Fatty Acid Synthase mRNA Expression Research Articles

Intervention effect of Erchen Decoction on methionine and choline deficient diet-induced non-alcoholic steatohepatitis in mice

This study investigated the effect of Erchen Decoction(ECD) on the prevention of non-alcoholic steatohepatitis(NASH) in mice and explored its possible mechanism, so as to provide scientific data for the clinical application of ECD in the prevention of NASH. C57BL/6 male mice were randomly divided into normal group(methionine and choline supplement, MCS), model group(methionine and choline deficient, MCD), low-dose ECD group(ECD＿L, 6 g·kg~(-1)), medium-dose ECD group(ECD＿M, 12 g·kg~(-1)), and high-dose ECD group(ECD＿H, 24 g·kg~(-1)), with eight mice in each group. The MCS group was fed with an MCS diet, and the other groups were fed with an MCD diet. The mice in each group were given corresponding diets, but the drug intervention group was given low-, medium-, and high-dose ECD(10 mL·kg~(-1)·d~(-1)) by intragastric administration for six weeks on the basis of MCD diet feeding, and the mice could eat and drink freely during the whole experiment. At the end of the experiment, mice were fasted overnight(12 h) and were anesthetized with 20% urethane. Thereafter, the blood and liver tissue were collected. The serum was used to detect the levels of alanine aminotransferase(ALT), aspartate aminotransaminase(AST), interleukin-1β(IL-1β), interleukin-6(IL-6), interleukin-10(IL-10), and tumor necrosis factor-α(TNF-α). Liver tissue was processed by hematoxylin-eosin(HE) staining and used for hepatic histological analysis and detection of the expression levels of genes and proteins related to nuclear factor erythroid 2-related factor 2/glutathione peroxidase 4(Nrf2/GPX4) pathway by real-time quantitative reverse transcriptase-polymerase chain reaction(RT-qPCR) and Western blot analysis, respectively. The results showed that compared with the MCS group, the MCD group showed higher serum ALT and AST levels; the HE staining exhibited fat vacuoles and obvious inflammatory cell infiltration in liver tissue; serum IL-1β, IL-6, and TNF-α levels were significantly increased, and the serum IL-10 level was significantly decreased. The mRNA expressions of fatty acid synthase(FASN), monocyte chemoattractant protein-1(MCP-1), and IL-1β in liver tissue were significantly up-regulated, while those of GPX4, Nrf2, and NAD(P)H:quinine oxidoreductase(NQO1) were significantly down-regulated. Compared with the MCD group, the serum ALT and AST levels of ECD＿M and ECD＿H groups were significantly decreased, and the AST level in the ECD＿L group was significantly decreased. The number of fat vacuoles and the degree of inflammatory cell infiltration in liver tissue were improved; serum IL-1β, IL-6, and TNF-α levels were significantly decreased, but the serum IL-10 level was significantly increased only in the ECD＿H group. The mRNA expressions of FASN, MCP-1, and IL-1β in liver tissue were significantly down-regulated, and those of GPX4 and NQO1 were significantly up-regulated. The mRNA expressions of Nrf2 in ECD＿M and ECD＿H groups were significantly up-regulated. Western blot results showed that compared with the MCD group, the protein expression levels of Nrf2 and GPX4 in each group were significantly increased after ECD administration, and the protein expression level of FASN was significantly decreased; the protein expression of NQO1 was increased in ECD＿M and ECD＿H groups. In summary, ECD can reduce hepatic lipid accumulation, oxidative stress, liver inflammation, and liver injury in NASH mice, which may be related to the activation of the Nrf2/GPX4 pathway.

Kaempferia parviflora rhizome extract exerts anti-obesity effect in high-fat diet-induced obese C57BL/6N mice.

Kaempferia parviflora (KP) rhizome, also called black ginger, has been used as a herbal medicine for many centuries. This current study was aimed at exploring whether KP rhizome extract (KPE) had anti-obesity effects and the mechanism involved. Five-week-old C57BL/6N male mice were allocated into five groups for 8-week feeding with control diet (CD), high-fat diet (HFD), HFD + 150 mg/kg body weight (BW)/day KPE (HFD+K150), HFD + 300 mg/kg BW/day KPE (HFD+K300), and HFD + 600 mg/kg BW/day KPE (HFD+K600). KPE decreased BW, body fat mass, adipose tissue weight, adipocyte size, and serum levels of glucose, triglycerides, cholesterol, insulin, and leptin in HFD-induced obese C57BL/6N mice. KPE inhibited adipogenesis by decreasing CCAAT/enhancer binding protein α, peroxisome proliferator-activated receptor γ, sterol regulatory element-binding protein-1c, acetyl-CoA carboxylase 1, ATP-citrate lyase, and fatty acid synthase mRNA expression. KPE improved lipolysis by increasing carnitine palmitoyl transferase 1 and hormone-sensitive lipase mRNA expression. These results suggest that KPE may have inhibited HFD-induced obesity by regulating several pathways involved in decreasing adipogenesis and enhancing lipolysis. Thus, the results suggest that KPE (or KP) may be applicable as an anti-obesity agent.

Allium macrostemon whole extract ameliorates obesity-induced inflammation and endoplasmic reticulum stress in adipose tissue of high-fat diet-fed C57BL/6N mice.

Obesity is a major risk factor for metabolic syndrome and a serious health concern worldwide. Various strategies exist to treat and prevent obesity, including dietary approaches using bioactive ingredients from natural sources. This study aimed to investigate the anti-obesity effect of whole-plant Allium macrostemon (also called as long-stamen chive) extract (AME) as a potential new functional food. C57BL/6N mice were divided into three groups and fed either a control diet (CD), high-fat diet (HFD), or HFD with AME treatment (200 mg/kg BW daily) for 9 weeks. The mice in the CD and HFD groups were treated with vehicle control. AME supplementation reduced HFD-induced body weight gain, fat mass, and adipocyte size. AME suppressed peroxisome proliferator-activated receptor γ and fatty acid synthase mRNA expression, indicating reduced adipogenesis and lipogenesis in adipose tissue. In addition, AME lowered inflammation in adipose tissue, as demonstrated by the lower number of crown-like structures, mRNA, and/or protein expression of macrophage filtration markers, as well as pro-inflammatory cytokines, including F4/80 and IL-6. Endoplasmic reticulum stress was also alleviated by AME administration in adipose tissue. Several phenolic acids known to have anti-obesity effects, including ellagic acid, protocatechuic acid, and catechin, have been identified in AME. By suppressing adipose tissue expansion and inflammation, AME is a potential functional food for the prevention and/or treatment of obesity and its complications.

Effects of Dietary Isoleucine Supplementation on the Production Performance, Health Status and Cecal Microbiota of Arbor Acre Broiler Chickens.

A total of 24,000 healthy 1-day-old Arbor Acres broilers with similar initial weights were used in this study and fed a basal diet supplemented with 0, 400 and 800 mg/kg isoleucine (Ile), denoted CON, ILE400 and ILE800, respectively. Results revealed that the final body weight, average daily weight gain, and eviscerated carcass rate, of broiler chickens in the ILE400 group were significantly higher than in other groups (p < 0.05). In addition, the ILE400 and ILE800 groups had a lower feed conversion rate and a higher survival rate and breast muscle rate (p < 0.05), while the abdominal fat rate was significantly lower than the CON group (p < 0.05). There were significantly lower serum concentrations of UREA, glucose (GLU) and total cholesterol (TCHO) in the ILE400 and ILE800 groups than in the CON group (p < 0.05); glutathione peroxidase (GSH-Px) activity was significantly higher in the ILE400 group than in the other groups, and tumor necrosis factor-alpha (TNF-α) concentration was considerably lower than in other groups (p < 0.05). Moreover, interleukin (IL)-10 concentration in the ILE800 group was significantly higher than in the other groups (p < 0.05). The ILE400 group significantly down-regulated the mRNA expressions of fatty-acid synthase (FASN) and solid alcohol regulatory element binding protein 1c (SREBP1c), and significantly up-regulated the mRNA expressions of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), lipoprotein lipase (LPL) and sirtuin1 (Sirt1) (p < 0.05). The ILE400 group had significantly higher intestinal villus height than the CON and ILE800 groups, while the ILE800 group had significantly lower intestinal villus height/crypt depth (p < 0.05). Furthermore, high-throughput sequencing showed that the Shannon index, and Verrucomicrobiota, Colidextribacter and Bacteroides abundances were significantly higher in the ILE400 group than in the CON group (p < 0.05). Interestingly, the ILE800 group reduced the Simpson index, phylum Firmicutes and Bacteroidota abundances (including genera Colidextribacter, Butyricicoccus, [Ruminococcus]_torques_group, Bacteroides, Alistipes, Barnesiella and Butyricimonas), and increased Proteobacteria and Cyanobacteria (including genera Dyella, Devosia, unidentified_Chloroplast and Hyphomicrobium) (p < 0.05). Overall, our study showed that adding 400 mg/kg Ile to the diet (diets total Ile levels at 1.01%, 0.90% and 0.87% during the starter, grower and finisher phases, respectively) increased production performance and improved the health status in broiler chickens.

Dietary isoleucine affects muscle fatty acid and amino acid profiles through regulating lipid metabolism and autophagy in hybrid catfish (Pelteobagrus vachelli ♀× Leiocassis longirostris ♂).

The present study explored the impacts of Ile on muscle fatty acid and amino acid profiles, lipid metabolism, and autophagy in hybrid catfish. Seven isonitrogenous (387.8g/kg protein) semi-purified diets were formulated to contain 5.0 (control), 7.5, 10.0, 12.5, 15.0, 17.5, and 20.0g Ile/kg diet respectively. The fish (initial weight of 33.11±0.09g) were randomly assigned to 7 groups for a 56-day trial. Each group has 3 replicates with 30 fish per replicate, fed at 08:00 and 18:00 each day. Results showed that muscle protein and lipid, C14:0, C18:0, C22:0, C14:1, C18:1n-9, polyunsaturated fatty acid (PUFA), Arg, Ile, Ala, Cys, Gly, Tyr, essential amino acid (EAA), and total amino acid (TAA) contents and flavor amino acid (FAA)/TAA in muscle had positive linear and/or quadratic responses to dietary Ile levels (P<0.05). Fatty acid synthase (FAS), stearoyl-CoA desaturase (SCD), acetyl-CoA carboxylase (ACC), and lipoprotein lipase (LPL) activities had positive linear and/or quadratic responses, but carnitine palmitoyl transferase 1 (CPT1) activity had a negative response with increasing dietary Ile levels (P<0.05). The mRNA expressions of FAS, SCD, ACC, LPL, fatty acid binding protein 4 (FABP4), FATP1, sterol response element-binding protein 1c (SREBP-1c), sequestosome 1 (SQSTM1), and adenosine 5'-monophosphate-activated protein kinase (AMPK) had positive linear and/or quadratic responses to dietary Ile levels (P<0.05). The mRNA expressions of hormone-sensitive lipase (HSL), CPT1, peroxisome proliferator-activated receptor α (PPARα), PPARγ, uncoordinated 51-like kinase 1 (ULK1), beclin1 (Becn1), autophagy-related protein 9α (Atg9α), Atg4b, Atg7, autophagy marker light chain 3B (LC3B), and SQSTM1 in muscle had negative linear and/or quadratic responses to dietary Ile levels (P<0.05). The p-AMPK and ULK1 protein levels, and p-AMPK/AMPK were decreased by 12.5g Ile/kg in the diet (P<0.05). Finally, SQSTM1 protein level had the opposite effect (P<0.05). The above results indicate that dietary Ile improves fish muscle fatty acid and amino acid profiles potentially via respectively regulating lipid metabolism and autophagy. The Ile requirement of hybrid catfish (33 to 72g) were estimated to be 12.63, 13.77, 13.75, 11.45, 10.50, 12.53 and 12.21g/kg diet based on the regression analysis of protein, lipid, SFA, PUFA, FAA, EAA, and TAA muscle contents, respectively.

Changes in the triglyceride metabolism in the thigh muscle and liver of broilers injected intravenously with angiopoietin-like protein 4

Angiopoietin-like protein 4 (ANGPTL4) is a potential circulating mediator connecting nutritional factors and fat metabolism, however, information is lacking on the exact role of ANGPTL4 on triglyceride metabolism in the thigh muscles and livers of broilers. The objective of this study was to determine the changes in the triglyceride metabolism in the thigh muscles and livers of broilers injected intravenously with ANGPTL4. In experiment 1, 36 male Arbor Acres broilers at 35 days of age were randomly allocated into six treatments with six replicates. The broilers were subjected to intravenous injection of polyhistidine-small ubiquitin-related modifier-ANGPTL4 (His-SUMO-ANGPTL4) once at a dose of 0, 20, 100, 500, 2 500, or 12 500 ng/kg body weight (BW), respectively. The results showed that the injection of His-SUMO-ANGPTL4 at a dose of 500, 2 500 and 12 500 ng/kg BW decreased (P &amp;lt; 0.05) the broilers’ heart-fatty acid-binding protein (H-FABP) mRNA expression in the thigh muscle. All of the His-SUMO-ANGPTL4 broiler injected groups had a lower (P &amp;lt; 0.05) adipocyte-fatty acid-binding protein mRNA expression in the thigh muscle. In experiment 2, 18 male Arbor Acres broilers at 35 days of age were randomly allocated into three treatments with six replicates. The broilers were given an injection of normal saline (NS), His-SUMO, or His-SUMO-ANGPTL4 (500 ng/kg BW) once. The results showed that the broilers receiving an injection of ANGPTL4 at a dose of 500 ng/kg BW decreased (P &amp;lt; 0.05) the H-FABP mRNA expression in the thigh muscle. Besides, the broilers given an injection of ANGPTL4 at a dose of 500 ng/kg BW increased (P &amp;lt; 0.05) the fatty acid synthase mRNA expression and activity and decreased (P &amp;lt; 0.05) the microsomal triglyceride transfer protein mRNA expression in the liver. However, the concentrations of the high-density lipoprotein, low-density lipoprotein, very low-density lipoprotein, insulin, growth hormone and leptin in the serum were not affected by the ANGPTL4 injection. In conclusion, ANGPTL4 has the ability to change the triglyceride metabolism in the thigh muscles and livers of broilers.

P10.08.A Lipogenesis inhibition by fatostatin shows effectiveness in glioblastoma models highly expressing fatty acid synthase (FASN)

Abstract Background Glioblastoma (GBM) is the most common and most aggressive primary brain tumour in adults. Despite intensive treatment, the medium overall survival of GBM patients remains below 20 months after diagnosis. Therefore, new tumour specific targets allowing successful therapeutic treatment are needed to distinctly enhance GBM patient overall survival. Reprogramming of lipid metabolism leading to highly upregulated anabolic pathways, like phosphatidylinositol-3-kinase (PI3K)/AKT pathway and subsequently lipogenesis, is a hallmark of cancer cells including glioblastomas to meet increased energy demands for proliferation and cell growth. Accordingly, lipogenesis inhibition might be a promising strategy to impede GBM cell growth. Therefore, it was aim of our study to analyse the effect of the lipogenesis inhibitor fatostatin on downstream targets e.g. fatty acid synthase (FASN) and its impact on cell growth in GBM cells in vitro. Material and Methods In a cohort of 52 GBM-derived cell lines, FASN mRNA was investigated by qRT-PCR. The impact of fatostatin on cell viability (IC50) was analysed in selected cell lines using cell viability assays (Cell Titer Glo®). To elucidate whether fatostatin exposure affects cell migration, wound healing assays were performed. The effect of fatostatin on cell cycle and apoptosis was analysed by flow cytometry. Additionally, expression of FASN and level of phosphorylated AKT, the active form of AKT serine/threonine kinase, were examined before and after fatostatin treatment with qRT-PCR (mRNA) and Western blot (protein), respectively. Results FASN mRNA was found to be expressed at varying levels in our GBM-derived cell line cohort (n=52). Compared to normal astrocytes, FASN mRNA expression was significantly upregulated in GBM cells (p=0.0127). Furthermore, high FASN mRNA expression was significantly associated with higher sensitivity against fatostatin (p=0.0352). Regarding corresponding recurrences, the response to the inhibitor was shown to be persistent. Accordingly, the effectiveness of fatostatin treatment resulted in substantial downregulation of AKT phosphorylation and consequently in the induction of apoptosis and G2/M arrest of the cell cycle. In addition, a significant inhibition of the migration potential by fatostatin treatment was observed. Conclusion In summary, FASN expression represents a promising biomarker and therapy target within the lipid metabolism indicated by a significant sensitivity to fatostatin in FASN overexpressing GBM cell lines. Consequently, lipogenesis inhibition by fatostatin might be a promising novel therapeutic option in glioblastoma.

FASN Knockdown Inhibited Anoikis Resistance of Gastric Cancer Cells via P-ERK1/2/Bcl-xL Pathway.

Anoikis resistance (AR) is a crucial step in tumor metastasis. The overexpression of fatty acid synthase (FASN) is not only related to the AR of osteosarcoma cells, but also evidenced on gastric cancer (GC). This study investigated the role of FASN in the AR of GC cells. Plates coated with poly-HEMA were used for the culture of cells with AR. Small interfering RNA targeting FASN (siFASN) was transfected into MNK-45 and AGS cells. The number and apoptosis of cells were assessed by a hemacytometer and Annexin-V-FITC/PI assay, respectively. Aggregated cells and colony numbers were manually counted under a microscope. The migration and invasion rates were measured via wound healing and Transwell invasion assays, respectively. The levels of FASN, phosphorylated (p)-ERK1/2, ERK1/2 and Bcl-xL were detected through western blot or quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The results showed that the cell numbers of MNK-45 and AGS were increased while that of GES-1 cell was decreased during the culture in suspension. A higher apoptosis rate and a smaller number of aggregated cells were observed in GES-1 cells in comparison with MNK-45 and AGS cells. A larger colony number, greater migration and invasion rates, and higher mRNA and protein expressions of FASN were presented in the AR group compared with the control group. Cells transfected with siFASN possessed lower migration and invasion rates, reduced expressions of FASN mRNA and protein, p-ERK1/2 and Bcl-xL, and induced a significantly declined ratio of p-ERK1/2 to ERK1/2. These findings suggest that down-regulation of FASN suppresses the AR of GC cells, which may be related to the inhibition of p-ERK1/2/Bcl-xL pathway.

THE SIMVASTATIN EFFECT ON ACETYL COA CARBOXYLASE1 AND FATTY ACID SYNTHASE GENE EXPRESSION IN RAT FED WITH HIGH FAT DIETS AND ITS ASSOCIATION WITH FATTY ACID PROPORTION AND CONCENTRATION

The aim of study was to determine the effect of different dosages of simvastatin on gene expression of Acetyl CoA Carboxylase 1 (ACC1) and Fatty Acid Synthase (FAS) in Wister rat hepatic tissues fed with high fat diets (HFD) and its association with serum fatty acid proportion and concentration. Four groups of rats (G1 to G4) were included. ACC1 and FAS expressions were analyzed by Real time quantitative polymerase chain reaction. Fatty acid concentration was measured by gas chromatography. There were significant differences when G4 versus G3, G4 and G3 versus G1 and G4 and G3 versus G2 was compared for total fatty acid concentration. The proportion of oleic acid to stearic acid showed significant decrease when G4 versus G3, G4 versus G2 and G4 versus G1 groups were compared, but the proportion of stearic acid to palmitic acid, linoleic acid to oleic acid (G3 versus G4) and oleic acid to palmitic acid in G4 increased when compared to G1, G2 and G3 groups. Treatment with simvastatin significantly increases or decreases some fatty acid ratio, serum fatty acid and total fatty acid concentrations. We also found that HFD led to no significant differences in ACC1 and FAS mRNA expression. Simvastatin increases proportion of linoleic acid to oleic acid, oleic acid to palmitic acid and oleic acid to stearic acid. Thus, statin therapy may be considered in prevention of cardiovascular and myocardial risk.

Triclosan down-regulates fatty acid synthase through microRNAs in HepG2 cells

Triclosan is a promising candidate of fatty acid synthase (FASN) inhibitor by blocking FASN activity, but its effect on FASN expression and the underling epigenetic mechanism remain elusive. In this study, the effect of triclosan on FASN mRNA and protein expressions in human HepG2 cells and the regulatory role of microRNAs (miRNAs) in the downregulation of FASN induced by triclosan were explored through experiments and bioinformatics analysis. The results showed that triclosan not only directly inhibited FASN activity, but also significantly decreased FASN mRNA and protein levels in human liver HepG2 cells. Nine miRNAs targeting FASN mRNA degradation were identified by miRNA prediction tools, and the expression levels of these nine miRNAs were then detected by real-time quantitative PCR. Triclosan significantly increased the expressions of the six miRNAs, namely miR-15a, miR-107, miR-195, miR-424, miR-497 and miR-503, leading to the downregulation of FASN. Further investigation revealed that the six triclosan-upregulated miRNAs played an important regulatory role in lipid metabolism and cell cycle by gene ontology annotations and pathway analysis. Consistent with the results of bioinformatics analyses, triclosan significantly reduced the intracellular lipid content by triglyceride assay, oil red O, BODIPY 493/503 and Nile Red staining, thereby inhibiting the growth of HepG2 cells through apoptosis. Taken together, our study reveals that triclosan downregulates FASN expression through a variety of miRNAs, providing new insight for triclosan as a FASN inhibitor candidate to regulate lipid metabolism in human hepatoma cells.

Fatty Acid Synthase Correlates With Prognosis-Related Abdominal Adipose Distribution and Metabolic Disorders of Clear Cell Renal Cell Carcinoma.

Purpose: Lipid metabolism reprogramming is a major pathway in tumor evolution. This study investigated fatty acid synthase (FASN) mRNA expression in anthropometric adipose tissue and elucidated the prognostic value and potential mechanism of clear cell renal cell carcinoma (ccRCC).Materials and Methods: Transcription profiles were obtained from 533 ccRCC samples in The Cancer Genome Atlas (TCGA) cohorts. Real-time quantitative PCR (RT-qPCR) and immunohistochemistry were performed to detect FASN expression in 380 paired ccRCC and normal tissues from the Fudan University Shanghai Cancer Center (FUSCC). Visceral adipose tissue (VAT) and subcutaneous adipose tissue were at the level of the umbilicus as measured by magnetic resonance imaging (MRI). Non-targeted metabolomics and in vitro experiments were used to reveal the biological functions of FASN.Results: Increased FASN expression was significantly relevant to advanced T, N, and American Joint Committee on Cancer (AJCC) stages (p < 0.01) and significantly correlated to poor progression-free survival (PFS) and overall survival (OS) of 913 ccRCC patients in FUSCC and TCGA cohorts. Pearson's correlation coefficient indicated that FASN amplification was positively correlated to VAT% (r = 0.772, p < 0.001), which significantly correlated to poor PFS (HR = 2.066, p = 0.028) and OS (HR = 2.773, p = 0.023) in the FUSCC cohort. Transient inhibition or overexpression of FASN significantly regulated A498 and 786O cell proliferation and migration by regulating epithelial–mesenchymal transition. Inhibition of FASN led to a higher apoptotic rate and decreased lipid droplet formation compared with normal control in ccRCC cells. Non-targeted metabolomics showed that decreased de novo lipogenesis might be required to sustain an elevation of glycolytic activity in 786O cells by regulating galactinol, dl-lactate, N-acetylaspartylglutamate, and sucrose, thereby participating in carcinogenesis and progression of ccRCC.Conclusion: This study demonstrated that FASN expression is positively related to aggressive cell proliferation, migration, apoptosis, and lipid droplet formation and regulates metabolic disorders of the ccRCC microenvironment. Additionally, elevated FASN mRNA expression is significantly correlated to the abdominal obesity distribution, especially VAT%, which is a significant predictor of a poor prognosis for ccRCC patients.

Comparison of performance, fatty acid composition, enzymes and gene expression between overfed Xupu geese with large and small liver

The aim of our study was to compare overfeeding performance, fatty acid composition, enzymes activity and gene expression between overfed Xupu geese with large and small liver. A total of sixty 80 d male Xupu geese were overfed by the same feed intake under the same conditions. The liver weight exhibited normal distribution. Based on the weight of liver, samples were divided into large liver (LL) and small liver (SL) Xupu geese. After overfeeding for 28 d: compared with the SL-Xupu geese, liver weight and liver-to-body weight ratio increased (p < .05), while abdominal fat weight and feed-to-liver weight ratio decreased (p < .05); the level of palmitic acid and methyltetracosanoate acid decreased (p < .05), and the level of oleic acid, linoleic acid, arachidonic acid, and docosahexaenoic acid increased (p < .05) in liver of LL-Xupu geese. Compared with the SL-Xupu geese, LL-Xupu geese had a higher plasma concentration of TG (triglyceride) (p < .05), and had a lower plasma concentration of VLDL-C (very low density lipoprotein cholesterol) (p < .05); and had a higher CHE (cholinesterase), LPS (lipase), LPL (lipoproteinlipase) activities (p < .05) in the liver. The mRNA expression of FABP4 (adipocyte fatty acid binding protein), SCD (stearoyl-CoA desaturase), FADS (fatty acid dehydrogenase), ELOVL1 (elongase of long-chain fatty acid 1), ACAT2 (acyl-Co A: cholesterol acyltransferase 2), and FASN (fatty acid synthase) (p < .05) were significantly upregulated in LL-Xupu geese than in SL-Xupu geese. The results showed that the level of unsaturated fatty acid in liver of LL-Xupu geese was higher than that of SL-Xupu geese, which may be closely related to enzymes and genes expression related to lipid metabolism. Highlights The content of unsaturated fatty acids in liver of LL-Xupu geese were significantly higher than in SL-Xupu geese. The mRNA expression of FABP4, SCD, FADS, ELOVL1, ACAT2, and FASN were significantly upregulated in LL-Xupu geese than in SL-Xupu geese. The level of unsaturated fatty acid in liver of LL-Xupu geese was higher than that of SL-Xupu geese, which may be closely related to enzymes and genes expression related to lipid metabolism.

Mechanism of maggot debridement therapy in promoting wound angiogenesis in patients with diabetic foot ulcer

Mechanism of maggot debridement therapy in promoting wound angiogenesis in patients with diabetic foot ulcer

Pivotal Role of Fatty Acid Synthase in c-MYC Driven Hepatocarcinogenesis.

Hepatocellular carcinoma (HCC) is a deadly form of liver malignancy with limited treatment options. Amplification and/or overexpression of c-MYC is one of the most frequent genetic events in human HCC. The mammalian target of Rapamycin Complex 1 (mTORC1) is a major functional axis regulating various aspects of cellular growth and metabolism. Recently, we demonstrated that mTORC1 is necessary for c-Myc driven hepatocarcinogenesis as well as for HCC cell growth in vitro. Among the pivotal downstream effectors of mTORC1, upregulation of Fatty Acid Synthase (FASN) and its mediated de novo lipogenesis is a hallmark of human HCC. Here, we investigated the importance of FASN on c-Myc-dependent hepatocarcinogenesis using in vitro and in vivo approaches. In mouse and human HCC cells, we found that FASN suppression by either gene silencing or soluble inhibitors more effectively suppressed proliferation and induced apoptosis in the presence of high c-MYC expression. In c-Myc/Myeloid cell leukemia 1 (MCL1) mouse liver tumor lesions, FASN expression was markedly upregulated. Most importantly, genetic ablation of Fasn profoundly delayed (without abolishing) c-Myc/MCL1 induced HCC formation. Liver tumors developing in c-Myc/MCL1 mice depleted of Fasn showed a reduction in proliferation and an increase in apoptosis when compared with corresponding lesions from c-Myc/MCL1 mice with an intact Fasn gene. In human HCC samples, a significant correlation between the levels of c-MYC transcriptional activity and the expression of FASN mRNA was detected. Altogether, our study indicates that FASN is an important effector downstream of mTORC1 in c-MYC induced HCC. Targeting FASN may be helpful for the treatment of human HCC, at least in the tumor subset displaying c-MYC amplification or activation.

Fat mass and obesity-associated protein regulates lipogenesis via m6 A modification in fatty acid synthase mRNA.

As the first identified N6 -methyladenosine (m6 A) demethylase, fat mass and obesity-associated (FTO) protein is associated with fatty acid synthase (FASN) and lipid accumulation. However, little is known about the regulatory role of FTO in the expression of FASN and de novo lipogenesis through m6 A modification. In this study, we used FTO small interfering RNA to explore the effects of FTO knockdown on hepatic lipogenesis and its underlying epigenetic mechanism in HepG2 cells. We found that knockdown of FTO increased m6 A levels in total RNA and enhanced the expression of YTH domain family member 2 which serves as the m6 A-binding protein. The de novo lipogenic enzymes and intracellular lipid content were significantly decreased under FTO knockdown. Mechanistically, knockdown of FTO dramatically enhanced m6 A levels in FASN messenger RNA (mRNA), leading to the reduced expression of FASN mRNA through m6 A-mediated mRNA decay. The protein expressions of FASN along with acetyl CoA carboxylase and ATP-citrate lyase were further decreased, which inhibited de novo lipogenesis, thereby resulting in the deficiency of lipid accumulation in HepG2 cells and the induction of cellular apoptosis. The results reveal that FTO regulates hepatic lipogenesis via FTO-dependent m6 A demethylation in FASN mRNA and indicate the critical role of FTO-mediated lipid metabolism in the survival of HepG2 cells. This study provides novel insights into a unique RNA epigenetic mechanism by which FTO mediates hepatic lipid accumulation through m6 A modification and indicates that FTO could be a potential target for obesity-related diseases and cancer.

Infusion of short chain fatty acids in the ileum improves the carcass traits, meat quality and lipid metabolism of growing pigs.

Short chain fatty acids (SCFA) are the main products of indigestible carbohydrates undergoing bacterial fermentation in the hindgut, which are related to some physiological functions. This study was designed to investigate the effects of SCFA infusion by ileum on the carcass traits, meat quality and lipid metabolism of growing pigs. In a 28-day study, 24 growing barrows fitted with a T-cannula in distal ileum were divided into 4 treatments: 1) Control, 2) antibiotics (AB), 3) AB + 300 mL of SCFA1 solution (ABS1), 4) AB + 300 mL of SCFA2 solution (ABS2). The concentrations of acetate, propionate and butyrate in SCFA1 solution were respectively 61.84, 18.62 and 12.55 mmol/L, and in SCFA2 were respectively 40.08, 15.41 and 9.78 mmol/L. The results showed that the SCFA infusion increased the average daily feed intake and average daily gain of pigs (P < 0.05). Meanwhile, the SCFA treatments increased longissimus dorsi area (P < 0.05) and carcass weight (P = 0.058), decreased the drip loss of longissimus dorsi (P = 0.059), and reduced serum concentrations of triglyceride, total cholesterol and urea nitrogen (P < 0.05). Besides, the SCFA administration inhibited the mRNA expressions of fatty acid synthase (FAS) and acetyl-CoA carboxylase in longissimus dorsi (P < 0.05), the mRNA expression of FAS in the liver (P < 0.05), and the mRNA expression of hormone-sensitive lipase in abdominal fat (P < 0.05). Short chain fatty acid infusion also enhanced the mRNA expression of carnitine palmitoyltransferase-1α in the liver (P < 0.05), the mRNA expressions of peroxisome proliferator activated receptor gamma and lipoprotein lipase in abdominal fat (P < 0.05), and the mRNA expressions of free fatty acid receptor 2, glucose-6-phosphatase and phosphoenolpyruvate carboxykinase 1 in the colon (P < 0.05). These results suggested that SCFA administration in the ileum could improve the carcass traits and meat quality of growing pigs, which was possibly due to the fact that SCFA modulated lipid metabolism.

Expression of Sirtuin 1 in visceral adipose tissue in Tibetan mini-pigs with obesity and insulin resistance induced by high fat/cholesterol diet

To investigate the role of Sirt1 in visceral adipose tissue in Tibetan mini-pigs with obesity and insulin resistance induced by high fat/cholesterol diet. Twelve male Tibetan mini-pigs were divided into 2 groups randomly: normal control (NC) group, high-fat/cholesterol (HFC) diet group, 6 in each group. After 16 weeks of modeling, fasting body weight and body mass index (BMI) were measured. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured in anterior venous blood, and atherosclerosis index (AI) was calculated. Meanwhile, intravenous glucose tolerance test was conducted to observe the changes of blood glucose and insulin, and the area under the curve (AUC) was calculated. After euthanasia, visceral fat rate was detected, and visceral fat tissue was taken for histopathological observation and fat cell diameter analysis. RT-PCR was used to observe the mRNA expression levels of Sirtuin1 (Sirt1), insulin-like growth factor-1 (IGF-1), glucose transporter 4 (GLUT4), peroxisome proliferator-activated receptor γ (PPARγ), peroxisome proliferator-activated receptor γ-assisted activator 1α (PGC-1α), forkhead box protein O1 (FoxO1), lipolysis-related gene hormone-sensitive lipase (HSL), and fat synthesis-related gene fatty acid synthase (FASN)changes in adipose tissue. Compared with the NC group, the body weight, BMI, TC, LDL-C, HDL-C, AI and visceral fat rate were significantly increased after 16 weeks of high-fat/cholesterol induction in Tibetan mini-pigs(P＜0.05,P＜0.01). Meanwhile, the glucose tolerance curve was significantly delayed and the area under the curve of blood glucose and insulin was significantly increased (P＜0.05). HE pathological observation and quantitative analysis showed that fat cells were hypertrophy and the average cell diameter was increased significantly (P＜0.01). In addition, the mRNA expression levels of Sirt1,PGC-1α, GLUT4, and HSL were all decreased in varying degrees in adipose tissue, among which the mRNA expressions of Sirt1 and HSL were significantly decreased (P＜0.05), while the mRNA expressions of FOXO1, IGF-1, PPARγ, and FASN were significantly increased (P＜0.05, P＜0.01). Tibetan mini-pigs were induced by high fat/cholesterol diet to form obesity model with phenotypic characteristics such as lipid disorder and insulin resistance, whereas Sirt1 plays a key role in visceral fat deposition and insulin sensitivity reduction in obese Tibetan mini-pigs.

FASN Protein Overexpression Indicates Poor Biochemical Recurrence-Free Survival in Prostate Cancer.

Backgrounds Fatty acid synthase (FASN) has been regarded as a prognostic marker in prostate cancer (PCa). In this study, we evaluated FASN expression at both mRNA and protein levels and assessed the association between FASN expression and prognosis in male Han Chinese with PCa treated with radical prostatectomy (RP). Methods Expression profile and prognostic value of FASN were analyzed in tissue microarray (TMA) and data retrieved from databases including TCGA public database, GEO database, and our sequencing data with whole clinicopathological characteristics. Results FASN expression was associated with clinical parameters and biochemical recurrence of prostate cancer. The relative expression of FASN mRNA was higher in the tumor tissue in all public databases and our sequencing data (p < 0.001). A similar result was seen in tissue microarray (TMA) (p < 0.001). Analysis of our sequencing data indicated that FASN's relative expression was associated with tumor stage (p = 0.048), and FASN expression was positively associated with the Gleason score (p = 0.004) and seminal vesicle invasion (p = 0.011) in TMA. We found that high FASN expression was an independent predictor of shorter BCR-free survival with univariate and multivariate survival analysis (p < 0.05), rendering FASN an optimal prognostic biomarker in male Han Chinese with prostate cancer. Conclusions Our study demonstrated that FASN was overexpressed at mRNA and protein levels in PCa. We found that patients with high FASN expression had a shorter BCR-free survival, showing its value as a prognostic biomarker in male Han Chinese with PCa.

Antroquinonol Attenuated Abdominal and Hepatic Fat Accumulation in Rats Fed an Obesogenic Diet.

An imbalance of energy intake and expenditure leads to fat accumulation and metabolic disorders. The aim of the study was to investigate the effects of antroquinonol on diet-induced obesity. Thirty-two rats were divided into a control group (C), an obesogenic group (OB), and two experimental groups consuming 25 (OB-AQ25) and 50 mg/kg (OB-AQ50) antroquinonol (n = 8). After a 12-week experimental period, we collected blood, liver, abdominal fat, and gastrocnemius muscle tissue for analysis. The obesogenic diet induced greater weight gain and fat accumulation, and increased hepatic lipids, and tumor necrosis factor-α and interleukin-1β concentrations in rats. Antroquinonol consumption reduced epididymal and hepatic lipids and inflammatory cytokines. We found that antroquinonol upregulated hepatic adenosine monophosphate-activated protein kinase and downregulated sterol regulatory element-binding protein-1 protein expressions and downregulated fatty acid synthase mRNA expression. In addition, gastrocnemius fibronectin type III domain containing 5 protein expression was also higher in the B group. In conclusion, our results suggested that consuming antroquinonol may ameliorate diet-induced abdominal and hepatic fat accumulation. PRACTICAL APPLICATION: Antroquinonol is a bioactive compound derived from Antrodia camphorate which is traditionally used in Chinese medicinal cuisine, and is used for developing functional foods in Taiwan. This is the first study investigating the possible effects of antroquinonol on obesity and we found that antroquinonol can ameliorate diet-induced obesity, and therefore may be used in further studies and functional food development.

Gene expressions of de novo hepatic lipogenesis in feline hepatic lipidosis

ObjectivesThe aim of this study was to evaluate if de novo hepatic lipid synthesis contributes to fatty acid overload in the liver of cats with feline hepatic lipidosis (FHL).MethodsLipogenic gene expression of peroxisome proliferator-activated receptor-alpha (PPAR-α), peroxisome proliferator-activated receptor-gamma (PPAR-γ), fatty acid synthase (FASN) and sterol regulatory element-binding factor (SREBF1) were evaluated using quantitative RT-PCR in liver tissue of six cats with FHL and compared with the liver tissue of eight healthy cats.ResultsIn liver tissue, PPAR-α, PPAR-γ and FASN mRNA expression levels were not significantly different (P >0.12, P >0.89 and P >0.5, respectively) in the FHL group compared with the control group. SREBF1 gene expression was downregulated around 10-fold in the FHL group vs the control group (P = 0.039).Conclusions and relevanceThe downregulation of SREBF1 in the liver tissue of cats with FHL does not support the hypothesis that de novo lipogenesis in the liver is an important pathway of fatty acid accumulation in FHL.