Role of Lipogenesis Rewiring in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Yi Zhou ◽  
Junyan Tao ◽  
Diego F. Calvisi ◽  
Xin Chen
Keyword(s):  
Hepatocellular Carcinoma ◽  
De Novo ◽  
Regulatory Element ◽  
Critical Role ◽  
De Novo Lipogenesis ◽  
Enhanced Expression ◽  
Sterol Regulatory Element ◽  
Functional Analyses ◽  
Transcription Factor 1

AbstractMetabolic rewiring is one of the hallmarks of cancer. Altered de novo lipogenesis is one of the pivotal metabolic events deregulated in cancers. Sterol regulatory element-binding transcription factor 1 (SREBP1) controls the transcription of major enzymes involved in de novo lipogenesis, including ACLY, ACACA, FASN, and SCD. Studies have shown the increased de novo lipogenesis in human hepatocellular carcinoma (HCC) samples. Multiple mechanisms, such as activation of the AKT/mechanistic target of rapamycin (mTOR) pathway, lead to high SREBP1 induction and the coordinated enhanced expression of ACLY, ACACA, FASN, and SCD genes. Subsequent functional analyses have unraveled these enzymes' critical role(s) and the related de novo lipogenesis in hepatocarcinogenesis. Importantly, targeting these molecules might be a promising strategy for HCC treatment. This paper comprehensively summarizes de novo lipogenesis rewiring in HCC and how this pathway might be therapeutically targeted.

scholarly journals Role of hepatoma‐derived growth factor in promoting de novo lipogenesis and tumorigenesis in hepatocellular carcinoma

2018 ◽  
Vol 12 (9) ◽  
pp. 1480-1497 ◽  
Author(s):  
Xuejie Min ◽  
Jun Wen ◽  
Li Zhao ◽  
Kaiying Wang ◽  
Qingli Li ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factor ◽  
De Novo ◽  
De Novo Lipogenesis

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.

scholarly journals SCAP/SREBP pathway is required for the full steroidogenic response to cyclic AMP

2016 ◽  
Vol 113 (38) ◽  
pp. E5685-E5693 ◽  
Author(s):  
Masami Shimizu-Albergine ◽  
Brian Van Yserloo ◽  
Martin G. Golkowski ◽  
Shao-En Ong ◽  
Joseph A. Beavo ◽  
...  
Keyword(s):  
Cyclic Amp ◽  
Leydig Cells ◽  
De Novo ◽  
Regulatory Element ◽  
De Novo Synthesis ◽  
Intracellular Lipid ◽  
Element Binding Protein ◽  
Short Palindromic Repeat ◽  
Sterol Regulatory Element

Luteinizing hormone (LH) stimulates steroidogenesis largely through a surge in cyclic AMP (cAMP). Steroidogenic rates are also critically dependent on the availability of cholesterol at mitochondrial sites of synthesis. This cholesterol is provided by cellular uptake of lipoproteins, mobilization of intracellular lipid, and de novo synthesis. Whether and how these pathways are coordinated by cAMP are poorly understood. Recent phosphoproteomic analyses of cAMP-dependent phosphorylation sites in MA10 Leydig cells suggested that cAMP regulates multiple steps in these processes, including activation of the SCAP/SREBP pathway. SCAP [sterol-regulatory element-binding protein (SREBP) cleavage-activating protein] acts as a cholesterol sensor responsible for regulating intracellular cholesterol balance. Its role in cAMP-mediated control of steroidogenesis has not been explored. We used two CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9 (CRISPR associated protein 9) knockout approaches to test the role of SCAP in steroidogenesis. Our results demonstrate that SCAP is required for progesterone production induced by concurrent inhibition of the cAMP phosphodiesterases PDE4 and PDE8. These inhibitors increased SCAP phosphorylation, SREBP2 activation, and subsequent expression of cholesterol biosynthetic genes, whereas SCAP deficiency largely prevented these effects. Reexpression of SCAP in SCAP-deficient cells restored SREBP2 protein expression and partially restored steroidogenic responses, confirming the requirement of SCAP–SREBP2 in steroidogenesis. Inhibitors of 3-hydroxy-3-methylglutaryl-Coenzyme A reductase and isoprenylation attenuated, whereas exogenously provided cholesterol augmented, PDE inhibitor-induced steroidogenesis, suggesting that the cholesterol substrate needed for steroidogenesis is provided by both de novo synthesis and isoprenylation-dependent mechanisms. Overall, these results demonstrate a novel role for LH/cAMP in SCAP/SREBP activation and subsequent regulation of steroidogenesis.

scholarly journals Endothelial cells provide an instructive niche for the differentiation and functional polarization of M2-like macrophages

Blood ◽  
2012 ◽  
Vol 120 (15) ◽  
pp. 3152-3162 ◽  
Author(s):  
Huanhuan He ◽  
Jingying Xu ◽  
Carmen M. Warren ◽  
Dan Duan ◽  
Xinmin Li ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Vascular Function ◽  
Critical Role ◽  
Colony Growth ◽  
Hematopoietic Progenitors ◽  
Enhanced Expression ◽  
Functional Polarization ◽  
Functional Analyses

Abstract Endothelial cells and macrophages are known to engage in tight and specific interactions that contribute to the modulation of vascular function. Here we show that adult endothelial cells provide critical signals for the selective growth and differentiation of macrophages from several hematopoietic progenitors. The process features the formation of well-organized colonies that exhibit progressive differentiation from the center to the periphery and toward an M2-like phenotype, characterized by enhanced expression of Tie2 and CD206/Mrc1. These colonies are long-lived depending on the contact with the endothelium; removal of the endothelial monolayer results in rapid colony dissolution. We further found that Csf1 produced by the endothelium is critical for the expansion of the macrophage colonies and that blockade of Csf1 receptor impairs colony growth. Functional analyses indicate that these macrophages are capable of accelerating angiogenesis, promoting tumor growth, and effectively engaging in tight associations with endothelial cells in vivo. These findings uncover a critical role of endothelial cells in the induction of macrophage differentiation and their ability to promote further polarization toward a proangiogenic phenotype. This work also highlights some of the molecules underlying the M2-like differentiation, a process that is relevant to the progression of both developmental and pathologic angiogenesis.

scholarly journals 4β-hydroxycholesterol is a pro-lipogenic factor that promotes SREBP1c expression and activity through Liver X-receptor

2020 ◽  
Author(s):  
Ofer Moldavski ◽  
Peter-James H. Zushin ◽  
Charles A. Berdan ◽  
Robert J. Van Eijkeren ◽  
Xuntian Jiang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
De Novo ◽  
Regulatory Element ◽  
Liver X Receptor ◽  
De Novo Lipogenesis ◽  
Primary Hepatocytes ◽  
Element Binding Protein ◽  
Sterol Regulatory Element ◽  
Derivatives Of ◽  
Oxidized Derivatives Of Cholesterol

Oxysterols are oxidized derivatives of cholesterol that play signaling roles in lipid biosynthesis and homeostasis. Here we show that 4β-hydroxycholesterol (4β-HC), a liver and serum abundant oxysterol of poorly defined function, is a potent and selective inducer of the master lipogenic transcription factor, Sterol Regulatory Element Binding Protein 1c (SREBP1c), but not the related steroidogenic transcription factor SREBP2. Mechanistically, 4β-HC acts as a putative agonist for Liver X receptor (LXR), a sterol sensor and transcriptional regulator previously linked to SREBP1c activation. Unique among the oxysterol agonists of LXR, 4β-HC induced expression of the lipogenic program downstream of SREBP1c, and triggered de novo lipogenesis both in primary hepatocytes and in mouse liver. 4β-HC-acted in parallel to insulin-PI3K-dependent signaling to stimulate triglyceride synthesis and lipid droplet accumulation. Thus, 4β-HC is an endogenous regulator of de novo lipogenesis through the LXR-SREBP1c axis.

Raman spectroscopic imaging for investigations of de novo lipogenesis in hepatocellular carcinoma

2014 ◽  
Vol 52 (08) ◽  
Author(s):  
T Tolstik ◽  
C Marquardt ◽  
C Matthäus ◽  
C Beleites ◽  
C Krafft ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
De Novo ◽  
Spectroscopic Imaging ◽  
De Novo Lipogenesis ◽  
Raman Spectroscopic

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 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.

scholarly journals Sterol regulatory element binding transcription factor 1 (SREBF1) polymorphism and milk fatty acid composition

2013 ◽  
Vol 96 (4) ◽  
pp. 2605-2616 ◽  
Author(s):  
R.A. Nafikov ◽  
J.P. Schoonmaker ◽  
K.T. Korn ◽  
K. Noack ◽  
D.J. Garrick ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Fatty Acid Composition ◽  
Fatty Acid ◽  
Acid Composition ◽  
Regulatory Element ◽  
Milk Fatty Acid ◽  
Sterol Regulatory Element ◽  
Transcription Factor 1
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