scholarly journals ChREBP Reciprocally Regulates Liver and Plasma Triacylglycerol Levels in Different Manners

Nutrients ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 1699 ◽  
Author(s):  
Katsumi Iizuka ◽  
Ken Takao ◽  
Takehiro Kato ◽  
Yukio Horikawa ◽  
Jun Takeda
Keyword(s):  
Fatty Acid ◽  
Fluorescent Protein ◽  
De Novo ◽  
Density Lipoprotein ◽  
Plasma Free Fatty Acid ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Fatty Acid Elongase ◽  
Plasma Triacylglycerol

Carbohydrate response element-binding protein (ChREBP) has an important role in the carbohydrate-mediated regulation of hepatic de novo lipogenesis, but the mechanism for how it regulates plasma triacylglycerol (TAG) levels has not been established. This study aimed to clarify the role of ChREBP in regulation of plasma TAG levels. We analyzed the metabolic changes in mice infected with an adenovirus expressing ChREBP Δ196 (Ad-ChREBP). Compared with adenovirus harboring green fluorescent protein infected mice, Ad-ChREBP-infected mice had higher plasma free fatty acid levels and paradoxically lower plasma 3-hydroxybutyrate levels through decreased fatty acid oxidation, rather than ketogenesis. Consistent with their hepatomegaly and increased lipogenic gene expression, the liver TAG contents were much higher. Regarding lipid composition, C16:0 was much lower and C18:1n-9 was much higher, compatible with increased stearoyl CoA desaturase-1 and ELOVL fatty acid elongase 6 expression. Furthermore, Ad-ChREBP-infected mice had decreased plasma TAG and very low density lipoprotein (VLDL)-TAG levels, consistent with decreased Angiopoietin-like protein 3 (Angptl3) and increased fibroblast growth factor (Fgf21) mRNA and protein levels. Finally, Ad-ChREBP infection increased white adipose tissue Ucp1 mRNA levels with increased plasma Fgf21 levels. Because Fgf21 and Angptl3 are known to activate and suppress lipolysis in adipose tissues and oxidative tissues, ChREBP appears to regulate plasma TAG levels by modulating Fgf21 and Angptl3 levels. Thus, ChREBP overexpression led to dissociation of hepatic steatosis from hyperlipidemia.

scholarly journals Fasting hepatic de novo lipogenesis is not reliably assessed using circulating fatty acid markers

2019 ◽  
Vol 109 (2) ◽  
pp. 260-268 ◽  
Author(s):  
Fredrik Rosqvist ◽  
Catriona A McNeil ◽  
Camilla Pramfalk ◽  
Sion A Parry ◽  
Wee Suan Low ◽  
...  
Keyword(s):  
Fatty Acid ◽  
De Novo ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Blood Lipid ◽  
De Novo Lipogenesis ◽  
Deuterated Water ◽  
Lipid Fractions ◽  
Habitual Diet ◽  
Fa Markers

ABSTRACT Background Observational studies often infer hepatic de novo lipogenesis (DNL) by measuring circulating fatty acid (FA) markers; however, it remains to be elucidated whether these markers accurately reflect hepatic DNL. Objectives We investigated associations between fasting hepatic DNL and proposed FA markers of DNL in subjects consuming their habitual diet. Methods Fasting hepatic DNL was assessed using 2H2O (deuterated water) in 149 nondiabetic men and women and measuring the synthesis of very low-density lipoprotein triglyceride (VLDL-TG) palmitate. FA markers of blood lipid fractions were determined by gas chromatography. Results Neither the lipogenic index (16:0/18:2n–6) nor the SCD index (16:1n–7/16:0) in VLDL-TG was associated with isotopically assessed DNL (r = 0.13, P = 0.1 and r = −0.08, P = 0.35, respectively). The relative abundances (mol%) of 14:0, 16:0, and 18:0 in VLDL-TG were weakly (r ≤ 0.35) associated with DNL, whereas the abundances of 16:1n–7, 18:1n–7, and 18:1n–9 were not associated. When the cohort was split by median DNL, only the abundances of 14:0 and 18:0 in VLDL-TG could discriminate between subjects having high (11.5%) and low (3.8%) fasting hepatic DNL. Based on a subgroup, FA markers in total plasma TG, plasma cholesteryl esters, plasma phospholipids, and red blood cell phospholipids were generally not associated with DNL. Conclusions The usefulness of circulating FAs as markers of hepatic DNL in healthy individuals consuming their habitual diet is limited due to their inability to discriminate clearly between individuals with low and high fasting hepatic DNL.

scholarly journals Vitamin D Supplementation Improves Adipose Tissue Inflammation and Reduces Hepatic Steatosis in Obese C57BL/6J Mice

Nutrients ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 342 ◽  
Author(s):  
Alexandra Marziou ◽  
Clothilde Philouze ◽  
Charlène Couturier ◽  
Julien Astier ◽  
Philippe Obert ◽  
...  
Keyword(s):  
Vitamin D ◽  
Adipose Tissue ◽  
Hepatic Steatosis ◽  
De Novo ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Adipose Tissue Inflammation ◽  
Tissue Inflammation ◽  
Triglyceride Accumulation

The beneficial effect of vitamin D (VD) supplementation on body weight gain limitation and inflammation has been highlighted in primary prevention mice models, but the long-term effect of VD supplementation in tertiary prevention has never been reported in obesity models. The curative effect of VD supplementation on obesity and associated disorders was evaluated in high-fat- and high-sucrose (HFS)-fed mice. Morphological, histological, and molecular phenotype were characterized. The increased body mass and adiposity caused by HFS diet as well as fat cell hypertrophy and glucose homeostasis were not improved by VD supplementation. However, VD supplementation led to a decrease of HFS-induced inflammation in inguinal adipose tissue, characterized by a decreased expression of chemokine mRNA levels. Moreover, a protective effect of VD on HFS-induced hepatic steatosis was highlighted by a decrease of lipid droplets and a reduction of triglyceride accumulation in the liver. This result was associated with a significant decrease of gene expression coding for key enzymes involved in hepatic de novo lipogenesis and fatty acid oxidation. Altogether, our results show that VD supplementation could be of interest to blunt the adipose tissue inflammation and hepatic steatosis and could represent an interesting nutritional strategy to fight obesity-associated comorbidities.

scholarly journals Sterol regulatory element binding protein and dietary lipid regulation of fatty acid synthesis in the mammary epithelium

2010 ◽  
Vol 299 (6) ◽  
pp. E918-E927 ◽  
Author(s):  
Michael C. Rudolph ◽  
Jenifer Monks ◽  
Valerie Burns ◽  
Meridee Phistry ◽  
Russell Marians ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Mammary Gland ◽  
Fatty Acid ◽  
Fatty Acid Synthesis ◽  
De Novo ◽  
Regulatory Element ◽  
Acid Synthesis ◽  
De Novo Lipogenesis ◽  
Mrna Levels ◽  
Sterol Regulatory Element

The lactating mammary gland synthesizes large amounts of triglyceride from fatty acids derived from the blood and from de novo lipogenesis. The latter is significantly increased at parturition and decreased when additional dietary fatty acids become available. To begin to understand the molecular regulation of de novo lipogenesis, we tested the hypothesis that the transcription factor sterol regulatory element binding factor (SREBF)-1c is a primary regulator of this system. Expression of Srebf1c mRNA and six of its known target genes increased ≥2.5-fold at parturition. However, Srebf1c-null mice showed only minor deficiencies in lipid synthesis during lactation, possibly due to compensation by Srebf1a expression. To abrogate the function of both isoforms of Srebf1, we bred mice to obtain a mammary epithelial cell-specific deletion of SREBF cleavage-activating protein (SCAP), the SREBF escort protein. These dams showed a significant lactation deficiency, and expression of mRNA for fatty acid synthase ( Fasn), insulin-induced gene 1 ( Insig1), mitochondrial citrate transporter ( Slc25a1), and stearoyl-CoA desaturase 2 ( Scd2) was reduced threefold or more; however, the mRNA levels of acetyl-CoA carboxylase-1α ( Acaca) and ATP citrate lyase ( Acly) were unchanged. Furthermore, a 46% fat diet significantly decreased de novo fatty acid synthesis and reduced the protein levels of ACACA, ACLY, and FASN significantly, with no change in their mRNA levels. These data lead us to conclude that two modes of regulation exist to control fatty acid synthesis in the mammary gland of the lactating mouse: the well-known SREBF1 system and a novel mechanism that acts at the posttranscriptional level in the presence of SCAP deletion and high-fat feeding to alter enzyme protein.

Reduction of JNK1 expression with antisense oligonucleotide improves adiposity in obese mice

2008 ◽  
Vol 295 (2) ◽  
pp. E436-E445 ◽  
Author(s):  
Xing Xian Yu ◽  
Susan F. Murray ◽  
Lynnetta Watts ◽  
Sheri L. Booten ◽  
Justin Tokorcheck ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Antisense Oligonucleotide ◽  
De Novo ◽  
Plasma Cholesterol ◽  
Liver Steatosis ◽  
Whole Body ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Obese Mice ◽  
Peripheral Tissues

To investigate the role of JNK1 in metabolism, male ob/ ob and diet-induced obese mice were treated with a JNK1-specific antisense oligonucleotide (ASO) or control ASO at 25 mg/kg or saline twice/wk for 6 and 7 wk, respectively. JNK1 ASO reduced JNK1 mRNA and activity by 65–95% in liver and fat tissues in both models. Compared with controls, treatment with JNK1 ASO did not change food intake but lowered body weight, fat pad weight, and whole body fat content. The treatment increased metabolic rate. In addition, the treatment markedly reduced plasma cholesterol levels and improved liver steatosis and insulin sensitivity. These positive observations were accompanied by the following changes: 1) increased mRNA levels of AR-β3 and UCP1 by >60% in BAT, 2) reduced mRNA levels of ACC1, ACC2, FAS, SCD1, DGAT1, DGAT2, and RBP4 by 30–60% in WAT, and 3) reduced mRNA levels of ACC1, FAS, G-6-Pase, and PKCε by 40–70% and increased levels of UCP2 and PPARα by more than twofold in liver. JNK1 ASO-treated mice demonstrated reduced levels of pIRS-1 Ser302 and pIRS-1 Ser307 and increased levels of pAkt Ser473 in liver and fat in response to insulin. JNK1 ASO-transfected mouse hepatocytes showed decreased rates of de novo sterol and fatty acid synthesis and an increased rate of fatty acid oxidation. These results indicate that inhibition of JNK1 expression in major peripheral tissues can improve adiposity via increasing fuel combustion and decreasing lipogenesis and could therefore provide clinical benefit for the treatment of obesity and related metabolic abnormalities.

scholarly journals Inhibition of Atherosclerosis and Liver Steatosis by Agmatine in Western Diet-Fed apoE-Knockout Mice Is Associated with Decrease in Hepatic De Novo Lipogenesis and Reduction in Plasma Triglyceride/High-Density Lipoprotein Cholesterol Ratio

2021 ◽  
Vol 22 (19) ◽  
pp. 10688
Author(s):  
Anna Wiśniewska ◽  
Aneta Stachowicz ◽  
Katarzyna Kuś ◽  
Magdalena Ulatowska-Białas ◽  
Justyna Totoń-Żurańska ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Hepatic Steatosis ◽  
De Novo ◽  
Therapeutic Potential ◽  
Liver Steatosis ◽  
Western Diet ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Cholesterol Ratio ◽  
Triglyceride Accumulation

Atherosclerosis and NAFLD are the leading causes of death worldwide. The hallmark of NAFLD is triglyceride accumulation caused by an imbalance between lipogenesis de novo and fatty acid oxidation. Agmatine, an endogenous metabolite of arginine, exerts a protective effect on mitochondria and can modulate fatty acid metabolism. In the present study, we investigate the influence of agmatine on the progression of atherosclerotic lesions and the development of hepatic steatosis in apoE−/− mice fed with a Western high-fat diet, with a particular focus on its effects on the DNL pathway in the liver. We have proved that treatment of agmatine inhibits the progression of atherosclerosis and attenuates hepatic steatosis in apoE−/− mice on a Western diet. Such effects are associated with decreased total macrophage content in atherosclerotic plaque as well as a decrease in the TG levels and the TG/HDL ratio in plasma. Agmatine also reduced TG accumulation in the liver and decreased the expression of hepatic genes and proteins involved in lipogenesis de novo such as SREBP-1c, FASN and SCD1. In conclusion, agmatine may present therapeutic potential for the treatment of atherosclerosis and fatty liver disease. However, an exact understanding of the mechanisms of the advantageous actions of agmatine requires further study.

scholarly journals A role for PPARα in the control of SREBP activity and lipid synthesis in the liver

2005 ◽  
Vol 389 (2) ◽  
pp. 413-421 ◽  
Author(s):  
Brian L. Knight ◽  
Abdel Hebbachi ◽  
David Hauton ◽  
Anna-Marie Brown ◽  
David Wiggins ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Cholesterol Synthesis ◽  
Fatty Acid Synthase ◽  
De Novo ◽  
Regulatory Element ◽  
Active Form ◽  
Dietary Cholesterol ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Hepatic Expression

Inclusion of the PPARα (peroxisome-proliferator-activated receptor α) activator WY 14,643 in the diet of normal mice stimulated the hepatic expression of not only genes of the fatty acid oxidation pathway, but also those of the de novo lipid synthetic pathways. Induction of fatty acid synthase mRNA by WY 14,643 was greater during the light phase of the diurnal cycle, when food intake was low and PPARα expression was high. Hepatic fatty acid pathway flux in vivo showed a similar pattern of increases. The abundance of mRNAs for genes involved in hepatic cholesterol synthesis was also increased by WY 14,643, but was associated with a decrease in cholesterogenic carbon flux. None of these changes were apparent in PPARα-null mice. Mice of both genotypes showed the expected decreases in 3-hydroxy-3-methylglutaryl-CoA reductase mRNA levels and cholesterol synthesis in response to an increase in dietary cholesterol. The increase in fatty acid synthesis due to WY 14,643 was not mediated by increased expression of SREBP-1c (sterol regulatory element binding protein-1c) mRNA, but by an increase in cleavage of the protein to the active form. An accompanying rise in stearoyl-CoA desaturase mRNA expression suggested that the increase in lipogenesis could have resulted from an alteration in membrane fatty acid composition that influenced SREBP activation.

scholarly journals Sex Differences in Hepatic De Novo Lipogenesis with Acute Fructose Feeding

Nutrients ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 1263 ◽  
Author(s):  
Wee Low ◽  
Thomas Cornfield ◽  
Catriona Charlton ◽  
Jeremy Tomlinson ◽  
Leanne Hodson
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
De Novo ◽  
Dietary Fatty Acid ◽  
De Novo Lipogenesis ◽  
Liver Fat ◽  
Acid Oxidation ◽  
Free Sugars ◽  
Isotope Tracer ◽  
High Fructose

Dietary free sugars have received much attention over the past few years. Much of the focus has been on the effect of fructose on hepatic de novo lipogenesis (DNL). Therefore the aim of the present study was to investigate the effects of meals high and low in fructose on postprandial hepatic DNL and fatty acid partitioning and dietary fatty acid oxidation. Sixteen healthy adults (eight men, eight women) participated in this randomised cross-over study; study days were separated by a 4-week wash-out period. Hepatic DNL and dietary fatty acid oxidation were assessed using stable-isotope tracer methodology. Consumption of the high fructose meal significantly increased postprandial hepatic DNL to a greater extent than consumption of the low fructose meal and this effect was evident in women but not men. Despite an increase in hepatic DNL, there was no change in dietary fatty acid oxidation. Taken together, our data show that women are more responsive to ingestion of higher amounts of fructose than men and if continued over time this may lead to changes in hepatic fatty acid partitioning and eventually liver fat content.

scholarly journals Expanding Roles of De Novo Lipogenesis in Breast Cancer

2021 ◽  
Vol 18 (7) ◽  
pp. 3575
Author(s):  
Pasquale Simeone ◽  
Stefano Tacconi ◽  
Serena Longo ◽  
Paola Lanuti ◽  
Sara Bravaccini ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Fatty Acid ◽  
De Novo ◽  
Breast Cancer Subtypes ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Breast Cancer Patients ◽  
Membrane Composition ◽  
Lipogenic Enzymes ◽  
Cancer Subtypes

In recent years, lipid metabolism has gained greater attention in several diseases including cancer. Dysregulation of fatty acid metabolism is a key component in breast cancer malignant transformation. In particular, de novo lipogenesis provides the substrate required by the proliferating tumor cells to maintain their membrane composition and energetic functions during enhanced growth. However, it appears that not all breast cancer subtypes depend on de novo lipogenesis for fatty acid replenishment. Indeed, while breast cancer luminal subtypes rely on de novo lipogenesis, the basal-like receptor-negative subtype overexpresses genes involved in the utilization of exogenous-derived fatty acids, in the synthesis of triacylglycerols and lipid droplets, and fatty acid oxidation. These metabolic differences are specifically associated with genomic and proteomic changes that can perturb lipogenic enzymes and related pathways. This behavior is further supported by the observation that breast cancer patients can be stratified according to their molecular profiles. Moreover, the discovery that extracellular vesicles act as a vehicle of metabolic enzymes and oncometabolites may provide the opportunity to noninvasively define tumor metabolic signature. Here, we focus on de novo lipogenesis and the specific differences exhibited by breast cancer subtypes and examine the functional contribution of lipogenic enzymes and associated transcription factors in the regulation of tumorigenic processes.

scholarly journals Treatment with a polyherbal extract improves fat metabolism, attenuates hepatic stellate cell activation and fibrogenesis.

2021 ◽  
Author(s):  
Pavan Kumar Bellamakondi ◽  
Rizwan Baig Mirza ◽  
Onkar Murthy Mallappa ◽  
Azeemuddin Mohammed ◽  
Hariprasad VR ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Cell Activation ◽  
De Novo ◽  
Stellate Cell ◽  
Stellate Cells ◽  
De Novo Lipogenesis ◽  
Acid Oxidation ◽  
Polyherbal Formulation

Non-alcoholic steatohepatitis (NASH) involves dysregulations in denovo lipogenesis, fatty acid oxidation, and fibrogenesis. Targeting these pathways holds promise for the treatment of liver disorders. Here we test the extract of a polyherbal formulation (namely Liv.52), which is approved by the Government of India's Drug Regulatory Authority - AYUSH. The current study evaluates the effect of Liv.52 on denovo lipogenesis, fatty acid oxidation, and fibrogenesis. Both in vivo and in vitro model systems were employed to evaluate the efficacy of this polyherbal formulation. Male Wistar rats were dosed with Liv.52 for 2 weeks (250mg/k.g) and expression levels of the genes involved in de novo lipogenesis and fatty acid oxidation pathways were analysed by quantitative real time PCR. Liv.52 treatment resulted in increased hepatic fatty acid oxidation and decreased de novo lipogenesis in these rats. It also reduced hepatic stellate cell activation in CCL4 treated Wistar rats as evidenced by histological evaluation. For in vitro experiments, HepG2 cells were cultured under lipotoxic conditions (using 200 micro molar palmitic acid) and the conditioned media from these cells were used for inducing activation and fibrogenesis in human hepatic stellate cells (HHSteC). Treatment with lipotoxic conditioned media resulted in activation of hepatic stellate cells and fibrogenesis, as evidenced by increased expression of alpha-smooth muscle actin (alpha-SMA), and desmin (markers of stellate cell activation) and increased levels of collagen and lumican (markers of fibrogenesis). Treatment with Liv.52 reversed the up-regulation of alpha-SMA, collagen and lumican levels in HHSteC cells. These results indicate that Liv.52 exerts its hepatoprotective effect by improving fatty acid metabolism and fibrogenesis.

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