scholarly journals Hepatic farnesyl diphosphate synthase expression is suppressed by polyunsaturated fatty acids

2005 ◽  
Vol 385 (3) ◽  
pp. 787-794 ◽  
Author(s):  
Catherine LE JOSSIC-CORCOS ◽  
Céline GONTHIER ◽  
Isabelle ZAGHINI ◽  
Emmanuelle LOGETTE ◽  
Ishaiahu SHECHTER ◽  
...  

Dietary vegetable oils and fish oils rich in PUFA (polyunsaturated fatty acids) exert hypocholesterolaemic and hypotriglyceridaemic effects in rodents. The plasma cholesterol-lowering properties of PUFA are due partly to a diminution of cholesterol synthesis and of the activity of the rate-limiting enzyme HMG-CoA reductase (3-hydroxy-3-methylglutaryl-CoA reductase). To better understand the mechanisms involved, we examined how tuna fish oil and individual n−3 and n−6 PUFA affect the expression of hepatic FPP synthase (farnesyl diphosphate synthase), a SREBP (sterol regulatory element-binding protein) target enzyme that is subject to negative-feedback regulation by sterols, in co-ordination with HMG-CoA reductase. Feeding mice on a tuna fish oil diet for 2 weeks decreased serum cholesterol and triacylglycerol levels, by 50% and 60% respectively. Hepatic levels of FPP synthase and HMG-CoA reductase mRNAs were also decreased, by 70% and 40% respectively. Individual n−3 and n−6 PUFA lowered FPP synthase and HMG-CoA reductase mRNA levels in H4IIEC3 rat hepatoma cells to a greater extent than did stearate and oleate, with the largest inhibitory effects occurring with arachidonate, EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid). We observed a similar inhibitory effect on protein levels of FPP synthase. The suppressive effect of PUFA on the FPP synthase mRNA level was not due to a decrease in mRNA stability, but to transcription inhibition. Moreover, a lower nuclear availability of both SREBP-1 and SREBP-2 mature forms was observed in HepG2 human hepatoblastoma cells treated with arachidonate, EPA or DHA. Taken together, these data suggest that PUFA can down-regulate hepatic cholesterol synthesis through inhibition of HMG-CoA reductase and FPP synthase, at least in part through impairment of the SREBP pathway.

2013 ◽  
Vol 94 ◽  
pp. 104-110 ◽  
Author(s):  
Kriti Bhandari ◽  
S.P. Chaurasia ◽  
A.K. Dalai ◽  
Alok Gupta ◽  
K. Singh

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Ling-Yan Li ◽  
Xu Wang ◽  
Ting-Chuan Zhang ◽  
Zong-Jun Liu ◽  
Jun-Qing Gao

Abstract This experiment proposed to investigate the efficiency of omega 3 fatty acids from fish that improves autoimmune against myocarditis in the rat. Fish oil was extracted from fresh Tuna fish and performed FAME analysis and mice bioassay. The autoimmune myocarditis was induced by subcutaneous injection of porcine cardiac myosin (PCM) into the footpads of rats on the first and seventh day. Rats were dissected on the 21st day to analyze the histopathological, hemodynamic, echocardiographic factors, and immunohistochemistry expressions. In the study, 73.90% of total fatty acids were recorded. Histological analysis revealed that omega 3 fatty acids administrated groups showed tremendous development in the multifocal myocardia hyaline degeneration and necrosis with inflammatory changes. Moreover, omega 3 fatty acids inhabited the expressions of inflammatory cells (CD4, CD8 and CD11b) and suppressed the level of NF-κB. The echocardiographic factors such as heartbeat, SBP, DBP, levels of LVDs, LVDd, LVPW percentage of LVFS, EF, expression levels of inflammatory cytokines (TNF, IL-1β, IFN-ɤ, IL-2, and IL-6) also significantly suppressed by omega 3 fatty acids. Hence, the present study proved that consuming fatty acid-enriched fish might be a successful therapy for improving the inflammatory profile, regenerates the heart tissues, and controlled the production of inflammatory cells.


1984 ◽  
Vol 219 (2) ◽  
pp. 461-470 ◽  
Author(s):  
D D Patel ◽  
C R Pullinger ◽  
B L Knight

The true rate of cholesterogenesis in cultured monocyte-macrophages was determined from the incorporation of [2-14C]acetate into cholesterol, using the desmosterol (cholesta-5,24-dien-3 beta-ol) that accumulated in the presence of the drug triparanol to estimate the specific radioactivity of the newly formed sterols. It was shown that this procedure could be successfully adapted for use with cultured monocytes despite the accumulation of other unidentified biosynthetic intermediates. In cells maintained in 20% (v/v) whole serum approx. 25% of the sterol carbon was derived from exogenous acetate. Cholesterol synthesis was as high in normal cells as in cells from homozygous familial hypercholesterolaemic (FH) subjects and accounted for 50% of the increase in cellular cholesterol. The addition of extra low-density lipoprotein (LDL) reduced cholesterol synthesis, apparently through a decrease in the activity of 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase). When incubated in lipoprotein-deficient serum some cells did not survive, but those that remained showed a normal increase in protein content; the amount of cellular protein and cholesterol in each well did not increase and cholesterol synthesis was reduced by over 80%. HMG-CoA reductase activity fell less dramatically and the proportion of sterol carbon derived from exogenous acetate increased, suggesting that the low rate of cholesterogenesis with lipoprotein-deficient serum was due to a shortage of substrate. The results indicate that under normal conditions monocyte-macrophages obtain cholesterol from endogenous synthesis rather than through receptor-mediated uptake of LDL, and that synthesis together with non-saturable uptake of LDL provides the majority of the cholesterol required to support growth.


2014 ◽  
Vol 45 (3) ◽  
pp. 195-202 ◽  
Author(s):  
Hai-Ning Yu ◽  
Jing Zhu ◽  
Wen-sheng Pan ◽  
Sheng-Rong Shen ◽  
Wei-Guang Shan ◽  
...  

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769501 ◽  
Author(s):  
Isha Rani ◽  
Bhoomika Sharma ◽  
Sandeep Kumar ◽  
Satinder Kaur ◽  
Navneet Agnihotri

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell–associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.


2011 ◽  
Vol 102 (14) ◽  
pp. 7154-7158 ◽  
Author(s):  
Jinyong Yan ◽  
Sanxiong Liu ◽  
Jiang Hu ◽  
Xiaohua Gui ◽  
Guilong Wang ◽  
...  

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