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

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.

Download Full-text

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

10.2337/figshare.13491342.v1 ◽

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.

Download Full-text

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

10.2337/figshare.13491342 ◽

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

Download Full-text

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

Endocrine Connections ◽

10.1530/ec-21-0248 ◽

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.

Download Full-text

Insulin Resistance, Ceramide Accumulation, and Endoplasmic Reticulum Stress in Human Chronic Alcohol-Related Liver Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2012/479348 ◽

2012 ◽

Vol 2012 ◽

pp. 1-17 ◽

Cited By ~ 56

Author(s):

Lisa Longato ◽

Kelsey Ripp ◽

Mashiko Setshedi ◽

Miroslav Dostalek ◽

Fatemeh Akhlaghi ◽

...

Keyword(s):

Insulin Resistance ◽

Lipid Metabolism ◽

Liver Disease ◽

Er Stress ◽

Enzyme Inhibitors ◽

Hepatic Insulin Resistance ◽

Stress Signaling ◽

Chronic Alcohol ◽

Related Liver Disease ◽

Ceramide Accumulation

Background. Chronic alcohol-related liver disease (ALD) is mediated by insulin resistance, mitochondrial dysfunction, inflammation, oxidative stress, and DNA damage. Recent studies suggest that dysregulated lipid metabolism with accumulation of ceramides, together with ER stress potentiate hepatic insulin resistance and may cause steatohepatitis to progress.Objective. We examined the degree to which hepatic insulin resistance in advanced human ALD is correlated with ER stress, dysregulated lipid metabolism, and ceramide accumulation.Methods. We assessed the integrity of insulin signaling through the Akt pathway and measured proceramide and ER stress gene expression, ER stress signaling proteins, and ceramide profiles in liver tissue.Results. Chronic ALD was associated with increased expression of insulin, IGF-1, and IGF-2 receptors, impaired signaling through IGF-1R and IRS1, increased expression of multiple proceramide and ER stress genes and proteins, and higher levels of the C14, C16, C18, and C20 ceramide species relative to control.Conclusions. In human chronic ALD, persistent hepatic insulin resistance is associated with dysregulated lipid metabolism, ceramide accumulation, and striking upregulation of multiple ER stress signaling molecules. Given the role of ceramides as mediators of ER stress and insulin resistance, treatment with ceramide enzyme inhibitors may help reverse or halt progression of chronic ALD.

Download Full-text

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

Molecular and Cellular Biology ◽

10.1128/mcb.00503-14 ◽

2014 ◽

Vol 35 (1) ◽

pp. 26-40 ◽

Cited By ~ 33

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.

Download Full-text