease circulating fetuin-A and significantly increased circulating fibroblast growth factor 21 (FGF21) without affecting markers of activation of hepatic protein kinase C-δ or p38 mitogen-activated protein kinase that we have previously involved in hepatic insulin resistance in this model. In conclusion: (i) PBA prevented hepatic insulin resistance caused by prolonged plasma FFA elevation without affecting hepatic ER stress markers; (ii) the PBA effect is likely due to increased FGF21 and/or decreased fetuin-A, which directly signal to upregulate Akt activation.

scholarly journals Aspalathin-Enriched Green Rooibos Extract Reduces Hepatic Insulin Resistance by Modulating PI3K/AKT and AMPK Pathways

2019 ◽  
Vol 20 (3) ◽  
pp. 633 ◽  
Author(s):  
Sithandiwe Mazibuko-Mbeje ◽  
Phiwayinkosi Dludla ◽  
Candice Roux ◽  
Rabia Johnson ◽  
Samira Ghoor ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Insulin Receptor ◽  
Glucose Transporter ◽  
Insulin Signalling ◽  
Hepatic Insulin Resistance ◽  
Insulin Resistant ◽  
Glucose Transporter 2

We previously demonstrated that an aspalathin-enriched green rooibos extract (GRE) reversed palmitate-induced insulin resistance in C2C12 skeletal muscle and 3T3-L1 fat cells by modulating key effectors of insulin signalling such as phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT) and AMP-activated protein kinase (AMPK). However, the effect of GRE on hepatic insulin resistance is unknown. The effects of GRE on lipid-induced hepatic insulin resistance using palmitate-exposed C3A liver cells and obese insulin resistant (OBIR) rats were explored. GRE attenuated the palmitate-induced impairment of glucose and lipid metabolism in treated C3A cells and improved insulin sensitivity in OBIR rats. Mechanistically, GRE treatment significantly increased PI3K/AKT and AMPK phosphorylation while concurrently enhancing glucose transporter 2 expression. These findings were further supported by marked stimulation of genes involved in glucose metabolism, such as insulin receptor (Insr) and insulin receptor substrate 1 and 2 (Irs1 and Irs2), as well as those involved in lipid metabolism, including Forkhead box protein O1 (FOXO1) and carnitine palmitoyl transferase 1 (CPT1) following GRE treatment. GRE showed a strong potential to ameliorate hepatic insulin resistance by improving insulin sensitivity through the regulation of PI3K/AKT, FOXO1 and AMPK-mediated pathways.

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