Fatty Acid Synthase Activity Research Articles

Effects of lycopene on abdominal fat deposition, serum lipids levels and hepatic lipid metabolism-related enzymes in broiler chickens.

ObjectiveThe present study was conducted to investigate the effects of lycopene on growth performance, abdominal fat deposition, serum lipids levels, activities of hepatic lipid metabolism related enzymes and genes expression in broiler chickens.MethodsA total of 256 healthy one-day-old male Arbor Acres broiler chicks were randomly divided into four groups with eight replicates of eight birds each. Birds were fed basal diet supplemented with 0 (control), 100, 200, and 400 mg/kg lycopene, respectively.ResultsDietary 100 mg/kg lycopene increased the body weight at 21 day of age compared to the control group (p<0.05). Compared to the basal diet, broilers fed diet with 100 mg/kg lycopene had decreased abdominal fat weight, and broilers fed diet with 100 and 200 mg/kg lycopene had decreased abdominal fat percentage (p<0.05). Compared to control, diets with 100, 200, and 400 mg/kg lycopene reduced the levels of total triglyceride and total cholesterol in serum, and diets with 100 and 200 mg/kg lycopene reduced the level of serum low density lipoprotein cholesterol (p<0.05). The activity of fatty acid synthase (FAS) in 400 mg/kg lycopene treated broilers and the activity of acetyl-CoA carboxylase (ACC) in 100, 200, and 400 mg/kg lycopene treated broilers were lower than those fed basal diet (p<0.05). Lycopene increased the mRNA abundance of adenosine monophosphate activated protein kinase α (AMPK-α), whereas decreased the mRNA abundance of sterol regulatory element-binding protein 1, FAS, and ACC compared to the control group (p<0.05).ConclusionDietary lycopene supplementation can alleviate abdominal fat deposition and decrease serum lipids levels, possibly through activating the AMPK signaling pathway, thereby regulating lipid metabolism such as lipogenesis. Therefore, lycopene or lycopene-rich plant materials might be added to poultry feed to regulate lipid metabolism.

1979MO Inhibition of fatty acid synthase (FASN) activity induces cytotoxicity on gefitinib- and osimertinib-resistant EGFR-mutated non-small cell lung cancer cells

1979MO Inhibition of fatty acid synthase (FASN) activity induces cytotoxicity on gefitinib- and osimertinib-resistant EGFR-mutated non-small cell lung cancer cells

Betulinic acid improves nonalcoholic fatty liver disease through YY1/FAS signaling pathway.

The increasing prevalence of nonalcoholic fatty liver disease (NAFLD) worldwide indicates the urgent need to develop novel and effective treatment strategies. Betulinic acid (BA), a naturally occurring plant-derived pentacyclic triterpenoid, has an outstanding effect in improving metabolism. However, the pharmacological action and mechanism of BA in NAFLD remain unclear. Here, we show that BA-treated high-fat diet mice and methionine-choline deficient diet-fed mice are resistant to hepatic steatosis when compared with vehicle-treated mice. BA alleviates fatty acid synthesis, fibrosis, and inflammation and promotes fatty acid oxidation. Meanwhile, fatty acid synthase (FAS) expression and activity are markedly inhibited with BA treatment both in vitro and in vivo. Moreover, BA inhibits FAS expression through transcriptional suppression of Yin Yang 1 (YY1), leading to retard hepatocytes triglyceride accumulation. Collectively, BA protects hepatocytes from abnormal lipid deposition in NAFLD through YY1/FAS pathway. Our findings establish a novel role of BA in representing a possible therapeutic strategy to reverse NAFLD.

Effect of different carbohydrate-to-lipid ratios elicits growth, feed utilization, lipid deposition and lipogenic enzyme activity in striped catfish (Pangasianodon hypophthalmus, Sauvage, 1878) fingerlings

This study evaluated the effects of diets containing various carbohydrate-to-lipid (CHO L-1) ratios on growth performance, nutrient utilization body indices and hepatic lipogenic enzyme (malic enzyme, 6-phosphogluconate dehydrogenase and fatty acid synthase) activities. Triplicate groups of Pangasianodon hypophthalmus fingerlings were fed eight isoenergetic and isonitrogenous diets with different carbohydrate-to-lipid ratios (0.51, 0.79, 1.12, 1.79, 2.41, 3.24, 4.43 and 7.62). Higher body fat deposition and lower growth performance were observed in P. hypophthalmus fingerlings fed with high-lipid diet than those fed with high-carbohydrate diet. The fish fed the diet with 7.62 CHO L-1 ratio exhibited significantly (p<0.05) higher hepatosomatic index compared to those fed higher lipid diets (0.51 and 0.79). High dietary carbohydrate level significantly increased (p<0.05) the activities of malic, 6-phosphogluconate dehydrogenase and fatty acid synthase enzyme. Based on the second-order polynomial regression analysis of weight gain, the optimal dietary carbohydrate and lipid contents for P. hypophthalmus fingerling were 304 and 103 g kg−1, respectively, which correspond to a dietary CHO L-1 ratio of 2.95.

Metabolic adaptability in liver and gastrocnemius muscle of mice following subacute lead toxicity.

Lead (Pb) is one of several environmental pollutants that adversely affect human health by producing toxicity at the tissue level. The aim of the study was to understand the effects of Pb on the metabolic profiles of liver and gastrocnemius muscle of mice in relation to carbohydrate and fat metabolisms. Swiss albino mice were chosen and divided into two groups, control and Pb-treated. The Pb-treated animals were exposed to Pb at a dose of 5 mg/kg body weight for 30 days orally, which resulted in hypoglycemia, glycosuria, and increased glycogenolysis in the liver and gastrocnemius muscle of treated mice. Pyruvic acid, the end product of glycolysis decreased in muscular tissue and increased in the liver. Additionally, the activity of G-6Pase was depressed in the liver, whereas lactate dehydrogenase activity was increased in skeletal muscle only. An adaptive mechanism was initiated by stimulating glycogenolytic and retarding glycolytic activity in the liver and also by alteration of liver and muscle pyruvate dehydrogenase activity along with increased activity of malate dehydrogenase in skeletal muscle. There was enhancement of succinate dehydrogenase and nicotinamide adenine dinucleotide phosphate oxidase activities in the studied tissues. Interestingly, cholesterol, high-density lipoprotein, and low-density lipoprotein levels were elevated, whereas those of triglycerides were decreased in Pb-treated mice serum. The activities of fatty acid synthase and glyceraldehyde 3 phosphate dehydrogenase were depressed in Pb-treated mice livers. Pb also significantly altered the morphological features of the liver, skeletal muscle, and pancreas. These data suggested that subacute Pb exposure was responsible for metabolic modulation in an adaptive fashion in the liver and skeletal muscle of mice.

Dietary Glucose Increases Glucose Absorption and Lipid Deposition via SGLT1/2 Signaling and Acetylated ChREBP in the Intestine and Isolated Intestinal Epithelial Cells of Yellow Catfish

Dietary carbohydrate affects intestinal glucose absorption and lipid deposition, but the underlying mechanisms are unknown. We used yellow catfish and their isolated intestinal epithelial cells (IECs) to test the hypothesis that sodium/glucose cotransporters (SGLTs) 1/2 and acetylated carbohydrate response element binding protein (ChREBP) mediated glucose-induced changes in glucose absorption and lipid metabolism. Yellow catfish (mean±SEM weight: 4.68±0.02g, 3mo old, mixed sex) were fed diets containing 250g carbohydrates/kg from glucose (G, control), corn starch (CS), sucrose (S), potato starch (PS), or dextrin (D) for 10 wk. IECs were isolated from different yellow catfish and incubated for 24h in a control or glucose (15mM) solution with or without a 2-h pretreatment with an inhibitor [sotagliflozin (LX-4211) or tubastatin A (TBSA)]. Human embryonic kidney cells (HEK293T cells) were transfected with a Flag-ChREBP plasmid to explore ChREBP acetylation. Triglyceride (TG) and glucose concentrations and enzymatic activities were measured in the intestine and IECs of yellow catfish. They also were subjected to immunofluorescence, immunoprecipitation, qPCR, and immunoblotting. Immunoblotting and immunoprecipitation were performed with HEK293T cells. The G group had greater intestine TGs (0.99- to 2.30-fold); activities of glucose 6-phospate dehydrogenase, 6-phosphogluconate dehydrogenase, and isocitrate dehydrogenase (0.12- to 2.10-fold); and expression of lipogenic genes (0.32- to 2.34-fold) thanthe CS,PS,andDgroups. The G group had greater intestine sglt1/2 mRNA and protein expression than the CS, Sand Dgroups (0.35- to 1.12-fold and 0.40- to 4.67-fold, respectively), but lower mRNA amounts of lipolytic genes(48.6%-65.8%) than the CS and PS groups. LX-4211 alleviated the glucose-induced increase in sglt1/2 mRNA (38.2%-47.4%) and SGLT1 protein (48.0%) expression, TGs (29.3%), and lipogenic enzyme activities (27.7%-42.1%) and gene expression (38.0%-55.5%) in the IECs. TBSA promoted the glucose-induced increase in TGs (11.3%), fatty acid synthase activity (32.6%), and lipogenic gene expression (21.6%-34.4%) in the IECs and acetylated ChREBP (10.5%) in HEK293T cells. SGLT1/2 signaling and acetylated ChREBP mediated glucose-induced changes in glucose absorption and lipid metabolism in the intestine and IECs of yellow catfish.

Moderate quantity of lard mixed with sunflower oil attenuate lipid accumulation in mice

Lard, a fat rich in saturated fatty acids (SFAs), is regarded as a risk factor for metabolic diseases. In the present study, effect of different lard blended with sunflower oil diets on lipid accumulation in adipose tissue, liver, and serum by mouse model was researched. Body weight, body fat percentage, cross-sectional area of adipocytes, liver triglycerides (TGs), and oil red stained area in mice liver of lard blend sunflower oil (L-SFO) group were significantly lower than those of sunflower oil (SFO) group, whereas no significant differences were observed between mice of lard and L-SFO groups. Serum TG and free fatty acid levels were significantly lower in L-SFO group than in other two groups. Furthermore, data showed that sunflower oil decreased contents of hormone-sensitive lipase and carnitine palmitoyl transferase 1 (CPT-1) and increased fatty acid synthase activity in liver tissue. A mixture of lard and sunflower oil rather than only sunflower oil or lard might promote body fat loss and reduce lipid accumulation in adipose tissue, serum, and liver by promoting hydrolysis of TG, increasing β-oxidation of fatty acids. These data suggested that mixing lard and vegetable oil (e.g. sunflower oil) for cooking, or alternate using lard and vegetable oil could be beneficial for reducing body fat.

Carbohydrate response element-binding protein regulates lipid metabolism via mTOR complex1 in diabetic nephropathy.

Lipid deposition caused by the disorder of renal lipid metabolism is involved in diabetic nephropathy (DN). Carbohydrate response element-binding protein (ChREBP) is a key transcription factor in high glucose-induced cellular fat synthesis. At present, the regulation and mechanism of ChREBP on fat metabolism in diabetic kidneys are still unclear. In this study, we showed that lack of ChREBP significantly improved renal injury, inhibited oxidative stress, lipid deposition, fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC) and thioredoxin-interacting protein (TXNIP) expression, as well as the activity of mammalian target of rapamycin complex 1 (mTORC1) in diabetic kidneys. Meanwhile, ChREBP deficiency upregulated the expression of peroxisome proliferator-activated receptor-α (PPARα), carnitine palmitoyltransferaser 1A (CPT1A) and acyl-coenzyme A oxidase 1 (ACOX1) in diabetic kidneys. In vitro, knockdown of ChREBP attenuated lipid deposition, mTORC1 activation, and expression of FASN and ACC, increased PPARα, CPT1A, and ACOX1 expression in HK-2 cells and podocytes under high glucose (HG) conditions. Moreover, HG-induced lipid deposition, increased expression of FASN and ACC and decreased expression of PPARα, CPT1A, and ACOX1 were reversed by rapamycin, a specific inhibitor of mTORC1, in HK-2 cells. These results indicate that ChREBP deficiency alleviates diabetes-associated renal lipid accumulation by inhibiting mTORC1 activity and suggest that reduction of ChREBP is a potential therapeutic strategy to treat DN.

Antiobesity and anti-inflammation effects of Hakka stir-fried tea of different storage years on high-fat diet-induced obese mice model via activating the AMPK/ACC/CPT1 pathway.

BackgroundAs a typical representative of metabolic syndrome, obesity is also one of the extremely dangerous factors of cardiovascular diseases. Thus, the prevention and treatment of obesity has gradually become a global campaign. There have been many reports that green tea is effective in preventing obesity, but as a kind of green tea with regional characteristics, there have been no reports that Hakka stir-fried tea (HT) of different storage years has a weight loss effect.AimsThe aim was to investigate the effect of HT in diet-induced obese mice.MethodsThe mice were divided into five groups as follows: the control group received normal diet; the obese model group received high-fat diet; and HT2003, HT2008, and HT2015 groups, after the induction of obesity via a high-fat diet, received HT of different storage years treatment for 6 weeks, respectively.ResultsIt was observed that HT decreased the levels of serum and liver triglyceride; the ratio of liver to body weight; accumulation of epididymal, perirenal, and mesenteric fat; the degree of hepatic steatosis; and adipocyte hypertrophy, with the concomitant reduction of body weight. Moreover, HT decreased the expression levels of proinflammatory cytokines tumor necrosis factor α (TNF α), inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and reduced fatty acid synthase (FAS) activity in liver tissue of obese mice. In addition, HT treatment also increased the phosphorylation of AMP-activated protein kinase (AMPK) and its direct downstream proteins, acetyl coenzyme A carboxylase (ACC), and carnitine palmitoyltransferase I (CPT-1), which participate in FAS pathway.ConclusionsThese findings demonstrate that HT treatment has a potential protection on high-fat diet-induced obesity mice via activating the AMPK/ACC/CPT1 pathway, and to a certain extent, it has nothing to do with the storage time of three kinds of HT.

Farnesol attenuates oxidative stress and liver injury and modulates fatty acid synthase and acetyl-CoA carboxylase in high cholesterol-fed rats.

Dyslipidemia is a risk factor for cardiovascular disease, steatohepatitis, and progression of liver disorders. This study investigated the protective effect of farnesol (FAR), a sesquiterpene alcohol, against liver injury in high cholesterol diet (HCD)-fed rats, and its modulatory effect on fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). HCD was supplemented for 10weeks, and the rats were concurrently treated with FAR. Rats that received HCD exhibited significant elevation of serum cholesterol, triacylglycerols, LDL and vLDL cholesterol, CRP, and pro-inflammatory cytokines and increased values of the cardiovascular risk indices. Serum transaminases, ALP, LDH and CK-MB, and hepatic lipid peroxidation (LPO), cholesterol, and triacylglycerols were increased in HCD-fed rats. Treatment with FAR greatly ameliorated dyslipidemia and liver function, reduced inflammatory mediators, LPO, and hepatic lipid infiltration and enhanced anti-oxidant defenses. FAR suppressed hepatic FAS, ACC, and SREPB-1c mRNA abundance and FAS activity in HDC-fed rats. In addition, molecular docking simulations pinpointed the binding modes of FAR to the active pocket residues of FAS and ACC. In conclusion, FAR possesses a strong anti-hyperlipidemic/anti-hypercholesterolemic activity mediated through its ability to modulate hepatic FAS, ACC, and SREPB-1c. FAR prevented oxidative stress, inflammation, and liver injury induced by HCD. Thus, FAR may represent a promising lipid-lowering agent that can protect against dyslipidemia and its linked metabolic deregulations.

Inhibiting fatty acid synthase in operable triple negative breast cancer.

584 Background: Fatty acid synthase (FASN) is overexpressed in 70% of newly diagnosed triple negative breast cancer (TNBC) and is associated with poor prognosis. In vitro, FASN overexpression induces drug resistance to DNA damaging agents. Proton pump inhibitors (PPI) selectively inhibit FASN activity and induce apoptosis in breast cancer cell lines with minimal effect on non-malignant cells. We report the results of a single arm phase II study of high dose omeprazole (OMP) in combination with anthracycline- taxane (AC-T) based neoadjuvant chemotherapy. Methods: Patients (pts) with operable TNBC independent of baseline FASN expression; and no prior PPI use within 12 months were enrolled. Pts began OMP 80 mg PO BID for 4-7 days prior to AC-T; carboplatin was allowed per physician discretion. OMP was continued until surgery. Paired biopsy samples were obtained before and after OMP monotherapy. The primary endpoint was pathologic complete response (pCR), defined as no residual invasive disease in breast or axilla, in pts with baseline FASN expression (FASN+) assessed using immunohistochemistry. Relevant secondary endpoints included pCR in the intent to treat population, change in FASN expression, enzyme activity and downstream target gene expression after OMP monotherapy; safety and limited OMP pharmacokinetics. We targeted a pCR rate of 60% in FASN+ pts (null pCR ~ 40%) with 80% power and alpha of 0.10. Results: A total of 42 pts were recruited from 5 US sites. Median age was 51y (28-72). Most pts had &gt;cT2 (33, 79%) and ≥N1 (22, 52%) disease. 14 (33%) were African American. FASN expression prior to AC-T was identified in 28 (85%) samples available for analysis. The pCR rate was 71.4% (95% CI 51.3 to 86.8) in FASN+ pts and 71.8 %( 95% CI 55.1 to 85.0) in all enrolled pts. Fifteen pts (36%) received carboplatin with AC-T; pCR in this subset was 73%. Peak OMP concentration was significantly higher than IC50 observed during preclinical testing; FASN positivity significantly decreased with OMP monotherapy from 0.53(SD 0.25) at baseline to 0.38(SD 0.30; p = 0.02). OMP was well tolerated with no known grade (G) 3 or 4 toxicities. Chemotherapy toxicity was similar to prior studies using AC-T with G3 or 4 neutropenia (19%), febrile neutropenia (7%) and peripheral neuropathy (7%) being the most common. Conclusions: Consistent with previous studies, FASN is frequently expressed in early stage TNBC. OMP can be safely administered in doses that inhibit FASN. The addition of high dose OMP to neoadjuvant AC-T yields a promising pCR rate without adding toxicity. Funded by the Breast Cancer Research Foundation. Clinical trial information: NCT02595372 .

Functional characterization of a low-frequency V1937I variant in FASN associated with susceptibility to esophageal squamous cell carcinoma.

Metabolic reprogramming has been regarded as one of the core hallmarks of cancer and increased de novo fatty acid synthesis has been documented in multiple tumors including esophageal squamous cell carcinoma (ESCC). Our previous exome-wide analyses found a Val1937Ile variant (rs17848945) in the 34th exon of fatty acid synthase (FASN) that showed a strong association with the risk of ESCC. In this study, we performed a series of functional assays to investigate the biological functions underlying this variant in the development of ESCC. We demonstrated that FASN was upregulated in ESCC and both knockdown and knockout of FASN significantly inhibited ESCC cell proliferation, suggesting a tumor promoter role for this gene in ESCC. Furthermore, the results showed that overexpression of FASN[I] in the ESCC cells substantially enhanced cell proliferation, compared with overexpression of FASN[V], or the control vector. Intriguingly, we found that the FASN[I] variant can enhance the enzyme activity of FASN, and, thus, increase the amount of the FASN end-product, palmitate in the ESCC cells. We also observed elevated palmitate levels in the plasma of the FASN[I] genotype carriers among a total of 632 healthy Chinese adults. In conclusion, our results suggested that the FASN V1937I variant influenced ESCC cell proliferation and susceptibility by altering the catabolic activity of FASN on palmitate. These findings may highlight an important role of palmitate metabolism in the development of ESCC and may contribute to the personalized medicine of this disease.

Evaluation of FASN inhibitors by a versatile toolkit reveals differences in pharmacology between human and rodent FASN preparations and in antiproliferative efficacy in vitro vs. in situ in human cancer cells

De novo synthesis of fatty acids is essential to maintain intensive proliferation of cancer cells. Unlike normal cells that utilize food-derived circulating lipids for their fuel, cancer cells rely on heightened lipogenesis irrespective of exogenous lipid availability. Overexpression and activity of the multidomain enzyme fatty acid synthase (FASN) is crucial in supplying palmitate for protumorigenic activity. Therefore, FASN has been proposed as an attractive target for drug development. As an effort to set up an effective toolkit to study FASN inhibitors in human and rodent tissues, we validated activity-based protein profiling (ABPP) as a viable approach to unveil inhibitors targeting FASN thioesterase domain (FASN-TE). ABPP was combined with multi-well plate-assays designed for classical substrate-based FASN activity analysis together with powerful monitoring of cancer cell proliferation using IncuCyte® Live Cell Analyzing System. FASN-TE inhibitors were identified by competitive ABPP using HEK293 cell lysates in a screen of in-house compounds (200+) designed to target serine hydrolase (SH) family. The identified compounds were tested for their inhibitor potencies in vitro using a substrate-based activity assay monitoring FASN-dependent NADPH consumption in LNCaP prostate cancer cell preparation, in parallel with selected reference inhibitors, including orlistat (THL), GSK2194069, GSK837149A, platensimycin and BI-99179. LNCaP lysate supernatant was validated as a reliable native preparation to monitor FASN-dependent NADPH consumption as opposed to human glioma GAMG cells, whereas FASN enrichment was a prerequisite for accurate assays. While inhibitor pharmacology was identical between human prostate and glioma cancer cell FASN preparations, notable differences were revealed between human and rodent FASN preparations, especially for inhibitors targeting FASN-TE. ABPP combined with substrate-based assays facilitated identification of pan thiol-reactive inhibitor scaffolds, exemplified by the 1,2,4-thiadiazole moiety. Finally, selected compounds were evaluated for their antiproliferative efficacy in situ using GAMG cells. These studies revealed that while the tested compounds acted as potent FASN inhibitors in vitro, only a few showed antiproliferative efficacy in situ. To conclude, we describe a versatile toolkit to study FASN inhibitors in vitro and in situ using human cancer cells and reveal dramatic pharmacological differences between human and rodent FASN preparations.

Dietary calcium regulates the risk renal injury in high fat diet induced obese rats by regulating renal lipid metabolism, oxidative stress and inflammation

Context: The antiobesity effect of dietary calcium by preventing fat accumulation and weight gain was well established from several epidemiological and animal studies.Objective: To evaluate the effect of dietary calcium against obesity-associated with renal injury in high fat diet induced obese rats. Materials and Methods: Obesity was induced by high fat diet (HFD) and then given either low or high calcium HFD (0.25% and 1.0%) for another 30 days.Results: The results showed that 1.0% high calcium group was effective in reducing renal lipogenesis activity, lipid accumulation, fatty acid synthase (FAS) activity, acetyl coenzyme A carboxylase (ACC) expression, oxidative stress, inflammation and increased the adenosine monophosphate kinase (AMPK) expression.Discussion and conclusion: Downregulation of renal lipid accumulation by high calcium diet through AMPK mediated lipogenesis activity, oxidative stress and the inflammatory response seemed to prevent the renal injury in high fat diet (HFD) induced obese rats.

Hayeobtan ameliorates high fat/high cholesterol diet‐induced hypertriglyceridemia and endothelial dysfunction

The leaves of lotus are called ‘Hayeob’ ( ), which is known to have the effect of extinguishing heat, smoothing water metabolism, clearing the blood, and releasing blood(1–2). This experimental study was designed to investigate the inhibitory effects of Hayeobtan on lipid metabolism in high fat/cholesterol diet (HFCD)‐induced hypertriglyceridemia(3–4). Sprague Dawley rats were fed the HFCD diet with/without fluvastatin (Flu, positive control) 3 mg/kg/day, and HYT 100 or 200 mg/kg/day, respectively. All groups received a regular diet or HF diet, respectively, for 13 weeks. The last three groups treatment of Flu and HYT 100, and HYT200 orally for 9 weeks. Treatment of HYT markedly attenuated plasma levels of triglycerides and augmented plasma levels of high‐density lipoprotein (HDL) in HFCD‐fed rats. HYT and Flu also led to an increase in lipoprotein lipase activity in the HFCD group. On the other hand, HYT and Flu led to an decrease in fatty acid synthase and free fatty acid activity in the HFCD group. Treatment with HYT suppressed increased expressions of PPAR‐α and AMPK in HFCD rat liver or muscle. In addition, the HYT attenuated triglyceridemia by inhibition of PPAR‐γ and FABP protein expression levels and LXR and SREBP‐1 gene expression in liver or muscle. The HYT significantly prevented the development of the metabolic disturbances such as hypertriglyceridemia and hyperlipidemia. Taken together, the administration of HYT improves hypertriglyceridemia through the alteration in suppression of triglyceride synthesis and accentuated of triglyceride decomposition. These results suggested that HYT is useful in the prevention or treatment of hypertriglyceridemia‐related disorders such as triglyceride metabolism.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (2017R1A5A2015805)(2019R1I1A3A01062432).

Effect of chronic exposure to monocrotophos on white adipose tissue in rats and its association with metabolic dyshomeostasis.

Earlier, we demonstrated that chronic exposure to monocrotophos (MCP) elicits insulin resistance in rats along with increased white adipose tissue (WAT) weights. This study was carried out to delineate the biochemical and molecular changes in adipose tissues of rats subjected to chronic exposure to MCP (0.9 and 1.8 mg/kg bw/d for 180 days). Pesticide-treated rats exhibited increased fasting glucose and hyperinsulinemia as well as dyslipidemia. Tumor necrosis factor-alpha and leptin levels were elevated, while adiponectin level was suppressed in plasma of treated rats. MCP treatment caused discernable increase in the weights of perirenal and epididymal WAT. Acetyl coenzyme A carboxylase, fatty acid synthase, glyceraldehyde-3-phosphate dehydrogenase, lipin-1, and lipolytic activities were elevated in the WAT of MCP-treated rats. Corroborative changes were observed in the expression profile of proteins that are involved in lipogenesis and adipose tissue differentiation. Our results clearly demonstrate that long-term exposure to organophosphorus insecticides (OPIs) such as MCP has far-reaching consequences on metabolic health as evidenced by the association of adipogenic outcomes with insulin resistance, hyperinsulinemia, endocrine dysregulations, and dyslipidemia. Taken together, our results suggest that long-term exposure to OPI may be a risk factor for metabolic dysregulations.

Evaluation of Fatty Acid Synthase as a Molecular Target for Stress-Dependent Fungicidal Activity of 1-Geranylgeranylpyridinium

Among various isoprenoid compounds, 1-geranylgeranylpyridinium (GGPy) showed remarkable lethal effects on Saccharomyces cerevisiae cells similarly under hypo- and hyperosmotic conditions at 30ºC. In addition to such osmotic stress, GGPy exhibited temperature-dependent lethal effects against S. cerevisiae and the pathogenic yeast Candida albicans at the human body temperature of 37ºC. Fatty acid synthase (FAS) was identified as one of the GGPy-binding proteins and was considered a molecular target of GGPy in its inhibitory effect on the fungal stress adaptation. GGPy was not inhibitory to the activity of FAS assayed upon NADPH oxidation involved in acyl chain elongation by this multi-functional enzyme complex. Nevertheless, the lethality of GGPy was repressed in the medium where polyoxyethylene sorbitan monopalmitate (Tween 40) supplemented as the water-soluble and esterase dependent source of palmitic acid. These findings may suggest that GGPy is permissive for acetyl unit incorporation into the growing chain of fatty acyl-CoA by FAS butis restrictive to its ultimate elongation to palmitoyl-CoA as a donor of the long-chain saturated fatty acid for the synthesis of stress-tolerant glycerophospholipids.

Effects of coated cysteamine on growth performance, carcass characteristics, meat quality and lipid metabolism in finishing pigs

This study was conducted to evaluate the effects of coated cysteamine (CCS) on growth performance, carcass characteristics, meat quality, and lipid metabolism in finishing pigs. A total of 160 pigs (62.12 ± 1.43 kg body weight) were randomly divided into 4 groups, with 4 pens per group and 10 pigs (5 gilts and 5 barrows) per pen. Pigs were fed a basal diet supplemented with 0, 100, 200, or 400 mg/kg CCS, corresponding to 0, 27, 54, or 108 mg/kg cysteamine, respectively. All pigs were given free access to feed and water for forty days. Average daily gain, average daily feed intake and feed to gain ratio were not affected by the CCS treatment. Supplemental CCS increased carcass lean ratio linearly (P < 0.05) and longissmus muscle area quadratically (P < 0.05), and the water-holding capacity as measured by 24 h drip loss was quadratically affected (P < 0.05) by CCS supplementation. The activity of hormone-sensitive lipase in subcutaneous adipose tissue was linearly increased (P < 0.001), while fatty acid synthase activity was linearly decreased (P < 0.05). Pigs fed CCS had a lower serum triacylglycerol (P < 0.001) level and lipase activity (P < 0.001), lower total cholesterol (P < 0.05) level, and a higher total protein (P < 0.001) and free fatty acids (P < 0.01) levels. In addition, CCS quadratically increased serum growth hormone (GH) (P < 0.001) level and quadratically affected somatostatin (SS) (P < 0.05) level. Consistently, significant effects of dietary CCS were observed on the mRNA expression of GH and SS in the anterior pituitary gland and the hypothalamus, respectively, where the intermediate CCS level showed the highest GH mRNA level and lowest SS mRNA level. The results indicate that dietary supplementation of CCS has beneficial effects on carcass characteristics and meat quality, and affects lipid metabolism in finishing pigs.

Low utilization of glucose in the liver causes diet-induced hypercholesterolemia in exogenously hypercholesterolemic rats.

Exogenously hypercholesterolemic (ExHC) rats develop diet-induced hypercholesterolemia (DIHC) when fed with dietary cholesterol. Previously, we reported that, under the high-sucrose-diet-feeding condition, a loss-of-function mutation in Smek2 results in low activity of fatty acid synthase (FAS) followed by the shortage of hepatic triacylglycerol content in ExHC rats and the onset of DIHC. However, the relationship between the Smek2 mutation and FAS dysfunction is still unclear. Here, we focused on carbohydrate metabolism, which provides substrates for FAS, and analyzed carbohydrate and lipid metabolisms in ExHC rats to clarify how the deficit of Smek2 causes DIHC. Male ExHC and SD rats were fed high-sucrose or high-starch diets containing 1% cholesterol for 2 weeks. Serum cholesterol levels of the ExHC rats were higher, regardless of the dietary carbohydrate. Hepatic triacylglycerol levels were higher in only the SD rats fed the high-sucrose diet. Moreover, the ExHC rats exhibited a diabetes-like status and accumulation of hepatic glycogen and low hepatic mRNA levels of liver-type phosphofructokinase (Pfkl), which encodes a rate-limiting enzyme for glycolysis. These results suggest that the glucose utilization, particularly glycolysis, is impaired in the liver of ExHC rats. To evaluate how the diet with extremely low glucose affect to DIHC, ExHC.BN-Dihc2BN, a congenic strain that does not develop DIHC, and ExHC rats were fed a high-fructose diet containing 1% cholesterol for 2 weeks. The serum cholesterol and hepatic triacylglycerol levels were similar in the strains. Results of water-soluble metabolite analysis with primary hepatocytes, an increase in fructose-6-phosphate and decreases in succinate, malate and aspartate in ExHC rats, support impaired glycolysis in the ExHC rats. Thus, the Smek2 mutation causes abnormal hepatic glucose utilization via downregulation of Pfkl expression. This abnormal glucose metabolism disrupts hepatic fatty acid synthesis and causes DIHC in the ExHC rats.

Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases

Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.