scholarly journals Role of miR-181c in Diet-Induced Obesity Through Regulation of Lipid Synthesis in Liver

2021 ◽  
Author(s):  
Kei Akiyoshi ◽  
Gretha J Boersma ◽  
Miranda D Johnson ◽  
Fernanda Carrizo Velasquez ◽  
Brittany Dunkerly-Eyring ◽  
...  
Keyword(s):  
Mitochondrial Gene ◽  
Lipid Synthesis ◽  
Mitochondrial Pathway ◽  
Isocitrate Dehydrogenase 1 ◽  
Diet Induced Obesity ◽  
Lipid Metabolism Disorders ◽  
Glucose Tolerance Tests ◽  
Insulin Insensitivity

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene (mt-COX1), and influence obesity-induced cardiac dysfunction through mitochondrial pathway. Liver plays a pivotal role during obesity. Therefore, we hypothesized that miR-181c plays an important role in pathophysiological complications associated with obesity. We used miR-181c/d -/- mice to study the miR-181c role in lipogenesis in hepatocytes during diet-induced obesity (DIO). Indirect calorimetric measurements were made during the 26 weeks high fat diet (HFD) exposure. qPCR was performed to examine the gene expression involved in lipid synthesis. Here, we show that miR-181c/d -/- mice are not protected against all metabolic consequences of HFD exposure. After 26 weeks of the HFD, miR-181c/d -/- mice had a significantly higher body fat (%) compared to WT. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d -/- mice. HFD-fed miR-181c/d -/- mice had higher serum and liver triglyceride levels compared to HFD-fed WT mice. qPCR data demonstrated that several genes which are regulated by isocitrate dehydrogenase 1 (IDH1) were upregulated in miR-181c/d -/- liver compared to WT liver. Furthermore, an AAV-8 was used to deliver miR-181c, in vivo , to validate the potential role of miR-181c in the liver. miR-181c delivery attenuate the lipogenesis by downregulating the same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

scholarly journals Role of miR-181c in Diet-induced obesity through regulation of lipid synthesis in liver

PLoS ONE ◽  
2021 ◽  
Vol 16 (12) ◽  
pp. e0256973
Author(s):  
Kei Akiyoshi ◽  
Gretha J. Boersma ◽  
Miranda D. Johnson ◽  
Fernanda Carrizo Velasquez ◽  
Brittany Dunkerly-Eyring ◽  
...  
Keyword(s):  
Mitochondrial Gene ◽  
Lipid Synthesis ◽  
Mitochondrial Pathway ◽  
Fat Percentage ◽  
Isocitrate Dehydrogenase 1 ◽  
Diet Induced Obesity ◽  
Expression Of Genes ◽  
Lipid Metabolism Disorders

We recently identified a nuclear-encoded miRNA (miR-181c) in cardiomyocytes that can translocate into mitochondria to regulate mitochondrial gene mt-COX1 and influence obesity-induced cardiac dysfunction through the mitochondrial pathway. Because liver plays a pivotal role during obesity, we hypothesized that miR-181c might contribute to the pathophysiological complications associated with obesity. Therefore, we used miR-181c/d-/- mice to study the role of miR-181c in hepatocyte lipogenesis during diet-induced obesity. The mice were fed a high-fat (HF) diet for 26 weeks, during which indirect calorimetric measurements were made. Quantitative PCR (qPCR) was used to examine the expression of genes involved in lipid synthesis. We found that miR-181c/d-/- mice were not protected against all metabolic consequences of HF exposure. After 26 weeks, the miR-181c/d-/- mice had a significantly higher body fat percentage than did wild-type (WT) mice. Glucose tolerance tests showed hyperinsulinemia and hyperglycemia, indicative of insulin insensitivity in the miR-181c/d-/- mice. miR-181c/d-/- mice fed the HF diet had higher serum and liver triglyceride levels than did WT mice fed the same diet. qPCR data showed that several genes regulated by isocitrate dehydrogenase 1 (IDH1) were more upregulated in miR-181c/d-/- liver than in WT liver. Furthermore, miR-181c delivered in vivo via adeno-associated virus attenuated the lipogenesis by downregulating these same lipid synthesis genes in the liver. In hepatocytes, miR-181c regulates lipid biosynthesis by targeting IDH1. Taken together, the data indicate that overexpression of miR-181c can be beneficial for various lipid metabolism disorders.

IL-4 increases surfactant and regulates metabolism in vivo

2000 ◽  
Vol 278 (1) ◽  
pp. L75-L80 ◽  
Author(s):  
Machiko Ikegami ◽  
Jeffrey A. Whitsett ◽  
Zissis C. Chroneos ◽  
Gary F. Ross ◽  
Jacquelyn A. Reed ◽  
...  
Keyword(s):  
Lipid Synthesis ◽  
Fold Increase ◽  
Surfactant Protein ◽  
Clara Cells ◽  
Wild Type ◽  
Surfactant Lipid ◽  
Alveolar Proteinosis ◽  
Selective Increase

Mice that express interleukin (IL)-4 in Clara cells (CCSP-IL-4) develop chronic airway inflammation and an alveolar proteinosis-like syndrome. To identify the role of IL-4 in surfactant homeostasis, we measured lipid and protein metabolism in the lungs of CCSP-IL-4 mice in vivo. Alveolar saturated phosphatidylcholine (Sat PC) pools were increased 6.5-fold and lung tissue Sat PC pools were increased 4.8-fold in the IL-4 transgenic mice. Whereas surfactant protein (SP) A was increased proportionately to Sat PC, SP-D was increased approximately 90-fold in the IL-4 mice compared with wild-type mice and was associated with 2.8-fold increase in SP-D mRNA. The incorporation of palmitate and choline into Sat PC was increased about twofold in CCSP-IL-4 mice. Although trace doses of radiolabeled Sat PC were cleared from the air spaces and lungs of CCSP-IL-4 mice more slowly than in wild-type mice, net clearance of Sat PC from the lungs of CCSP-IL-4 mice was sixfold higher in the IL-4 mice than in wild-type mice because of the larger Sat PC pool sizes. Expression of IL-4 in Clara cells increased surfactant lipid synthesis and clearance, establishing a new equilibrium with increased surfactant pools and an alveolar proteinosis associated with a selective increase in SP-D protein, demonstrating a previously unexpected effect of IL-4 in pulmonary surfactant homeostasis.

scholarly journals Detection of Metabolic Changes Induced via Drug Treatments in Live Cancer Cells and Tissue Using Raman Imaging Microscopy

Biosensors ◽  
2018 ◽  
Vol 9 (1) ◽  
pp. 5 ◽  
Author(s):  
Mioara Larion ◽  
Tyrone Dowdy ◽  
Victor Ruiz-Rodado ◽  
Matthew Meyer ◽  
Hua Song ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Idh1 Mutation ◽  
Raman Imaging ◽  
Metabolic Changes ◽  
Isocitrate Dehydrogenase 1 ◽  
Fibrosarcoma Cells ◽  
Drug Treatments

Isocitrate dehydrogenase 1 (IDH1) mutations in gliomas, fibrosarcoma, and other cancers leads to a novel metabolite, D-2-hydroxyglutarate, which is proposed to cause tumorigenesis. The production of this metabolite also causes vulnerabilities in cellular metabolism, such as lowering NADPH levels. To exploit this vulnerability, we treated glioma and fibrosarcoma cells that harbor an IDH1 mutation with an inhibitor of nicotinamide adenine dinucleotide (NAD+) salvage pathway, FK866, and observed decreased viability in these cells. To understand the mechanism of action by which the inhibitor FK866 works, we used Raman imaging microscopy and identified that proteins and lipids are decreased upon treatment with the drug. Raman imaging showed a different distribution of lipids throughout the cell in the presence of the drug compared with the untreated cells. We employed nuclear magnetic resonance NMR spectroscopy and mass spectrometry to identify the classes of lipids altered. Our combined analyses point to a decrease in cell division due to loss of lipid content that contributes to membrane formation in the in vitro setting. However, the FK866 drug did not have the same potency in vivo. The use of Raman imaging microscopy indicated an opposite trend of lipid distribution in the tissue collected from treated versus untreated mice when compared with the cells. These results demonstrate the role of Raman imaging microscopy to identify and quantify metabolic changes in cancer cells and tissue.

scholarly journals Impairment of the Gβγ-SNAP25 brake on exocytosis enhances insulin action, protects against diet-induced obesity, and promotes adipocyte browning

2020 ◽  
Author(s):  
Ryan P. Ceddia ◽  
Zack Zurawski ◽  
Analisa Thompson Gray ◽  
Feyisayo Adegboye ◽  
Fubiao Shi ◽  
...  
Keyword(s):  
High Fat Diet ◽  
Adrenergic Receptor ◽  
Snare Complex ◽  
Diet Induced Obesity ◽  
Voltage Gated Calcium Channels ◽  
Energy Stores ◽  
Vesicle Exocytosis ◽  
Glucose Stimulated Insulin Secretion

The Gβγ complex inhibits vesicle exocytosis by two mechanisms: inhibiting calcium entry by binding to voltage gated calcium channels, and binding to SNAP25 in the SNAP Receptor (SNARE) complex. To de-convolute the role of each of these mechanisms in vivo, we have made a mouse with the second mechanism disabled. The SNAP25Δ3 mutation renders the SNARE complex deficient in binding to Gβγ and was used to investigate the importance of the Gβγ-SNAP25 interaction in glucose stimulated insulin secretion (GSIS) and global metabolic homeostasis. GSIS and α2A adrenergic receptor-mediated inhibition of GSIS were not altered in SNAP25Δ3/Δ3 mice. Nevertheless, SNAP25Δ3/Δ3 mice exhibited a marked improvement in insulin sensitivity and were resistant to weight gain when challenged with a high fat diet (HFD). Reduced food consumption in the early stages of HFD feeding were partly responsible for the inability of SNAP25Δ3/Δ3 mice to gain weight on HFD. Additionally, improved insulin-mediated glucose uptake into white adipose tissue and increased ‘browning’ were observed in SNAP25Δ3/Δ3 mice, which is consistent with an impaired ability to retain energy stores. These phenotypic changes in SNAP25Δ3/Δ3 mice are all metabolically protective, indicating that pharmacological targeting of the Gβγ-SNAP25 interaction may have a metabolic benefit.

scholarly journals The role of chloroplasts and microsomal fractions in polar-lipid synthesis from [1-14C]acetate by cell-free preparations from spinach (Spinacia oleracea) leaves

1980 ◽  
Vol 188 (1) ◽  
pp. 17-24 ◽  
Author(s):  
P G Roughan ◽  
R Holland ◽  
C R Slack
Keyword(s):  
Fatty Acids ◽  
Microsomal Fraction ◽  
Spinacia Oleracea ◽  
Lipid Synthesis ◽  
Free Medium ◽  
Plant Lipid ◽  
Esterified Fatty Acids ◽  
Isolated Chloroplasts

1. Isolated spinach (Spinacia oleracea) chloroplasts were incapable of accumulating polar lipids when incubated with [1-14C]acetate in a cofactor-free medium. When CoA, ATP and glycerol 3-phosphate were added to incubation media, the accumulated products were non-esterified fatty acids, acyl-CoA and 1,2-diacylglycerol, all intermediates of lipid metabolism. 2. Chloroplast acyl-CoA was used to synthesize phosphatidylcholine only when a microsomal fraction was added back to the incubation medium. 3. The 1,2-diacylglycerol synthesized by isolated chloroplasts was converted almost quantitatively into diacylgalactosylglycerol when exogenous UDP-galactose was available. 4. Stereospecific analyses of the isolated lipids suggested that the diacylglycerol synthesized by isolated chloroplasts may be an important precursor for the synthesis in vivo of diacylgalactosylglycerol and phosphatidylglycerol but was unlikely to be a precursor of phosphatidylcholine. 5. A scheme for plant-lipid biosynthesis is presented that integrates the functions of chloroplasts, the cytoplasm and the endoplasmic reticulum.

scholarly journals HKDC1 Is a Novel Hexokinase Involved in Whole-Body Glucose Use

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3452-3461 ◽  
Author(s):  
Anton E. Ludvik ◽  
Carolina M. Pusec ◽  
Medha Priyadarshini ◽  
Anthony R. Angueira ◽  
Cong Guo ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Mouse Model ◽  
Glucose Homeostasis ◽  
Genome Wide Association Study ◽  
Whole Body ◽  
Glucose Levels ◽  
Genome Wide ◽  
Glucose Tolerance Tests

In a recent genome-wide association study, hexokinase domain-containing protein 1, or HKDC1, was found to be associated with gestational glucose levels during 2-hour glucose tolerance tests at 28 weeks of pregnancy. Because our understanding of the mediators of gestational glucose homeostasis is incomplete, we have generated the first transgenic mouse model to begin to understand the role of HKDC1 in whole-body glucose homeostasis. Interestingly, deletion of both HKDC1 alleles results in in utero embryonic lethality. Thus, in this study, we report the in vivo role of HKDC1 in whole-body glucose homeostasis using a heterozygous-deleted HKDC1 mouse model (HKDC1+/−) as compared with matched wild-type mice. First, we observed no weight, fasting or random glucose, or fasting insulin abnormalities with aging in male and female HKDC1+/− mice. However, during glucose tolerance tests, glucose levels were impaired in both female and male HKDC1+/− mice at 15, 30, and 120 minutes at a later age (28 wk of age). These glucose tolerance differences also existed in the female HKDC1+/− mice at earlier ages but only during pregnancy. And finally, the impaired glucose tolerance in HKDC1+/− mice was likely due to diminished whole-body glucose use, as indicated by the decreased hepatic energy storage and reduced peripheral tissue uptake of glucose in HKDC1+/− mice. Collectively, these data highlight that HKDC1 is needed to maintain whole-body glucose homeostasis during pregnancy but also with aging, possibly through its role in glucose use.

scholarly journals Depletion of Prmt1 in Adipocytes Impairs Glucose Homeostasis in Diet-Induced Obesity

2021 ◽  
Author(s):  
Seri Choi ◽  
Dahee Choi ◽  
Yun-Kyung Lee ◽  
Seung Hyun Ahn ◽  
Je Kyung Seong ◽  
...  
Keyword(s):  
Whole Body ◽  
Peripheral Tissues ◽  
Lipid Catabolism ◽  
Diet Induced Obesity ◽  
Insulin Tolerance ◽  
Impaired Insulin ◽  
Lipid Droplet Size ◽  
Mitochondrial Lipid

Protein arginine methyltransferase (PRMT) 1 is involved in the regulation of various metabolic pathways such as glucose metabolism in liver and atrophy in the skeletal muscle. However, the role of PRMT1 in the fat tissues under the disease state has not been elucidated to date. <p>Here, we delineate the function of this protein in adipocytes <i>in vivo</i>. PRMT1 expression was abundant in the white adipose tissues (WAT), which was induced upon high fat diet in mice as well as by obesity in humans. We found that adipocyte-specific depletion of <i>Prmt1</i> resulted in the decreased fat mass without overall changes in body weight in mice. Mechanistically, the depletion of <i>Prmt1</i> in WAT led to the activation of AMPK pathway, which was causal to the increased lipophagy, mitochondrial lipid catabolism and the resultant reduction in lipid droplet size in WAT <i>in vivo</i>. Interestingly, in spite of the increased energy expenditure, we observed a promotion of adipose tissue inflammation and an ectopic accumulation of triglycerides in the peripheral tissues in <i>Prmt1</i> adipocyte-specific knockout mice, which promoted the impaired insulin tolerance that is reminiscent of mouse models of lipodystrophy. These data collectively suggest that PRMT1 prevents WAT from excessive degradation of triglycerides by limiting AMPK-mediated lipid catabolism to control whole body metabolic homeostasis in diet-induced obesity conditions. </p>

scholarly journals Depletion of Prmt1 in Adipocytes Impairs Glucose Homeostasis in Diet-Induced Obesity

2021 ◽  
Author(s):  
Seri Choi ◽  
Dahee Choi ◽  
Yun-Kyung Lee ◽  
Seung Hyun Ahn ◽  
Je Kyung Seong ◽  
...  
Keyword(s):  
Whole Body ◽  
Peripheral Tissues ◽  
Lipid Catabolism ◽  
Diet Induced Obesity ◽  
Insulin Tolerance ◽  
Impaired Insulin ◽  
Lipid Droplet Size ◽  
Mitochondrial Lipid

Protein arginine methyltransferase (PRMT) 1 is involved in the regulation of various metabolic pathways such as glucose metabolism in liver and atrophy in the skeletal muscle. However, the role of PRMT1 in the fat tissues under the disease state has not been elucidated to date. <p>Here, we delineate the function of this protein in adipocytes <i>in vivo</i>. PRMT1 expression was abundant in the white adipose tissues (WAT), which was induced upon high fat diet in mice as well as by obesity in humans. We found that adipocyte-specific depletion of <i>Prmt1</i> resulted in the decreased fat mass without overall changes in body weight in mice. Mechanistically, the depletion of <i>Prmt1</i> in WAT led to the activation of AMPK pathway, which was causal to the increased lipophagy, mitochondrial lipid catabolism and the resultant reduction in lipid droplet size in WAT <i>in vivo</i>. Interestingly, in spite of the increased energy expenditure, we observed a promotion of adipose tissue inflammation and an ectopic accumulation of triglycerides in the peripheral tissues in <i>Prmt1</i> adipocyte-specific knockout mice, which promoted the impaired insulin tolerance that is reminiscent of mouse models of lipodystrophy. These data collectively suggest that PRMT1 prevents WAT from excessive degradation of triglycerides by limiting AMPK-mediated lipid catabolism to control whole body metabolic homeostasis in diet-induced obesity conditions. </p>

scholarly journals The role of prolactin and progesterone in the regulation of lipogenesis in maternal and foetal rat liver in vivo and in isolated hepatocytes during the last day of gestation

1986 ◽  
Vol 239 (1) ◽  
pp. 135-139 ◽  
Author(s):  
M Lorenzo ◽  
C Roncero ◽  
M Benito
Keyword(s):  
Rat Liver ◽  
Lipid Synthesis ◽  
Isolated Hepatocytes ◽  
Hepatic Lipogenesis ◽  
Treatment Conditions ◽  
Foetal Liver ◽  
Foetal Rat

The administration of progesterone on day 21 of gestation increases the rates of lipogenesis in the liver in vivo and in hepatocytes isolated from rats on day 22 of pregnancy. Bromocriptine administration increases the rates of hepatic lipogenesis in vivo, but has no effect on lipid synthesis in hepatocytes under the same treatment conditions. Concurrently, the administration of progesterone or bromocriptine on day 21 to the mother increases the rates of lipogenesis in the foetal liver in vivo on day 22. The rates of lipid synthesis in foetal isolated hepatocytes are increased by progesterone administration, but remain unchanged by bromocriptine.

Mitochondrial matrix calcium ions regulate energy production in myocardium: A cytochemical study

1990 ◽  
Vol 48 (2) ◽  
pp. 166-167
Author(s):  
W.A. Jacob ◽  
R. Hertsens ◽  
A. Van Bogaert ◽  
M. De Smet
Keyword(s):  
Energy Metabolism ◽  
Calcium Ions ◽  
Energy Production ◽  
Regulation Of Respiration ◽  
Free Calcium ◽  
Mitochondrial Matrix ◽  
Cytochemical Study ◽  
Nmr Techniques

In the past most studies of the control of energy metabolism focus on the role of the phosphorylation potential ATP/ADP.Pi on the regulation of respiration. Studies using NMR techniques have demonstrated that the concentrations of these compounds for oxidation phosphorylation do not change appreciably throughout the cardiac cycle and during increases in cardiac work. Hence regulation of energy production by calcium ions, present in the mitochondrial matrix, has been the object of a number of recent studies.Three exclusively intramitochondnal dehydrogenases are key enzymes for the regulation of oxidative metabolism. They are activated by calcium ions in the low micromolar range. Since, however, earlier estimates of the intramitochondnal calcium, based on equilibrium thermodynamic considerations, were in the millimolar range, a physiological correlation was not evident. The introduction of calcium-sensitive probes fura-2 and indo-1 made monitoring of free calcium during changing energy metabolism possible. These studies were performed on isolated mitochondria and extrapolation to the in vivo situation is more or less speculative.

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