scholarly journals Hepatic microRNAs in Type II Diabetes Pathogenesis

2020 ◽  
Vol 3 ◽  
Author(s):  
Gene Qian ◽  
Nuria Morral
Keyword(s):  
Fatty Acid ◽  
Insulin Signaling ◽  
Mirna Expression ◽  
Metabolic Pathways ◽  
Type Ii Diabetes ◽  
Expression Profiles ◽  
Future Research ◽  
Acid Oxidation ◽  
Type Ii ◽  
Pubmed Database

Background/Objective:  Diabetes mellitus is a disease with increasing incidence worldwide affecting more than 435 million patients, most of whom have Type II diabetes (T2D). Of the many organs affected by T2D, the liver is responsible for much of the dysregulated metabolic pathways in response to insulin signaling. These include, but are not limited to gluconeogenesis, glycogen storage, fatty acid and cholesterol biosynthesis and transport, and fatty acid oxidation. Recent studies show significant differences in miRNA expression profiles between healthy and disease states of T2D. This implicates an important role of miRNAs in T2D pathogenesis and makes miRNAs an attractive therapeutic target and diagnostic marker for T2D patients. The aim of this review is to provide an overview of the hepatic miRNAs relevant to T2D pathogenesis.    Methods:  We compiled and reviewed articles from the PubMed database that were relevant to miRNAs and T2D pathogenesis in the liver.    Results:  We found that hepatic miRNAs affect most if not all dysregulated metabolic pathways in T2D pathogenesis, which we categorized into carbohydrate metabolism, lipid metabolism, and insulin signaling. The miRNAs that are most represented in our literature include miR-122, miR-33a/b, miR-29, and miR-21. These miRNAs target a variety of molecules, including transcription factors that are master regulators of metabolic pathways (FOXO1, HNF4α), lipid transporters (ABCA1, ABCG1), or key insulin signaling molecules (IRS1/2, caveolin-1). In addition, circulating miR-122 is associated with the risk of developing metabolic syndrome and T2D in the general population.    Conclusion and Potential Impact:  Multiple miRNAs are dysregulated in the liver of animal models of T2D. Administration of miRNA mimics or antagomirs to correct aberrant miRNA expression improved the pathophysiology in vivo. miRNAs are also promising tools as markers for disease development. Ultimately, the identification of miRNAs can guide future research to facilitate the diagnosis and improve the treatment of T2D. 

scholarly journals Nonalcoholic Fatty Hepatitis: An Important Clinical Condition

1989 ◽  
Vol 3 (5) ◽  
pp. 189-197 ◽  
Author(s):  
Samuel W. French ◽  
Leslie B. Eidus ◽  
J. Freeman
Keyword(s):  
Fatty Acid ◽  
Clinical Condition ◽  
Type Ii Diabetes ◽  
Acid Oxidation ◽  
Clinical Settings ◽  
Type Ii ◽  
Fatty Change ◽  
Body Formation ◽  
The Common ◽  
Clinical Conditions

The entity fatty hepatitis is defined and the literature characterizing the clinical settings in which it develops is reviewed. The pathogenesis is discussed with emphasis on the common denominators shared by the various clinical conditions with which it is associated. The roles of alcohol, obesity and type II diabetes are stressed where inhibition of fatty acid oxidation by the liver is the basic defect in metabolism leading to fatty change, balloon degeneration and Mallory body formation. It is concluded that this important entity is more common than is generally appreciated.

Abstract 282: Adropin Enhancement of Cardiac Insulin Sensitivity and Inhibition of Fatty Acid Oxidation are Associated With Improvement of Cardiac Function and Efficiency in Hearts From Fasted Mice

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Tariq R Altamimi ◽  
Arata Fukushima ◽  
Liyan Zhang ◽  
Su Gao ◽  
Abhishek Gupta ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Diabetic Cardiomyopathy ◽  
Insulin Signaling ◽  
Plasma Levels ◽  
Acid Oxidation ◽  
Post Translational Modification ◽  
Cardiac Efficiency ◽  
Oxidation Rates ◽  
Cardiac Energy

Impaired cardiac insulin signaling and high cardiac fatty acid oxidation rates are characteristics of diabetic cardiomyopathy. Potential roles for liver-derived metabolic factors in mediating cardiac energy homeostasis are underappreciated. Plasma levels of adropin, a liver secreted peptide, increase during feeding and decrease during fasting and diabetes. In skeletal muscle, adropin preferentially promotes glucose over fatty acid oxidation. We therefore determined what effect adropin has on cardiac energy metabolism, insulin signaling and cardiac efficiency. C57Bl/6 mice were fasted to accentuate the differences in adropin plasma levels between animals injected 3 times over 24 hr with either vehicle or adropin (450 nmol/kg i.p.). Despite fasting-induced predominance of fatty acid oxidation measured in isolated working hearts, insulin inhibition of fatty acid oxidation was re-established in adropin-treated mice (from 1022±143 to 517±56 nmol. g dry wt -1 . min -1 , p <0.05) compared to vehicle-treated mice (from 757±104 to 818±103 nmol. g dry wt -1 . min -1 ). Adropin-treated mice hearts showed higher cardiac work over the course of perfusion (p<0.05 vs. vehicle), which was accompanied by improved cardiac efficiency and enhanced phosphorylation of insulin signaling enzymes (tyrosine-IRS-1, AS160, p<0.05). Acute addition of adropin (2nM) to isolated working hearts from non-fasting mice showed a robust stimulation of glucose oxidation compared to vehicle-treated hearts (3025±401 vs 1708±292 nmol. g dry wt -1 . min -1 , p<0.05, respectively) with a corresponding inhibition of palmitate oxidation (325±61 vs 731±160 nmol. g dry wt -1 . min -1 , p<0.05, respectively), even in the presence of insulin. Acute adropin addition to hearts also increased IRS-1 tyrosine-phosphorylation as well as Akt, and GSK3β phosphorylation (p<0.05), suggesting acute receptor- and/or post-translational modification-mediated mechanisms. These results suggest adropin as a putative candidate for the treatment of diabetic cardiomyopathy.

scholarly journals Overexpression of Long-Chain Acyl-CoA Synthetase 5 Increases Fatty Acid Oxidation and Free Radical Formation While Attenuating Insulin Signaling in Primary Human Skeletal Myotubes

2019 ◽  
Vol 16 (7) ◽  
pp. 1157 ◽  
Author(s):  
Hyo-Bum Kwak ◽  
Tracey Woodlief ◽  
Thomas Green ◽  
Julie Cox ◽  
Robert Hickner ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Free Radical ◽  
Fatty Acid Oxidation ◽  
Insulin Signaling ◽  
Human Skeletal Muscle ◽  
Acid Oxidation ◽  
Protein Levels ◽  
Human Skeletal Muscle Cells ◽  
Mitochondrial Fatty Acid

In rodent skeletal muscle, acyl-coenzyme A (CoA) synthetase 5 (ACSL-5) is suggested to localize to the mitochondria but its precise function in human skeletal muscle is unknown. The purpose of these studies was to define the role of ACSL-5 in mitochondrial fatty acid metabolism and the potential effects on insulin action in human skeletal muscle cells (HSKMC). Primary myoblasts isolated from vastus lateralis (obese women (body mass index (BMI) = 34.7 ± 3.1 kg/m2)) were transfected with ACSL-5 plasmid DNA or green fluorescent protein (GFP) vector (control), differentiated into myotubes, and harvested (7 days). HSKMC were assayed for complete and incomplete fatty acid oxidation ([1-14C] palmitate) or permeabilized to determine mitochondrial respiratory capacity (basal (non-ADP stimulated state 4), maximal uncoupled (carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP)-linked) respiration, and free radical (superoxide) emitting potential). Protein levels of ACSL-5 were 2-fold higher in ACSL-5 overexpressed HSKMC. Both complete and incomplete fatty acid oxidation increased by 2-fold (p < 0.05). In permeabilized HSKMC, ACSL-5 overexpression significantly increased basal and maximal uncoupled respiration (p < 0.05). Unexpectedly, however, elevated ACSL-5 expression increased mitochondrial superoxide production (+30%), which was associated with a significant reduction (p < 0.05) in insulin-stimulated p-Akt and p-AS160 protein levels. We concluded that ACSL-5 in human skeletal muscle functions to increase mitochondrial fatty acid oxidation, but contrary to conventional wisdom, is associated with increased free radical production and reduced insulin signaling.

Phospholipid and fatty acid composition of erythrocytes in type I and type II diabetes

Metabolism ◽  
1989 ◽  
Vol 38 (7) ◽  
pp. 673-678 ◽  
Author(s):  
G. Freyburger ◽  
H. Gin ◽  
A. Heape ◽  
H. Juguelin ◽  
M.R. Boisseau ◽  
...  
Keyword(s):  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Acid Composition ◽  
Type Ii Diabetes ◽  
Type I ◽  
Type Ii

High PRMT1 Expression Promotes the Progression of Acute Megakaryocytic Leukemia Via Controlling Metabolic Pathways

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1551-1551
Author(s):  
Hairui Su ◽  
Han Guo ◽  
Ngoc-Tung Tran ◽  
Minkui Luo ◽  
Xinyang Zhao
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Metabolic Pathways ◽  
Metabolic Stress ◽  
Metabolic Reprogramming ◽  
Metabolic Inhibitors ◽  
Acid Oxidation ◽  
Epigenetic Changes ◽  
Acute Megakaryocytic Leukemia ◽  
Megakaryocyte Differentiation

Abstract Metabolic reprogramming is needed not only to accommodate but also to drive leukemia progression. Yet very little is known on genetic factors other than IDH1 mutations, which can drive leukemogenesis via metabolic reprogramming. Here, we will present data to suggest that protein arginine methyltransferases 1 (PRMT1) is a driver for acute megakaryocytic leukemia via reprogramming metabolism. PRMT1 is highly expressed in megakaryocyte-erythrocyte progenitor cells and downregulated during the terminal differentiation of megakaryocytes. Constitutively high expression of PRMT1 in acute megakaryoblastic leukemia (AMKL) blocks megakaryocyte differentiation. PRMT1 upregulates RBM15 protein level via methylation-dependent ubiquitylation pathway (Zheng et al. Elife, 2015). In this presentation, we discovered that metabolic stress such as hypoxia downregulates PRMT1 protein level. Thus, metabolic stress is the upstream signal for the PRMT1-RBM15 pathway. We have identified that RBM15 specifically binds to 3'UTR of mRNAs of genes involved in metabolic pathways. Using RNA-immunoprecipitation with anti-RBM15 antibody and real-time PCR assays, we validated that RBM15 binds to mRNAs of genes involved in fatty acid oxidation and glycolysis. We transduced PRMT1 into an RBM15-MKL1 expressing cell line 6133. Overexpression of PRMT1 renders 6133 cells to grow in a cytokine-independent manner with increased mitochondria biogenesis, which in turn produces higher concentration of ATP in our metabolomic analysis. Based on the analysis of metabolomics data and RBM15-target genes, we conclude that PRMT1 promotes the usage of glucose as bioenergy via oxidative phosphorylation and inhibits fatty acid oxidation. Given that acetyl-coA is higher in PRMT1 expressing 6133 cells, we asked whether histone acetylation is upregulated in PRMT1 overexpressed 6133 cells. Indeed, we found higher histone acetylation level in PRMT1 highly expressed cells. We also found that propionylated histone is reduced, which is consistent with reduced fatty acid oxidation. Propionyl-CoA molecules are produced from fatty acids with odd carbon numbers. Thus PRMT1-mediated metabolic reprogramming changes epigenetic programming during leukemia progression. Intriguing, we also found PRMT1 overexpression enhances histone H3S10 phosphorylation via methylation-dependent ubiquitylation of DUSP4. DUSP4 promotes polyploidy during megakaryocyte differentiation. Thus PRMT1 caused profound epigenetic changes to promote leukemogenesis. In this vein, we established mouse AMKL models by bone marrow transplantation of 6133 cells as well as human AMKL patient samples respectively. Using this mouse model, we tested PRMT1 inhibitors, acetyltransferase inhibitors as well as other metabolic inhibitors. Treating cells with PRMT1 inhibitors as well as metabolic inhibitors promote MK differentiation of AMKL leukemia cells. Metabolomics analysis of cells recovered from mouse models will be discussed in the presentation. In summary, our data demonstrated that PRMT1 is a major sensor for metabolic stress and that PRMT1 in turn reprograms metabolic pathways to bring epigenetic changes in leukemogenesis. Therefore, targeting PRMT1 and downstream PRMT1-regulated metabolic pathways will offer new avenues in treating acute megakaryocytic leukemia and other hematological malignancies with defective megakaryocyte differentiation. Disclosures No relevant conflicts of interest to declare.

Discovery of Potent and Selective Agonists for the Free Fatty Acid Receptor 1 (FFA1/GPR40), a Potential Target for the Treatment of Type II Diabetes

2008 ◽  
Vol 51 (22) ◽  
pp. 7061-7064 ◽  
Author(s):  
Elisabeth Christiansen ◽  
Christian Urban ◽  
Nicole Merten ◽  
Kathrin Liebscher ◽  
Kasper K. Karlsen ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Free Fatty Acid ◽  
Type Ii Diabetes ◽  
Type Ii ◽  
Acid Receptor ◽  
Potential Target ◽  
Free Fatty Acid Receptor ◽  
Selective Agonists ◽  
Fatty Acid Receptor

scholarly journals Quantifying the patterns of metabolic plasticity and heterogeneity along the epithelial-hybrid-mesenchymal spectrum in cancer

2021 ◽  
Author(s):  
Srinath Muralidharan ◽  
Sarthak Sahoo ◽  
Aryamaan Saha ◽  
Sanjay Chandran ◽  
Sauma Suvra Majumdar ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Oxidative Phosphorylation ◽  
Cancer Cells ◽  
Metabolic Pathways ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Acid Oxidation ◽  
Mesenchymal Transition ◽  
Metabolic Plasticity ◽  
Cell Data

Cancer metastasis is the leading cause of cancer-related mortality and the process of Epithelial to Mesenchymal Transition (EMT) is crucial for cancer metastasis. Either a partial or complete EMT have been reported to influence the metabolic plasticity of cancer cells in terms of switching among oxidative phosphorylation, fatty acid oxidation and glycolysis pathways. However, a comprehensive analysis of these major metabolic pathways their associations with EMT across different cancers is lacking. Here, we analyse more than 180 cancer cell datasets and show diverse associations of these metabolic pathways with the EMT status of cancer cells. Our bulk data analysis shows that EMT generally positively correlates with glycolysis but negatively with oxidative phosphorylation and fatty acid metabolism. These correlations are also consistent at the level of their molecular master regulators, namely AMPK and HIF1α. Yet, these associations are shown to not be universal. Analysis of single-cell data of EMT induction shows dynamic changes along the different axes of metabolic pathways, consistent with general trends seen in bulk samples. Together, our results reveal underlying patterns of metabolic plasticity and heterogeneity as cancer cells traverse through the epithelial-hybrid-mesenchymal spectrum of states.

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