scholarly journals FASN-dependent de novo lipogenesis is required for brain development

2022 ◽  
Vol 119 (2) ◽  
pp. e2112040119
Author(s):  
Daniel Gonzalez-Bohorquez ◽  
Isabel M. Gallego López ◽  
Baptiste N. Jaeger ◽  
Sibylle Pfammatter ◽  
Megan Bowers ◽  
...  
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Cell Polarity ◽  
Fatty Acid Synthase ◽  
Radial Glia ◽  
De Novo ◽  
Building Blocks ◽  
De Novo Lipogenesis ◽  
Mammalian Brain

Fate and behavior of neural progenitor cells are tightly regulated during mammalian brain development. Metabolic pathways, such as glycolysis and oxidative phosphorylation, that are required for supplying energy and providing molecular building blocks to generate cells govern progenitor function. However, the role of de novo lipogenesis, which is the conversion of glucose into fatty acids through the multienzyme protein fatty acid synthase (FASN), for brain development remains unknown. Using Emx1Cre-mediated, tissue-specific deletion of Fasn in the mouse embryonic telencephalon, we show that loss of FASN causes severe microcephaly, largely due to altered polarity of apical, radial glia progenitors and reduced progenitor proliferation. Furthermore, genetic deletion and pharmacological inhibition of FASN in human embryonic stem cell–derived forebrain organoids identifies a conserved role of FASN-dependent lipogenesis for radial glia cell polarity in human brain organoids. Thus, our data establish a role of de novo lipogenesis for mouse and human brain development and identify a link between progenitor-cell polarity and lipid metabolism.

scholarly journals Spatio-Temporal Roles of ASD-Associated Variants in Human Brain Development

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 535
Author(s):  
Yujin Kim ◽  
Joon-Yong An
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
De Novo ◽  
Autism Spectrum ◽  
Network Analyses ◽  
Regulatory Variants ◽  
Human Brain Development ◽  
Early Brain Development ◽  
Spatio Temporal

Transcriptional regulation of the genome arguably provides the basis for the anatomical elaboration and dynamic operation of the human brain. It logically follows that genetic variations affecting gene transcription contribute to mental health disorders, including autism spectrum disorder (ASD). A number of recent studies have shown the role of de novo variants (DNVs) in disrupting early neurodevelopment. However, there is limited knowledge concerning the role of inherited variants during the early brain development of ASD. In this study, we investigate the role of rare inherited variations in neurodevelopment. We conducted co-expression network analyses using an anatomically comprehensive atlas of the developing human brain and examined whether rare coding and regulatory variants, identified from our genetic screening of Australian families with ASD, work in different spatio-temporal functions.

scholarly journals Interleukin-1α deficiency reduces adiposity, glucose intolerance and hepatic de-novo lipogenesis in diet-induced obese mice

2019 ◽  
Vol 7 (1) ◽  
pp. e000650 ◽  
Author(s):  
Tal Almog ◽  
Michal Kandel Kfir ◽  
Hana Levkovich ◽  
Gadi Shlomai ◽  
Iris Barshack ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Total Cholesterol ◽  
Glucose Intolerance ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Myeloid Cell ◽  
De Novo Lipogenesis ◽  
Whole Body ◽  
Primary Mouse

ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

scholarly journals Acetyl-CoA mediated autoacetylation of fatty acid synthase in de novo lipogenesis

2022 ◽  
Author(s):  
Ting Miao ◽  
Jinoh Kim ◽  
Ping Kang ◽  
Hua Bai
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory System ◽  
De Novo Lipogenesis ◽  
Lysine Acetylation ◽  
Dependent Manner ◽  
Acetyl Coa ◽  
Lipogenic Genes

De novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL.

scholarly journals Hepatic De Novo Lipogenesis Is Present in Liver-Specific ACC1-Deficient Mice

2007 ◽  
Vol 27 (5) ◽  
pp. 1881-1888 ◽  
Author(s):  
Naomoto Harada ◽  
Zenjun Oda ◽  
Yoshikazu Hara ◽  
Koji Fujinami ◽  
Mayumi Okawa ◽  
...  
Keyword(s):  
Fatty Acid Synthase ◽  
De Novo ◽  
Physiological Role ◽  
De Novo Lipogenesis ◽  
Null Mouse ◽  
Acetyl Coa ◽  
Dual Inhibitor ◽  
Malonyl Coa ◽  
Deficient Mice

ABSTRACT Acetyl coenzyme A (acetyl-CoA) carboxylase (ACC) catalyzes carboxylation of acetyl-CoA to form malonyl-CoA. In mammals, two isozymes exist with distinct physiological roles: cytosolic ACC1 participates in de novo lipogenesis (DNL), and mitochondrial ACC2 is involved in negative regulation of mitochondrial β-oxidation. Since systemic ACC1 null mice were embryonic lethal, to clarify the physiological role of ACC1 in hepatic DNL, we generated the liver-specific ACC1 null mouse by crossbreeding of an Acc1 lox(ex46) mouse, in which exon 46 of Acc1 was flanked by two loxP sequences and the liver-specific Cre transgenic mouse. In liver-specific ACC1 null mice, neither hepatic Acc1 mRNA nor protein was detected. However, to compensate for ACC1 function, hepatic ACC2 protein and activity were induced 1.4 and 2.2 times, respectively. Surprisingly, hepatic DNL and malonyl-CoA were maintained at the same physiological levels as in wild-type mice. Furthermore, hepatic DNL was completely inhibited by an ACC1/2 dual inhibitor, 5-tetradecyloxyl-2-furancarboxylic acid. These results strongly demonstrate that malonyl-CoA from ACC2 can access fatty acid synthase and become the substrate for the DNL pathway under the unphysiological circumstances that result with ACC1 disruption. Therefore, there does not appear to be strict compartmentalization of malonyl-CoA from either of the ACC isozymes in the liver.

HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming

2021 ◽  
Author(s):  
Xiaodong Lu ◽  
Ka-wing Fong ◽  
Fang Wang ◽  
Galina Gritsina ◽  
Sylvan C. Baca ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Xenograft Tumor ◽  
Dna Hypermethylation ◽  
Castration Resistant

ABSTRACTHOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) function and promotes androgen-dependent prostate cancer (PCa) growth. However, the functions of HOXB13 in an AR-independent context remain elusive. Here we report an essential role of HOXB13 in directly suppressing lipogenic transcriptional programs in both AR-positive and -negative PCa cells. The MEIS domain (aa70-150) of HOXB13 interacts with the histone deacetylase HDAC3, which is disrupted by HOXB13 G84E mutation that has been associated with early-onset PCa. Thus, HOXB13 wildtype (WT), but not G84E mutant, recruits HDAC3 to lipogenic enhancers to catalyze histone de-acetylation and suppress lipogenic programs. HOXB13 knockdown unleashes the expression of key lipogenic regulators such as fatty acid synthase (FASN), requiring HDAC3. Analysis of human tissues revealed that HOXB13 is lost in about 30% of metastatic castration-resistant PCa, at least in part, through DNA hypermethylation. Functionally, loss of HOXB13 leads to massive lipid accumulation in PCa cells, thereby promoting cell motility in vitro and fueling xenograft tumor metastasis in vivo, which is mitigated by pharmaceutical inhibitors of FASN. In summary, our study discovers an essential AR-independent function of HOXB13 in repressing de novo lipogenesis and inhibiting tumor metastasis and defines a subclass of PCa that may benefit from lipogenic pathway inhibitors.

249 ROLE OF DE NOVO LIPOGENESIS IN GROWING VERY LOW BIRTH WEIGHT BREASTFED INFANTS.

2004 ◽  
Vol 52 (Suppl 1) ◽  
pp. S122.6-S123
Author(s):  
M. Garg ◽  
C. Bell ◽  
L. Rogers ◽  
S. Bassilian ◽  
W. N.P. Lee
Keyword(s):  
Birth Weight ◽  
Low Birth Weight ◽  
Very Low Birth Weight ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Breastfed Infants

scholarly journals Single-cell atlas of early human brain development highlights heterogeneity of human neuroepithelial cells and early radial glia

2021 ◽  
Author(s):  
Ugomma C. Eze ◽  
Aparna Bhaduri ◽  
Maximilian Haeussler ◽  
Tomasz J. Nowakowski ◽  
Arnold R. Kriegstein
Keyword(s):  
Human Brain ◽  
Brain Development ◽  
Single Cell ◽  
Radial Glia ◽  
Cortical Development ◽  
Cell Types ◽  
Human Cortex ◽  
Early Stages ◽  
Human Brain Development ◽  
Neuroepithelial Cells

AbstractThe human cortex comprises diverse cell types that emerge from an initially uniform neuroepithelium that gives rise to radial glia, the neural stem cells of the cortex. To characterize the earliest stages of human brain development, we performed single-cell RNA-sequencing across regions of the developing human brain, including the telencephalon, diencephalon, midbrain, hindbrain and cerebellum. We identify nine progenitor populations physically proximal to the telencephalon, suggesting more heterogeneity than previously described, including a highly prevalent mesenchymal-like population that disappears once neurogenesis begins. Comparison of human and mouse progenitor populations at corresponding stages identifies two progenitor clusters that are enriched in the early stages of human cortical development. We also find that organoid systems display low fidelity to neuroepithelial and early radial glia cell types, but improve as neurogenesis progresses. Overall, we provide a comprehensive molecular and spatial atlas of early stages of human brain and cortical development.

scholarly journals A Narrative Review on the Role of AMPK on De Novo Lipogenesis in Non-Alcoholic Fatty Liver Disease: Evidence from Human Studies

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1822
Author(s):  
Christian von Loeffelholz ◽  
Sina M. Coldewey ◽  
Andreas L. Birkenfeld
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Mammalian Cells ◽  
De Novo ◽  
Adenosine Monophosphate ◽  
De Novo Lipogenesis ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

5′AMP-activated protein kinase (AMPK) is known as metabolic sensor in mammalian cells that becomes activated by an increasing adenosine monophosphate (AMP)/adenosine triphosphate (ATP) ratio. The heterotrimeric AMPK protein comprises three subunits, each of which has multiple phosphorylation sites, playing an important role in the regulation of essential molecular pathways. By phosphorylation of downstream proteins and modulation of gene transcription AMPK functions as a master switch of energy homeostasis in tissues with high metabolic turnover, such as the liver, skeletal muscle, and adipose tissue. Regulation of AMPK under conditions of chronic caloric oversupply emerged as substantial research target to get deeper insight into the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Evidence supporting the role of AMPK in NAFLD is mainly derived from preclinical cell culture and animal studies. Dysbalanced de novo lipogenesis has been identified as one of the key processes in NAFLD pathogenesis. Thus, the scope of this review is to provide an integrative overview of evidence, in particular from clinical studies and human samples, on the role of AMPK in the regulation of primarily de novo lipogenesis in human NAFLD.

TAMI-37. STEAROYL-COA DESATURASE 1 IS ESSENTIAL FOR THE GROWTH OF IDH MUTANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi206-vi206
Author(s):  
Tomohiro Yamasaki ◽  
Lumin Zhang ◽  
Tyrone Dowdy ◽  
Adrian Lita ◽  
Mark Gilbert ◽  
...  
Keyword(s):  
Glioma Cell ◽  
De Novo ◽  
Glioma Cells ◽  
Model Systems ◽  
De Novo Lipogenesis ◽  
Wild Type ◽  
Knock Out ◽  
Stearoyl Coa Desaturase ◽  
Scd1 Expression

Abstract BACKGROUND Increased de novo lipogenesis is a hallmark of cancer metabolism. In this study, we interrogated the role of de novo lipogenesis in IDH1 mutated glioma’s growth and identified the key enzyme, Stearoyl-CoA desaturase 1 (SCD1) that provides this growth advantage. MATERIALS ANDMETHODS We prepared genetically engineered glioma cell lines (U251 wild-type: U251WT and U251 IDHR132H mutant: U251RH) and normal human astrocytes (empty vector induced-NHA: NHAEV and IDHR132H mutant: NHARH). Lipid metabolic analysis was conducted by using LC-MS and Raman imaging microscopy. SCD1 expression was investigated by The Cancer Genome Atlas (TCGA) data analysis and Western-blotting method. Knock-out of SCD1 was conducted by using CRISPR/Cas9 and shRNA. RESULTS Previously, we showed that IDH1 mut glioma cells have increased monounsaturated fatty acids (MUFAs). TCGA data revealed IDH mut glioma shows significantly higher SCD1 mRNA expression than wild-type glioma. Our model systems of IDH1 mut (U251RH, NHARH) showed increased expression of this enzyme compared with their wild-type counterpart. Moreover, addition of D-2HG to U251WT increased SCD1 expression. Herein, we showed that inhibition of SCD1 with CAY10566 decreased relative cell number and sphere forming capacity in a dose-dependent manner. Furthermore, addition of MUFAs were able to rescue the SCD1 inhibitor induced-cell death and sphere forming capacity. Knock out of SCD1 revealed decreased cell proliferation and sphere forming ability. Decreasing lipid content from the media did not alter the growth of these cells, suggesting that glioma cells rely on de novo lipid synthesis rather than scavenging them from the microenvironment. CONCLUSION Overexpression of IDH mutant gene altered lipid composition in U251 cells to enrich MUFA levels and we confirmed that D-2HG caused SCD1 upregulation in U251WT. We demonstrated the glioma cell growth requires SCD1 expression and the results of the present study may provide novel insights into the role of SCD1 in IDH mut gliomas growth.

Regulation of the SREBP transcription factors by mTORC1

2011 ◽  
Vol 39 (2) ◽  
pp. 495-499 ◽  
Author(s):  
Caroline A. Lewis ◽  
Beatrice Griffiths ◽  
Claudio R. Santos ◽  
Mario Pende ◽  
Almut Schulze
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Target Genes ◽  
De Novo ◽  
Regulatory Element ◽  
Cholesterol Biosynthesis ◽  
Mammalian Target Of Rapamycin ◽  
Lipid Biosynthesis ◽  
De Novo Lipogenesis ◽  
Genes Encoding

In recent years several reports have linked mTORC1 (mammalian target of rapamycin complex 1) to lipogenesis via the SREBPs (sterol-regulatory-element-binding proteins). SREBPs regulate the expression of genes encoding enzymes required for fatty acid and cholesterol biosynthesis. Lipid metabolism is perturbed in some diseases and SREBP target genes, such as FASN (fatty acid synthase), have been shown to be up-regulated in some cancers. We have previously shown that mTORC1 plays a role in SREBP activation and Akt/PKB (protein kinase B)-dependent de novo lipogenesis. Our findings suggest that mTORC1 plays a crucial role in the activation of SREBP and that the activation of lipid biosynthesis through the induction of SREBP could be part of a regulatory pathway that co-ordinates protein and lipid biosynthesis during cell growth. In the present paper, we discuss the increasing amount of data supporting the potential mechanisms of mTORC1-dependent activation of SREBP as well as the implications of this signalling pathway in cancer.

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