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1.
Ursodeoxycholic Acid Suppresses Lipogenesis in Mouse Liver: Possible Role of the Decrease in β-Muricholic Acid,a Farnesoid X Receptor Antagonist
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The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR. We observed that the dietary administration of UDCA in mice decreased the expression levels of SREBP1c and its target lipogenic genes. Alpha- and β-muricholic acids (MCA) and cholic acid (CA) were the major bile acids in the mouse liver but their contents decreased upon UDCA administration. The hepatic contents of chenodeoxycholic acid and deoxycholic acid (DCA) were relatively low but were not changed by UDCA. UDCA did not show FXR agonistic or antagonistic potency in in vitro FXR transactivation assay. Taking these together, we deduced that the above-mentioned change in hepatic bile acid composition induced upon UDCA administration might cause the relative increase in the FXR activity in the liver, mainly by the reduction in the content of β-MCA, a farnesoid X receptor antagonist, which suggests a mechanism by which UDCA suppresses lipogenesis and decreases the lipid contents in the mouse liver. 相似文献
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We examined the in vivo contribution of insulin, T090137 (T09), agonist of liver X receptor (LXR), fenofibrate, agonist of
peroxisome proliferator activated receptor (PPAR-α) and sterol regulatory element binding protein-1c (SREBP-1c) on the unsaturated
fatty acid synthesis controlled by Δ6 and Δ5 desaturases, compared with the effects on stearoylcoenzyme A desaturase-1. When
possible they were checked at three levels: messenger RNA (mRNA), desaturase protein and enzymatic activity. In control rats,
only fenofibrate increased the insulinemia that was maintained by the simultaneous administration of T09, but this increase
has no specific effect on desaturase activity. T09 enhanced SREBP-1 in control animals and the mRNAs and activity of the three
desaturases in control and type-1 diabetic rats, demonstrating a LXR/SREBP-1-mediated activation independent of insulin. However,
simultaneous administration of insulin and T09 to diabetic rats led to a several-fold increase of the mRNAs of the desaturases,
suggesting a strong synergic effect between insulin and LXR/retinoic X receptor (RXR). Moreover, this demonstrates the existence
of an interaction between unsaturated fatty acids and cholesterol metabolism performed by the insulin/SREBP-1c system and
LXR/RXR. PPAR-α also increased the expression and activity of the three desaturases independently of the insulinemia since
it was equivalently evoked in streptozotocin diabetic rats. Besides, PPAR-α increased the palmitoylcoenzyme A elongase, evidencing
a dual regulation in the fatty acid biosynthesis at the level of desaturases and elongases. The simultaneous administration
of fenofibrate and T09 did not show additive effects on the mRNA expression and activity of the desaturases. Therefore, the
results indicate a necessary sophisticated interaction of all these factors to produce the physiological effects. 相似文献
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Trans fatty acid consumption is associated with an increased risk of coronary heart disease. This increased risk has been attributed to decreased levels of HDL cholesterol and increased levels of LDL cholesterol. However, the mechanism by which trans fatty acid modulates cholesterol transit remains poorly defined. ATP-binding cassette transporter A1 (ABCA1)-mediated macrophage cholesterol efflux is the rate-limiting step initiating apolipoprotein A-I lipidation. In this study, elaidic acid, the most abundant trans fatty acid in partially hydrogenated vegetable oil, was shown to stabilize macrophage ABCA1 protein levels in comparison to that of its cis fatty acid isomer, oleic acid. The mechanism responsible for the disparate effects of oleic and elaidic acid on ABCA1 levels was through accelerated ABCA1 protein degradation in cells treated with oleic acid. In contrast, no apparent differences were observed in ABCA1 mRNA levels, and only minor changes were observed in Liver X receptor/Retinoic X receptor promoter activity in cells treated with elaidic and oleic acid. Efflux of both tracers and cholesterol mass revealed that elaidic acid slightly increased ABCA1-mediated cholesterol efflux, while oleic acid led to decreased ABCA1-mediated efflux. In conclusion, these studies show that cis and trans structural differences in 18 carbon n-9 monoenoic fatty acids variably impact cholesterol efflux through disparate effects on ABCA1 protein degradation. 相似文献
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Martín-Fuentes P García-Otín AL Calvo L Gómez-Coronado D Civeira F Cenarro A 《Lipids》2009,44(2):115-123
Statins, inhibitors of HMG-CoA reductase, reduce plasma low-density lipoprotein (LDL) cholesterol levels decreasing the incidence
of coronary events. However, the observed benefit of statins appears to extend beyond their lipid-lowering effects. Previous
studies by our group have demonstrated that atorvastatin in oxidized LDL incubated macrophages modifies the gene expression
profile of certain enzymes involved in fatty acid metabolism, mainly stearoyl-CoA desaturase (SCD). SCD is a rate-limiting
enzyme in the biosynthesis of monounsaturated fatty acids and its expression is mediated by sterol regulatory element-binding
protein-1 (SREBP-1). The aim of this study was to determine whether atorvastatin might affect the fatty acid composition in
macrophages and if their SCD gene expression profile could explain this effect. Therefore, THP-1 macrophages were treated
with atorvastatin and native or oxidized LDL, their fatty acid composition was determined by gas-chromatography, and the SCD
and SREBP-1 gene expression profile was analysed using quantitative RT-PCR. We found that atorvastatin reduces the percentage
of palmitoleic and oleic acids in THP-1 cells incubated with oxLDL, which could be explained by the inhibition of SCD and
SREBP-1 gene expression. The observed results were reversed when mevalonate was added to THP-1 macrophages. This would suggest
that inhibition of SCD in THP-1 macrophages incubated with oxLDL and the change in fatty acid composition is an important
effect of atorvastatin. 相似文献
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The influence of (−)-hydroxycitrate, a potent competitive inhibitor of adenosine triphosphate (ATP) citrate lyase, on serum
triglyceride and cholesterol levels, and in vitro and in vivo rates of hepatic fatty acid and cholesterol synthesis was investigated
in normal and hyperlipidemic rat model systems. (−)-Hydroxycitrate reduced equivalently the biosynthesis of triglycerides,
phospholipids, cholesterol, diglycerides, cholesteryl esters, and free fatty acids in isolated liver cells. In vivo hepatic
rates of fatty acid and cholesterol synthesis determined in meal-fed normolipidemic rats were suppressed significantly by
the oral administration of (−)-hydroxycitrate for 6 hr, when control animals exhibited maximal rates of lipid synthesis; serum
triglyceride and cholesterol levels were significantly reduced by (−)-hydroxycitrate. In two hypertryglyceridemic models—the
genetically obese Zucker rat and the fructose-treated rat—elevated triglyceride levels were due, in part, to enhanced hepatic
rates of fatty acid synthesis. (−)-Hydroxycitrate significantly reduced the hypertriglyceridemia and hyperlipogenesis in both
models. The marked hypertriglyceridemia exhibited by the triton-treated rat was only minimally due to increased hepatic lipogenesis;
(−)-hydroxycitrate significantly inhibited both serum triglyceride levels and lipogenesis in this model. 相似文献
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Obesity is associated with impaired fatty acid (FA) oxidation and increased de novo hepatic lipogenesis that may contribute to the development of hypertriglyceridemia, an important risk factor for the development of cardiovascular disease. Strategies to improve hepatocyte FA metabolism, including dietary interventions, are therefore important for the prevention of obesity-associated co-morbidities. Farnesol is consumed in the diet as a component of plant products. In the present study, we administered farnesol orally to rats for seven days and found significantly reduced serum triglyceride concentrations compared with controls. Potential mechanisms underlying the hypotriglyceridemic effect of farnesol were investigated using clone-9 cultured rat hepatocytes. Farnesol significantly upregulated expression of peroxisome proliferator-activated receptor alpha (PPARalpha) and the PPARalpha-regulated genes fatty acyl-CoA oxidase and carnitine palmitoyl transferase 1a, suggesting that increased hepatic FA oxidation may contribute to serum triglyceride lowering in rats. Farnesol did not change SREBP-1c mRNA levels, but significantly down-regulated fatty acid synthase (FAS) mRNA and protein levels and activity, indicating that attenuated lipogenesis may also contribute to hypotriglyceridemic effects of farnesol in vivo. Rescue experiments revealed that down-regulation of FAS by farnesol was not related to activation of PPARalpha, but rather was caused by a 9-cis retinoic acid mediated mechanism that involved down-regulation of retinoid X receptor beta. Diets rich in plant products are associated with a lower risk of cardiovascular disease. Our findings suggest that farnesol may contribute to this protective effect by lowering serum TG levels. 相似文献
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Mechanisms of regulation of gene expression by fatty acids 总被引:10,自引:1,他引:10
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Roglans N Verd JC Peris C Alegret M Vázquez M Adzet T Díaz C Hernández G Laguna JC Sánchez RM 《Lipids》2002,37(5):445-454
Treatments with high doses of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors may induce the expression
of sterol regulatory element binding protein (SREBP)-target genes, causing different effects from those attributed to the
reduction of hepatic cholesterol content. The aim of this study was to investigate the effects of high doses of statins on
the key enzymes involved in VLDL production in normolipidemic rats. To examine whether the effects caused by statin treatment
are a consequence of HMG-CoA reductase inhibition, we tested the effect of atorvastation on these enzymes in mevalonatefed
rats. Atorvastatin and simvastatin enhanced not only HMG-CoA reductase but also the expression of the SREBP-2 gene itself.
As a result of the overexpression of SREBP-2 caused by the statin treatment, genes regulated basically by SREBP-1, as FA synthase
and acetyl-coenzyme A carboxylase, were also induced and their mRNA levels increased. DAG acyltransferase and microsomal IG
transfer protein mRNA levels as well as phosphatidate phosphohydrolase activity were increased by both statins. Simvastatin
raised liver cholesterol content, ACAT mRNA levles, and CTP:phosphocholine cytidylyltransferase activity, whereas it reduced
liver DAG and phospholipid content. Mevalonate feeding reversed all changes induced by the atorvastatin treatment. These results
show that treatment with high doses of statins induces key enzymes controlling rat liver lipid synthesis and VLDL assembly,
probably as a result of SREBP-2 overexpression. Despite the induction of the key enzymes involved in VLDL production, both
statins markedly reduced plasma TG levels, suggesting that different mechanisms may be involved in the hypotriglyceridemic
effect of statins at high or low doses. 相似文献
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The present work was undertaken to study the metabolism of fatty acids with trans double bonds by rat hepatocytes. In liver mitochondria, elaidoyl-CoA was a poorer substrate for carnitine palmitoyltransferase
I (CPT-I) than oleoyl-CoA. Likewise, incubation, of hepatocytes with oleic acid produced a more pronounced stimulation of
CPT-I than incubation with trans fatty acids. This was not due to a differential effect of cis and trans fatty acids on acetyl-CoA carboxylase (ACC) activity and malonyl-CoA levels. Elaidic acid was metabolized by hepatocytes
at a higher rate than oleic acid. Surprisingly, compared to oleic acid, elaidic acid was a better substrate for mitochondrial
and, especially, peroxisomal oxidation, but a poorer substrate for cellular and very low density lipoprotein triacylglycerol
synthesis. Results thus show that trans fatty acids are preferentially oxidized by hepatic peroxisomes, and that the ACC/malonyl-CoA/CPT-I system for coordinate
control of fatty acid metabolism is not responsible for the distinct hepatic utilization of cis and trans fatty acids. 相似文献
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Atif B. Awad 《Lipids》1978,13(12):850-859
The incorporation of elaidic acid into Ehrlich ascites tumor cells (EATC) upon feeding the host an elaidic acid-rich diet
has been investigated in the present study. The EATC lipids contained only one-half the concentration of elaidic acid found
in the lipids of either the host livers or of livers from normal mice. On the other hand, elaidic acid incorporation into
tumor cells was close to that of ascites fluid. This incorporation was mainly into phospholipids; the highest into choline
phospholipids and ethanolamine phospholipids. Some changes in the EATC fatty acid composition were noted due to this incorporation.
EATC phospholipids had reduced polyunsaturated fatty acids as compared with oleic acid-grown cells. The same was true with
respect to ascites fluid phospholipids, but neutral lipids were not altered. Tumor development was accompanied by an increase
in elaidic acid of the host’s liver. Elaidic acid incorporation into tumor cells resulted in a reduction in the amount of
all major lipids in the tumor. In contrast, elaidic acid had no effect on lipid composition of livers from normal mice and-tumor
bearing mice, and also had no effect upon the lipids of the ascites fluid that bathes the tumor cells. The incorporation of
elaidic acid into the lipids of EATC, normal liver and host liver did not affect the relative composition of phospholipids
in these tissues. The development of the tumor did result in decreases in triacylglycerols and esterified cholesterol, and
increases in phospholipids and free cholesterol in the livers of host animals. 相似文献
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Tharnath Nanthirudjanar Hidehiro Furumoto Jiawen Zheng Young‐Il Kim Tsuyoshi Goto Nobuyuki Takahashi Teruo Kawada Si‐Bum Park Akiko Hirata Nahoko Kitamura Shigenobu Kishino Jun Ogawa Takashi Hirata Tatsuya Sugawara 《Lipids》2015,50(11):1093-1102
Hydroxy and oxo fatty acids were recently found to be produced as intermediates during gut microbial fatty acid metabolism. Lactobacillus plantarum produces these fatty acids from unsaturated fatty acids such as linoleic acid. In this study, we investigated the effects of these gut microbial fatty acid metabolites on the lipogenesis in liver cells. We screened their effect on sterol regulatory element binding protein‐1c (SREBP‐1c) expression in HepG2 cells treated with a synthetic liver X receptor α (LXRα) agonist (T0901317). The results showed that 10‐hydroxy‐12(Z)‐octadecenoic acid (18:1) (HYA), 10‐hydroxy‐6(Z),12(Z)‐octadecadienoic acid (18:2) (γHYA), 10‐oxo‐12(Z)‐18:1 (KetoA), and 10‐oxo‐6(Z),12(Z)‐18:2 (γKetoA) significantly decreased SREBP‐1c mRNA expression induced by T0901317. These fatty acids also downregulated the mRNA expression of lipogenic genes by suppressing LXRα activity and inhibiting SREBP‐1 maturation. Oral administration of KetoA, which effectively reduced triacylglycerol accumulation and acetyl‐CoA carboxylase 2 (ACC2) expression in HepG2 cells, for 2 weeks significantly decreased Srebp‐1c, Scd‐1, and Acc2 expression in the liver of mice fed a high‐sucrose diet. Our findings suggest that the hypolipidemic effect of the fatty acid metabolites produced by L. plantarum can be exploited in the treatment of cardiovascular diseases or dyslipidemia. 相似文献
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The effects of feeding diets containing either cholesterol (0.24% w/w) or cholestyramine (2.5% w/w) and of fasting on sterol
synthesis in the liver, ileum, and lung of both male and female guinea pigs have been studied by measuring the incorporation
by tissue slices of14C-labeled acetate into total digitonin-precipitable sterols. Cholesterol feeding significantly decreased (P<0.05) sterol synthesis
in the liver, ileum, and lung of the males and in the ileum of females. Cholestyramine feeding stimulated the rate of hepatic
sterol synthesis 13-fold but did not significantly affect sterologenesis in the ileum. Sterol synthesis in the lung was significantly
increased (P<0.05) but to a much lesser extent than in the liver. Fatty acid synthesis in the liver, ileum, and lung was not
significantly affected by either cholesterol or cholestyramine feeding. In guinea pigs fasted for 24 hr, sterol synthesis
was inhibited in all three tissues, the most pronounced effect occurring in the liver. Only in the lung was fatty acid synthesis
significantly decreased (P<0.001) by fasting. Cholesterol feeding resulted in increased concentrations of cholesterol in the
plasma and liver. Cholestyramine feeding reduced plasma cholesterol concentration by 81% in females and by 64% in males. However,
it did not significantly change the tissue cholesterol concentrations. Fasting resulted in a significant increase (P<0.05)
in plasma cholesterol concentration but did not affect the concentration of cholesterol in the tissues. It was concluded that
in the normal guinea pig, the feedback inhibition produced by both cholesterol and also possibly by bile acids suppresses
sterol synthesis in the liver to very low rates compared to those in the small intestine, where sterologenesis is not only
less sensitive to the cholesterol negative feedback system than that in the liver, but also is not subject to regulation by
the bile acid negative feedback system. 相似文献
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Sayaka Nomura Dr. Kaori Endo‐Umeda Prof. Makoto Makishima Prof. Yuichi Hashimoto Dr. Minoru Ishikawa 《ChemMedChem》2016,11(20):2347-2360
Liver X receptor (LXR) agonists are candidates for the treatment of atherosclerosis via induction of ABCA1 (ATP‐binding cassette A1) gene expression, which contributes to reverse cholesterol transport (RCT) and to cholesterol efflux from the liver and intestine. However, LXR agonists also induce genes involved in lipogenesis, such as SREBP‐1c (sterol regulatory binding element protein 1c) and FAS (fatty acid synthase), thereby causing an undesirable increase in plasma and hepatic triglyceride (TG) levels. Recent studies indicate that LXRα contributes to lipogenesis in liver, and selective LXRβ activation improves RCT in mice. Therefore, LXRβ‐selective agonists are promising candidates to improve atherosclerosis without increasing plasma or hepatic TG levels. However, the ligand‐binding domains in the two LXR isoforms α/β share high sequence identity, and few LXR ligands show subtype selectivity. In this study we identified a tetrachlorophthalimide analogue as an LXRβ‐selective agonist. Structural development led to (E)‐4,5,6,7‐tetrachloro‐2‐(2‐styrylphenyl)isoindoline‐1,3‐dione ( 24 a ), which shows potent and selective LXRβ agonistic activity in reporter gene assays. In binding assays, compound 24 a bound to LXRβ preferentially over LXRα. It also induced the expression of ABCA1 mRNA but not SREBP‐1c mRNA in cells. Compound 24 a appears to be a promising lead compound for therapeutic agents to treat atherosclerosis without the side effects induced by LXRα/β dual agonists. 相似文献
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Fei Zhao Ping Xie Jiali Jiang Lingqiang Zhang Wei An Yutao Zhan 《International journal of molecular sciences》2014,15(3):4019-4030
The aim of this study was to determine the effect and mechanism of tamoxifen (TAM)-induced steatosis in vitro. HepG 2 (Human hepatocellular liver carcinoma cell line) cells were treated with different concentrations of TAM for 72 h. Steatosis of hepatocytes was determined after Oil Red O staining and measurement of triglyceride (TG) concentration. The expressions of genes in the TG homeostasis pathway, including sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), stearoyl-CoA desaturase (SCD), carnitine palmitoyltransferase 1 (CPT1) and microsomal triglyceride transfer protein (MTP), were examined using quantitative real-time PCR and Western blot analysis. Cell proliferation was examined using the cell counting kit-8 (CCK-8) assay. We found that hepatocytes treated with TAM had: (1) induced hepatocyte steatosis and increased hepatocyte TG; (2) upregulation of SREBP-1c, FAS, ACC, SCD and MTP mRNA expressions (300%, 600%, 70%, 130% and 160%, respectively); (3) corresponding upregulation of protein expression; and (4) no difference in HepG 2 cell proliferation. Our results suggest that TAM can induce hepatocyte steatosis in vitro and that the enhancement of fatty acid synthesis through the upregulations of SREBP-1c and its downstream target genes (FAS, ACC and SCD) may be the key mechanism of TAM-induced hepatocyte steatosis. 相似文献