Maternal dietary iron restriction modulates hepatic lipid metabolism in the fetuses

2005 ◽  
Vol 288 (1) ◽  
pp. R104-R111 ◽  
Author(s):  
Junlong Zhang ◽  
Rohan M. Lewis ◽  
Chunli Wang ◽  
Nicholas Hales ◽  
Christopher D. Byrne
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Plasma Cholesterol ◽  
Liver Lipid ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Mrna Levels ◽  
Protein Levels

Maternal dietary Fe restriction reduced fasting plasma cholesterol and triglyceride (TG) concentrations in the fetuses, as well as decreased plasma TG levels in the adult offspring. To investigate how maternal Fe restriction was affecting fetal lipid metabolism, we investigated whether there were changes in liver lipid metabolism in the full-term fetuses. There was a ∼27% ( P < 0.05) increase in cholesterol but ∼29% reduction ( P = 0.01) in TG concentrations in the liver of the Fe-restricted fetuses. Hepatic mRNA levels of cholesterol 7α hydroxylase and liver X receptor-α (LXRα) were reduced by ∼50% ( P < 0.01) and ∼34% ( P < 0.01), respectively. As LXRα regulates expression of sterol response element binding protein-1c (SREBP-1c) expression, we measured SREBP-1c expression. There was an ∼43% ( P < 0.001) reduction in mRNA levels of SREBP-1c and its response genes, including acetyl-CoA carboxylase by ∼35% ( P = 0.01), fatty acid synthase by ∼18% ( P = 0.05), and diacylglycerol acyltransferase by ∼19% ( P = 0.03). Furthermore, protein levels of CD36 were reduced by ∼27% ( P = 0.02) in Fe-restricted fetuses. In conclusion, changes in liver cholesterol and TG concentrations in Fe-restricted fetuses may be coordinated through reduced expression of heme-containing cholesterol 7α hydroxylase and its regulator LXRα, mainly via downregulation of expression of genes in bile acid synthesis and fatty acid synthesis pathways.

scholarly journals 25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway

2008 ◽  
Vol 295 (6) ◽  
pp. E1369-E1379 ◽  
Author(s):  
Yongjie Ma ◽  
Leyuan Xu ◽  
Daniel Rodriguez-Agudo ◽  
Xiaobo Li ◽  
Douglas M. Heuman ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Fatty Acid Synthase ◽  
Lipid Synthesis ◽  
Mrna Levels ◽  
Intracellular Lipids ◽  
Protein Levels ◽  
Regulatory Molecule ◽  
Fas Mrna

The oxysterol receptor LXR is a key transcriptional regulator of lipid metabolism. LXR increases expression of SREBP-1, which in turn regulates at least 32 genes involved in lipid synthesis and transport. We recently identified 25-hydroxycholesterol-3-sulfate (25HC3S) as an important regulatory molecule in the liver. We have now studied the effects of 25HC3S and its precursor, 25-hydroxycholesterol (25HC), on lipid metabolism as mediated by the LXR/SREBP-1 signaling in macrophages. Addition of 25HC3S to human THP-1-derived macrophages markedly decreased nuclear LXR protein levels. 25HC3S administration was followed by dose- and time-dependent decreases in SREBP-1 mature protein and mRNA levels. 25HC3S decreased the expression of SREBP-1-responsive genes, acetyl-CoA carboxylase-1, and fatty acid synthase (FAS) as well as HMGR and LDLR, which are key proteins involved in lipid metabolism. Subsequently, 25HC3S decreased intracellular lipids and increased cell proliferation. In contrast to 25HC3S, 25HC acted as an LXR ligand, increasing ABCA1, ABCG1, SREBP-1, and FAS mRNA levels. In the presence of 25HC3S, 25HC, and LXR agonist T0901317, stimulation of LXR targeting gene expression was repressed. We conclude that 25HC3S acts in macrophages as a cholesterol satiety signal, downregulating cholesterol and fatty acid synthetic pathways via inhibition of LXR/SREBP signaling. A possible role of oxysterol sulfation is proposed.

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 Reducing FASN expression sensitizes acute myeloid leukemia cells to differentiation therapy

2021 ◽  
Author(s):  
Magali Humbert ◽  
Kristina Seiler ◽  
Severin Mosimann ◽  
Vreni Rentsch ◽  
Katyayani Sharma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Fatty Acid ◽  
Myeloid Leukemia ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Acid Synthesis ◽  
Mrna Levels ◽  
Differentiation Therapy ◽  
Granulocytic Differentiation ◽  
Acute Myeloid

AbstractFatty acid synthase (FASN) is the only human lipogenic enzyme available for de novo fatty acid synthesis and is often highly expressed in cancer cells. We found that FASN mRNA levels were significantly higher in acute myeloid leukemia (AML) patients than in healthy granulocytes or CD34+ hematopoietic progenitors. Accordingly, FASN levels decreased during all-trans retinoic acid (ATRA)-mediated granulocytic differentiation of acute promyelocytic leukemia (APL) cells, partially via autophagic degradation. Furthermore, our data suggest that inhibition of FASN expression levels using RNAi or (-)-epigallocatechin-3-gallate (EGCG) accelerated the differentiation of APL cell lines and significantly re-sensitized ATRA refractory non-APL AML cells. FASN reduction promoted translocation of transcription factor EB (TFEB) to the nucleus, paralleled by activation of CLEAR network genes and lysosomal biogenesis. Together, our data demonstrate that inhibition of FASN expression in combination with ATRA treatment facilitates granulocytic differentiation of APL cells and may extend differentiation therapy to non-APL AML cells.

scholarly journals Catechins and Caffeine Inhibit Fat Accumulation in Mice through the Improvement of Hepatic Lipid Metabolism

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Chikako Sugiura ◽  
Shiho Nishimatsu ◽  
Tatsuya Moriyama ◽  
Sayaka Ozasa ◽  
Teruo Kawada ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Epigallocatechin Gallate ◽  
Acid Synthesis ◽  
Control Group ◽  
Mrna Levels ◽  
Fat Accumulation ◽  
Treatment Groups ◽  
Fas Mrna ◽  
Carnitine Palmitoyltransferase Ii

To elucidate the inhibiting mechanisms of fat accumulation by catechins, caffeine, and epigallocatechin gallate (EGCG), ICR mice were fed diets containing either 0.3% catechins or 0.1% EGCG and/or 0.05% caffeine for 4 weeks. After the feeding, intraperitoneal adipose tissues weights were significantly lower in the caffeine, catechins + caffeine, and EGCG + caffeine groups compared to controls. Hepatic fatty acid synthase (FAS) activity in the catechins + caffeine group was significantly lower, and the activities of acyl-CoA oxidase (ACO) and carnitine palmitoyltransferase-II (CPT-II) were significantly higher, compared to the control group. However, these activities were not observed in the other groups. FAS mRNA expression levels in the catechins + caffeine group were significantly lower than in the control group. ACO and CPT-II mRNA levels were not different among all of the treatment groups. These findings indicate that the inhibitory effects of fat accumulation via a combination of catechins, EGCG, or caffeine were stronger collectively than by either catechins, EGCG, or caffeine alone. Moreover, it was demonstrated that the combination of catechins and caffeine induced inhibition of fat accumulation by suppression of fatty acid synthesis and upregulation of the enzymatic activities involved inβ-oxidation of fatty acid in the liver, but this result was not observed by combination of EGCG and caffeine.

scholarly journals Somatotropin-dependent decrease in fatty acid synthase mRNA abundance in 3T3-F442A adipocytes is the result of a decrease in both gene transcription and mRNA stability

1998 ◽  
Vol 331 (3) ◽  
pp. 815-820 ◽  
Author(s):  
Dezhong YIN ◽  
Steven D. CLARKE ◽  
Jana L. PETERS ◽  
Terry D. ETHERTON
Keyword(s):  
Fatty Acid ◽  
Mrna Stability ◽  
Fatty Acid Synthase ◽  
Insulin Treatment ◽  
Acid Synthesis ◽  
Mrna Abundance ◽  
Mrna Levels ◽  
Reporter Construct ◽  
Fas Mrna ◽  
Flanking Region

Somatotropin (ST) markedly decreases lipogenesis, fatty acid synthase (FAS) enzyme activity and mRNA abundance in pig adipocytes. The present study was conducted to determine whether the decrease in FAS mRNA in 3T3-F442A adipocytes was the result of a decrease in transcription of the FAS gene and/or a change in FAS mRNA stability. Insulin increased the abundance of FAS mRNA 2–13-fold and fatty acid synthesis 3–7-fold. Somatotropin decreased the stimulatory effect of insulin on the abundance of FAS mRNA and lipogenesis by 40–70% and 20–60% respectively. Subsequent run-on analyses demonstrated that the decrease observed in FAS mRNA in response to ST was associated with an 82% decrease in transcription; ST significantly shortened the half-life of FAS mRNA from 35 to 11 h. To corroborate the run-on analyses, cells were stably transfected with a pFAS–CAT5 (in which CAT stands for chloramphenicol acetyltransferase) reporter construct that contained 2195 bp of the 5´ flanking region of the rat FAS gene. Insulin treatment increased FAS–CAT activity 4.7-fold. When ST was added to the insulin-containing medium there was an approx. 60% reduction in FAS–CAT activity. In summary, our results indicate that ST decreases FAS mRNA levels and that this is the result of a marked decrease in both transcription of the FAS gene and stability of the FAS mRNA.

Upregulation of adipocyte metabolism by agouti protein: possible paracrine actions in yellow mouse obesity

1996 ◽  
Vol 270 (1) ◽  
pp. E192-E196 ◽  
Author(s):  
B. H. Jones ◽  
J. H. Kim ◽  
M. B. Zemel ◽  
R. P. Woychik ◽  
E. J. Michaud ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Ectopic Expression ◽  
Acid Synthesis ◽  
Mrna Levels ◽  
Simultaneous Treatment ◽  
Agouti Protein ◽  
Agouti Gene

Mutations leading to ectopic expression of the murine agouti gene (a) result in progressive obesity. To further characterize this model, we analyzed adipose and hepatic mRNA levels for fatty acid synthase (FAS) and stearoyl-CoA desaturase (SCD), two key enzymes in de novo fatty acid synthesis and desaturation, respectively. FAS and SCD mRNA in both tissues of obese (Avy) mice were dramatically increased relative to lean (ala) controls. Excessive expression of these genes in this model could be due to direct effects of the agouti gene product; to test this possibility we treated 3T3-L1 adipocytes in vitro with recombinant agouti protein. Agouti treatment increased FAS and SCD mRNA levels by 1.5- and 4-fold, respectively. In addition, FAS activity and triglyceride content were 3-fold higher in agoutitreated 3T3-L1 cells relative to controls; these effects were attenuated by simultaneous treatment with a calcium channel blocker (nitrendipine). These data demonstrate that the agouti protein can directly increase lipogenesis in adipocytes and suggest that these effects are mediated through an intracellular calcium-dependent mechanism.

Endurance training-induced accumulation of muscle triglycerides is coupled to upregulation of stearoyl-CoA desaturase 1

2010 ◽  
Vol 109 (6) ◽  
pp. 1653-1661 ◽  
Author(s):  
Pawel Dobrzyn ◽  
Aleksandra Pyrkowska ◽  
Magdalena Jazurek ◽  
Konrad Szymanski ◽  
Jozef Langfort ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Endurance Training ◽  
Fatty Acid Synthase ◽  
Fatty Acid Transport ◽  
Mrna Levels ◽  
Acid Transport ◽  
Protein Levels ◽  
Stearoyl Coa Desaturase ◽  
Scd1 Expression

Stearoyl-CoA desaturase (SCD), a rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, has recently been shown to be a critical control point in regulation of liver and skeletal muscle metabolism. Herein, we demonstrate that endurance training significantly increases both SCD1 mRNA and protein levels in the soleus muscle, whereas it does not affect SCD1 expression in the EDL muscle and liver. Desaturation index (18:1Δ9/18:0 ratio), an indirect indicator of SCD1 activity, was also significantly higher (3.6-fold) in soleus of trained rats compared with untrained animals. Consistent with greater SCD1 expression/activity, the contents of free fatty acids, diacylglycerol, and triglyceride were elevated in soleus of trained rats. However, training did not affect lipid concentration in EDL and liver. Additionally, endurance training activated the AMP-activated protein kinase pathway as well as increased peroxisome proliferator-activated receptor (PPAR)-δ and PPARα gene expression and activity in soleus and liver. Increased lipid accumulation in soleus was coupled with elevated protein levels of fatty acid synthase, mRNA levels of diacylglycerol acyltransferase and glycerol-3-phosphate transferase, as well as increased levels of proteins involved in fatty acid transport (fatty acid translocase/CD36, fatty acid transport protein 1). Interestingly, sterol regulatory element-binding protein (SREBP)-1c expression and SREBP-1 protein levels were not affected by exercise training. Together, the obtained data suggest that SCD1 upregulation plays an important role in adaptation of oxidative muscle to endurance training.

scholarly journals Liver Bile Acid Changes in Mouse Models of Alzheimer’s Disease

2021 ◽  
Vol 22 (14) ◽  
pp. 7451
Author(s):  
Harpreet Kaur ◽  
Drew Seeger ◽  
Svetlana Golovko ◽  
Mikhail Golovko ◽  
Colin Kelly Combs
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Bile Acid ◽  
Bile Acids ◽  
Cholesterol Metabolism ◽  
Amyloid Β ◽  
Acid Synthesis ◽  
Bile Acid Synthesis ◽  
Liver Cholesterol ◽  
Bile Acid Metabolism

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive impairment. It is hypothesized to develop due to the dysfunction of two major proteins, amyloid-β (Aβ) and microtubule-associated protein, tau. Evidence supports the involvement of cholesterol changes in both the generation and deposition of Aβ. This study was performed to better understand the role of liver cholesterol and bile acid metabolism in the pathophysiology of AD. We used male and female wild-type control (C57BL/6J) mice to compare to two well-characterized amyloidosis models of AD, APP/PS1, and AppNL-G-F. Both conjugated and unconjugated primary and secondary bile acids were quantified using UPLC-MS/MS from livers of control and AD mice. We also measured cholesterol and its metabolites and identified changes in levels of proteins associated with bile acid synthesis and signaling. We observed sex differences in liver cholesterol levels accompanied by differences in levels of synthesis intermediates and conjugated and unconjugated liver primary bile acids in both APP/PS1 and AppNL-G-F mice when compared to controls. Our data revealed fundamental deficiencies in cholesterol metabolism and bile acid synthesis in the livers of two different AD mouse lines. These findings strengthen the involvement of liver metabolism in the pathophysiology of AD.

scholarly journals Circulating Levels of Pro-Neurotensin and Its Relationship with Nonalcoholic Steatohepatitis and Hepatic Lipid Metabolism

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 373
Author(s):  
Beatriz Villar ◽  
Laia Bertran ◽  
Carmen Aguilar ◽  
Jessica Binetti ◽  
Salomé Martínez ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Nonalcoholic Steatohepatitis ◽  
Liver Lipid ◽  
Normal Liver ◽  
Normal Weight ◽  
Published Data ◽  
Mrna Levels ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Expression ◽  
Liver Lipid Metabolism

Recent studies suggest a link between pro-neurotensin (pro-NT) and nonalcoholic fatty liver disease (NAFLD), but the published data are conflicting. Thus, we aimed to analyze pro-NT levels in women with morbid obesity (MO) and NAFLD to investigate if this molecule is involved in NAFLD and liver lipid metabolism. Plasma levels of pro-NT were determined in 56 subjects with MO and 18 with normal weight (NW). All patients with MO were subclassified according to their liver histology into the normal liver (NL, n = 20) and NAFLD (n = 36) groups. The NAFLD group had 17 subjects with simple steatosis (SS) and 19 with nonalcoholic steatohepatitis (NASH). We used a chemiluminescence sandwich immunoassay to quantify pro-NT in plasma and RT-qPCR to evaluate the hepatic mRNA levels of several lipid metabolism-related genes. We reported that pro-NT levels were significantly higher in MO with NAFLD than in MO without NAFLD. Additionally, pro-NT levels were higher in NASH patients than in NL. The hepatic expression of lipid metabolism-related genes was found to be altered in NAFLD, as previously reported. Additionally, although pro-NT levels correlated with LDL, there was no association with the main lipid metabolism-related genes. These findings suggest that pro-NT could be related to NAFLD progression.

scholarly journals LINC00842 inactivates transcription co-regulator PGC-1α to promote pancreatic cancer malignancy through metabolic remodelling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xudong Huang ◽  
Ling Pan ◽  
Zhixiang Zuo ◽  
Mei Li ◽  
Lingxing Zeng ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Synthase ◽  
Acid Synthesis ◽  
Ductal Adenocarcinoma ◽  
High Concentration ◽  
Metabolic Switch ◽  
Non Coding Rna ◽  
Xenograft Models ◽  
Transcription Factor Yy1 ◽  
Catabolic Process

AbstractThe molecular mechanism underlying pancreatic ductal adenocarcinoma (PDAC) malignancy remains unclear. Here, we characterize a long intergenic non-coding RNA LINC00842 that plays a role in PDAC progression. LINC00842 expression is upregulated in PDAC and induced by high concentration of glucose via transcription factor YY1. LINC00842 binds to and prevents acetylated PGC-1α from deacetylation by deacetylase SIRT1 to form PGC-1α, an important transcription co-factor in regulating cellular metabolism. LINC00842 overexpression causes metabolic switch from mitochondrial oxidative catabolic process to fatty acid synthesis, enhancing the malignant phenotypes of PDAC cells. High LINC00842 levels are correlated with elevated acetylated- PGC-1α levels in PDAC and poor patient survival. Decreasing LINC00842 level and inhibiting fatty acid synthase activity significantly repress PDAC growth and invasiveness in mouse pancreatic xenograft or patient-derived xenograft models. These results demonstrate that LINC00842 plays a role in promoting PDAC malignancy and thus might serve as a druggable target.

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