scholarly journals Hepatic Transcriptomics Reveals that Lipogenesis Is a Key Signaling Pathway in Isocitrate Dehydrogenase 2 Deficient Mice

Genes ◽  
2019 ◽  
Vol 10 (9) ◽  
pp. 728
Author(s):  
Jeong Hoon Pan ◽  
Jingsi Tang ◽  
Mersady C. Redding ◽  
Kaleigh E. Beane ◽  
Cara L. Conner ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Isocitrate Dehydrogenase ◽  
De Novo ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Tca Cycle ◽  
De Novo Lipogenesis ◽  
Oxidative Decarboxylation ◽  
Qpcr Analysis ◽  
Isocitrate Dehydrogenase 2 ◽  
Mice Liver

Mitochondrial nicotinamide adenine dinucleotide phosphate (NADP+)-dependent isocitrate dehydrogenase (IDH2) plays a key role in the intermediary metabolism and energy production via catalysing oxidative decarboxylation of isocitrate to α-ketoglutarate in the tricarboxylic acid (TCA) cycle. Despite studies reporting potential interlinks between IDH2 and various diseases, there is lack of effort to comprehensively characterize signature(s) of IDH2 knockout (IDH2 KO) mice. A total of 6583 transcripts were identified from both wild-type (WT) and IDH2 KO mice liver tissues. Afterwards, 167 differentially expressed genes in the IDH2 KO group were short-listed compared to the WT group based on our criteria. The online bioinformatic analyses indicated that lipid metabolism is the most significantly influenced metabolic process in IDH2 KO mice. Moreover, the TR/RXR activation pathway was predicted as the top canonical pathway significantly affected by IDH2 KO. The key transcripts found in the bioinformatic analyses were validated by qPCR analysis, corresponding to the transcriptomics results. Further, an additional qPCR analysis confirmed that IDH2 KO caused a decrease in hepatic de novo lipogenesis via the activation of the fatty acid β-oxidation process. Our unbiased transcriptomics approach and validation experiments suggested that IDH2 might play a key role in homeostasis of lipid metabolism.

scholarly journals Lipid Metabolism Is Dysregulated before, during and after Pregnancy in a Mouse Model of Gestational Diabetes

2021 ◽  
Vol 22 (14) ◽  
pp. 7452
Author(s):  
Samuel Furse ◽  
Denise S. Fernandez-Twinn ◽  
Davide Chiarugi ◽  
Albert Koulman ◽  
Susan E. Ozanne
Keyword(s):  
Lipid Metabolism ◽  
Gestational Diabetes ◽  
Glucose Tolerance ◽  
Mouse Model ◽  
Time Course ◽  
De Novo ◽  
Lipid Analysis ◽  
Temporal Distribution ◽  
De Novo Lipogenesis ◽  
Analysis Tool

The aim of the current study was to test the hypothesis that maternal lipid metabolism was modulated during normal pregnancy and that these modulations are altered in gestational diabetes mellitus (GDM). We tested this hypothesis using an established mouse model of diet-induced obesity with pregnancy-associated loss of glucose tolerance and a novel lipid analysis tool, Lipid Traffic Analysis, that uses the temporal distribution of lipids to identify differences in the control of lipid metabolism through a time course. Our results suggest that the start of pregnancy is associated with several changes in lipid metabolism, including fewer variables associated with de novo lipogenesis and fewer PUFA-containing lipids in the circulation. Several of the changes in lipid metabolism in healthy pregnancies were less apparent or occurred later in dams who developed GDM. Some changes in maternal lipid metabolism in the obese-GDM group were so late as to only occur as the control dams’ systems began to switch back towards the non-pregnant state. These results demonstrate that lipid metabolism is modulated in healthy pregnancy and the timing of these changes is altered in GDM pregnancies. These findings raise important questions about how lipid metabolism contributes to changes in metabolism during healthy pregnancies. Furthermore, as alterations in the lipidome are present before the loss of glucose tolerance, they could contribute to the development of GDM mechanistically.

scholarly journals Glial Hedgehog and lipid metabolism regulate neural stem cell proliferation in Drosophila

2020 ◽  
Author(s):  
Qian Dong ◽  
Michael Zavortink ◽  
Francesca Froldi ◽  
Sofya Golenkina ◽  
Tammy Lam ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Cell Cycle Progression ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Post Translational Modification ◽  
Final Size ◽  
Neural Lineage ◽  
Signalling Molecule ◽  
Lipid Metabolism Genes ◽  
And Function

AbstractThe final size and function of the adult central nervous system (CNS) is determined by neuronal lineages generated by neural stem cells (NSCs) in the developing brain. In Drosophila, NSCs called neuroblasts (NBs) reside within a specialised microenvironment called the glial niche. Here, we explore non-autonomous glial regulation of NB proliferation. We show that lipid droplets (LDs) which reside within the glial niche are closely associated with the signalling molecule Hedgehog (Hh). Under physiological conditions, cortex glial Hh is autonomously required to sustain niche chamber formation, and non-autonomously restrained to prevent ectopic Hh signalling in the NBs. In the context of cortex glial overgrowth, induced by Fibroblast Growth Factor (FGF) activation, Hh and lipid storage regulators Lsd-2 and Fasn1 were upregulated, resulting in activation of Hh signalling in the NBs; which in turn disrupted NB cell cycle progression and reduced neuronal production. We show that the LD regulator Lsd-2 modulates Hh’s ability to signal to NBs, and de novo lipogenesis gene Fasn1 regulates Hh post-translational modification via palmitoylation. Together, our data suggest that the glial niche non-autonomously regulates NB proliferation and neural lineage size via Hh signaling that is modulated by lipid metabolism genes.

scholarly journals AMPK Activation Reduces Hepatic Lipid Content by Increasing Fat Oxidation In Vivo

2018 ◽  
Vol 19 (9) ◽  
pp. 2826 ◽  
Author(s):  
Marc Foretz ◽  
Patrick Even ◽  
Benoit Viollet
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
Fat Oxidation ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Ampk Activation ◽  
Hepatic Lipid ◽  
Adenoviral Delivery ◽  
Body Production

The energy sensor AMP-activated protein kinase (AMPK) is a key player in the control of energy metabolism. AMPK regulates hepatic lipid metabolism through the phosphorylation of its well-recognized downstream target acetyl CoA carboxylase (ACC). Although AMPK activation is proposed to lower hepatic triglyceride (TG) content via the inhibition of ACC to cause inhibition of de novo lipogenesis and stimulation of fatty acid oxidation (FAO), its contribution to the inhibition of FAO in vivo has been recently questioned. We generated a mouse model of AMPK activation specifically in the liver, achieved by expression of a constitutively active AMPK using adenoviral delivery. Indirect calorimetry studies revealed that liver-specific AMPK activation is sufficient to induce a reduction in the respiratory exchange ratio and an increase in FAO rates in vivo. This led to a more rapid metabolic switch from carbohydrate to lipid oxidation during the transition from fed to fasting. Finally, mice with chronic AMPK activation in the liver display high fat oxidation capacity evidenced by increased [C14]-palmitate oxidation and ketone body production leading to reduced hepatic TG content and body adiposity. Our findings suggest a role for hepatic AMPK in the remodeling of lipid metabolism between the liver and adipose tissue.

scholarly journals DHT Causes Liver Steatosis via Transcriptional Regulation of SCAP in Lean female Mice

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. A807-A807
Author(s):  
Stanley Andrisse ◽  
Jessie Myer ◽  
Dilip “Bobby” Bogle ◽  
Nicole Eregha ◽  
Taylor Lofton
Keyword(s):  
Lipid Metabolism ◽  
Protein Expression ◽  
Low Dose ◽  
De Novo ◽  
Polycystic Ovary ◽  
Liver Steatosis ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Female Mice ◽  
Real Time Quantitative Pcr

Abstract Hyperandrogenemia (HA) and insulin resistance are hallmarks of polycystic ovary syndrome (PCOS). These hallmarks are also integral elements of non-alcoholic fatty liver disease (NALFD). Administering low dose dihydrotestosterone (DHT) induced a lean PCOS-like female mouse model. The molecular mechanism of HA-induced NAFLD has not been determined. We hypothesized that low dose DHT would interrupt hepatic lipid metabolism leading to NAFLD. We extracted white adipose tissue (WAT), liver, and skeletal muscle from control and low dose DHT female mice; and performed histological and biochemical lipid profiles, Western blot, immunoprecipitation, chromatin immunoprecipitation, and real-time quantitative PCR analyses. DHT lowered the 65 kD form of cytosolic SREBP1 in the liver and WAT compared to controls. However, DHT did not alter the levels of the active and inactive forms of SREBP2 in the liver and WAT. DHT increased SCAP protein expression and SCAP-SREBP1 binding via AR binding to intron-8 of SCAP leading to increased SCAP mRNA. FAS mRNA and protein expression was increased in liver of DHT mice. p-ACC levels were unaltered in liver but decreased in WAT. Other lipid metabolism pathways were examined in liver and WAT, but no changes were observed. Our findings suggest that DHT increased de novo lipogenic proteins resulting in increased NAFLD via regulation of SREBP1 in liver. We show that in the presence of DHT the SCAP-SREBP1 interaction is elevated leading to increased nuclear SREBP1 resulting in increased de novo lipogenesis. We propose that the mechanism of action is increased AR binding to an ARE in SCAP intron-8.

scholarly journals Central Resistin Regulates Hypothalamic and Peripheral Lipid Metabolism in a Nutritional-Dependent Fashion

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4534-4543 ◽  
Author(s):  
María J. Vázquez ◽  
C. Ruth González ◽  
Luis Varela ◽  
Ricardo Lage ◽  
Sulay Tovar ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Mrna Expression ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Acid Synthesis ◽  
Inhibitory Effect ◽  
De Novo Lipogenesis ◽  
Dependent Manner ◽  
Fed State

Evidence suggests that the adipocyte-derived hormone resistin (RSTN) directly regulates both feeding and peripheral metabolism through, so far, undefined hypothalamic-mediated mechanisms. Here, we demonstrate that the anorectic effect of RSTN is associated with inappropriately decreased mRNA expression of orexigenic (agouti-related protein and neuropeptide Y) and increased mRNA expression of anorexigenic (cocaine and amphetamine-regulated transcript) neuropeptides in the arcuate nucleus of the hypothalamus. Of interest, RSTN also exerts a profound nutrition-dependent inhibitory effect on hypothalamic fatty acid metabolism, as indicated by increased phosphorylation levels of both AMP-activated protein kinase and its downstream target acetyl-coenzyme A carboxylase, associated with decreased expression of fatty acid synthase in the ventromedial nucleus of the hypothalamus. In addition, we also demonstrate that chronic central RSTN infusion results in decreased body weight and major changes in peripheral expression of lipogenic enzymes, in a tissue-specific and nutrition-dependent manner. Thus, in the fed state central RSTN is associated with induced expression of fatty acid synthesis enzymes and proinflammatory cytokines in liver, whereas its administration in the fasted state does so in white adipose tissue. Overall, our results indicate that RSTN controls feeding and peripheral lipid metabolism and suggest that hepatic RSTN-induced insulin resistance may be mediated by central activation of de novo lipogenesis in liver.

scholarly journals Effect of Central Corticotropin-Releasing Factor on Hepatic Lipid Metabolism and Inflammation-Related Gene Expression in Rats

2021 ◽  
Vol 22 (8) ◽  
pp. 3940
Author(s):  
Yukiomi Nakade ◽  
Rena Kitano ◽  
Taeko Yamauchi ◽  
Satoshi Kimoto ◽  
Kazumasa Sakamoto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lipid Metabolism ◽  
De Novo ◽  
Corticotropin Releasing Factor ◽  
De Novo Lipogenesis ◽  
Control Group ◽  
Mrna Levels ◽  
Related Gene ◽  
Hepatic Lipid Metabolism ◽  
Hepatic Lipid

Corticotropin-releasing factor (CRF) in the brain acts on physiological and pathophysiological modulation of the hepatobiliary system. Central CRF administration aggravates experimental acute liver injury by decreasing hepatic blood flow. Conversely, minimal evidence is available regarding the effect of centrally acting CRF on hepatic lipid metabolism and inflammation. We examined whether central CRF affects hepatic lipid metabolism and inflammation-related gene expression in rats. Male Long Evans rats were intracisternally injected with CRF (10 μg) or saline. Rats were sacrificed 2 h, 6 h, and 24 h after the CRF injection, the liver was isolated, and mRNA was extracted. Next, hepatic lipid metabolism and inflammation-related gene expression were examined. Hepatic SREBF1 (sterol regulatory element-binding transcription factor 1) mRNA levels were significantly increased 6 h and 24 h after intracisternal CRF administration when compared with those in the control group. Hepatic TNFα and IL1β mRNA levels increased significantly 6 h after intracisternal CRF administration. Hepatic sympathectomy or guanethidine treatment, not hepatic branch vagotomy or atropine treatment, inhibited central CRF-induced increase in hepatic SREBF1, TNFα and IL1β mRNA levels. These results indicated that central CRF affects hepatic de novo lipogenesis and inflammation-related gene expression through the sympathetic-noradrenergic nervous system in rats.

scholarly journals Fructose-enriched diet affects hepatic lipid metabolism in young male and female rats in different ways

2019 ◽  
Vol 71 (3) ◽  
pp. 417-424 ◽  
Author(s):  
Jelena Brkljacic ◽  
Natasa Velickovic ◽  
Ivana Elakovic ◽  
Ana Teofilovic ◽  
Danijela Vojnovic-Milutinovic ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Female Rats ◽  
Acid Oxidation ◽  
Hepatic Lipid Metabolism ◽  
Male And Female ◽  
Hepatic Lipid ◽  
Male And Female Rats ◽  
Dietary Fructose

An increase in fructose consumption coincides with a rising incidence of metabolic disorders. Dietary fructose has been shown to affect hepatic lipid metabolism in a way that may lead to lipid deposition in the liver. In this study, we tested the hypothesis that the effects of fructose overconsumption on hepatic lipid metabolism differ between sexes. To that end we examined the effects of a high-fructose diet on the expression of key enzymes and transcription factors involved in the regulation of fatty acid oxidation and de novo lipogenesis in the liver of 12-week-old male and female Wistar rats. Immediately after weaning, the rats were subjected to a standard diet and 10% fructose solution or drinking water for 9 weeks. The fructose-enriched diet induced hypertriglyceridemia and increased hepatic de novo lipogenesis in both sexes, without lipid deposition in the liver. At the same time, visceral adiposity was observed only in female rats, while in males the treatment stimulated hepatic fatty acid oxidation. The fructose-enriched diet induced sex-specific effects on hepatic lipid metabolism in young rats. These results imply that male and female rats employ different strategies to cope with dietary fructose-related energy overload and to avoid lipid accumulation in the liver. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. III41009]

Quantitative analysis of acetoacetate metabolism in AS-30D hepatoma cells with 13C and 14C isotopic techniques

1997 ◽  
Vol 272 (6) ◽  
pp. E945-E951 ◽  
Author(s):  
A. L. Holleran ◽  
G. Fiskum ◽  
J. K. Kelleher
Keyword(s):  
De Novo ◽  
Lipid Synthesis ◽  
Tca Cycle ◽  
Hepatoma Cells ◽  
Dichloroacetic Acid ◽  
De Novo Lipogenesis ◽  
Ratio Method ◽  
Acetyl Coa ◽  
Isotopic Methods ◽  
Host Metabolism

Experimental hepatoma cells utilize acetoacetate as an oxidative energy source and as a precursor for lipid synthesis. The significance of ketone body metabolism in tumors lies in the study of tumor-host metabolism and the ketoneMic condition that is often present in cancer patients. The quantitative importance of acetoacetate and glucose was investigated in AS-30D cells with use of 13C and 14C isotopic methods. In addition, the effects of acetoacetate were compared with those of dichloroacetic acid (DCA), an activator of pyruvate dehydrogenase (PDH). The 14CO2 ratio method evaluated the entry of pyruvate into the tricarboxylic acid (TCA) cycle and revealed that acetoacetate diverted pyruvate from PDH to pyruvate carboxylation. In contrast, DCA increased the oxidation of glucose largely through PDH, indicating that PDH is not maximally active in the absence of DCA. Isotopomer spectral analysis of lipid synthesis demonstrated that, in the absence of acetoacetate, glucose supplied 65% of the acetyl-CoA used for de novo lipogenesis. When 5 mM acetoacetate was included in the incubation, glucose was displaced as a lipogenic precursor and acetoacetate supplied 85% of the acetyl-CoA for lipogenesis vs. only 2% for glucose. Thus AS-30D cells have a large capacity for acetoacetate utilization for de novo lipogenesis.

scholarly journals Circadian lipid synthesis in brown fat maintains murine body temperature during chronic cold

2019 ◽  
Vol 116 (37) ◽  
pp. 18691-18699 ◽  
Author(s):  
Marine Adlanmerini ◽  
Bryce J. Carpenter ◽  
Jarrett R. Remsberg ◽  
Yann Aubert ◽  
Lindsey C. Peed ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Body Temperature ◽  
Cold Exposure ◽  
De Novo ◽  
Lipid Synthesis ◽  
Acid Synthesis ◽  
High Amplitude ◽  
De Novo Lipogenesis ◽  
Brown Adipose ◽  
The Impact

Ambient temperature influences the molecular clock and lipid metabolism, but the impact of chronic cold exposure on circadian lipid metabolism in thermogenic brown adipose tissue (BAT) has not been studied. Here we show that during chronic cold exposure (1 wk at 4 °C), genes controlling de novo lipogenesis (DNL) includingSrebp1, the master transcriptional regulator of DNL, acquired high-amplitude circadian rhythms in thermogenic BAT. These conditions activated mechanistic target of rapamycin 1 (mTORC1), an inducer ofSrebp1expression, and engaged circadian transcriptional repressors REV-ERBα and β as rhythmic regulators ofSrebp1in BAT. SREBP was required in BAT for the thermogenic response to norepinephrine, and depletion of SREBP prevented maintenance of body temperature both during circadian cycles as well as during fasting of chronically cold mice. By contrast, deletion of REV-ERBα and β in BAT allowed mice to maintain their body temperature in chronic cold. Thus, the environmental challenge of prolonged noncircadian exposure to cold temperature induces circadian induction of SREBP1 that drives fuel synthesis in BAT and is necessary to maintain circadian body temperature during chronic cold exposure. The requirement for BAT fatty acid synthesis has broad implications for adaptation to cold.

scholarly journals Lipid Identification and Transcriptional Analysis of Controlling Enzymes in Bovine Ovarian Follicle

2018 ◽  
Vol 19 (10) ◽  
pp. 3261 ◽  
Author(s):  
Priscila Bertevello ◽  
Ana-Paula Teixeira-Gomes ◽  
Alexandre Seyer ◽  
Anaïs Vitorino Carvalho ◽  
Valérie Labas ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Lipid Composition ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Ovarian Follicle ◽  
Ovarian Follicles ◽  
De Novo Lipogenesis ◽  
Transcriptional Analysis ◽  
Follicular Cells ◽  
Metabolism Regulation

Ovarian follicle provides a favorable environment for enclosed oocytes, which acquire their competence in supporting embryo development in tight communications with somatic follicular cells and follicular fluid (FF). Although steroidogenesis in theca (TH) and granulosa cells (GC) is largely studied, and the molecular mechanisms of fatty acid (FA) metabolism in cumulus cells (CC) and oocytes are emerging, little data is available regarding lipid metabolism regulation within ovarian follicles. In this study, we investigated lipid composition and the transcriptional regulation of FA metabolism in 3–8 mm ovarian follicles in bovine. Using liquid chromatography and mass spectrometry (MS), 438 and 439 lipids were identified in FF and follicular cells, respectively. From the MALDI-TOF MS lipid fingerprints of FF, TH, GC, CC, and oocytes, and the MS imaging of ovarian sections, we identified 197 peaks and determined more abundant lipids in each compartment. Transcriptomics revealed lipid metabolism-related genes, which were expressed constitutively or more specifically in TH, GC, CC, or oocytes. Coupled with differential lipid composition, these data suggest that the ovarian follicle contains the metabolic machinery that is potentially capable of metabolizing FA from nutrient uptake, degrading and producing lipoproteins, performing de novo lipogenesis, and accumulating lipid reserves, thus assuring oocyte energy supply, membrane synthesis, and lipid-mediated signaling to maintain follicular homeostasis.

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