| Inflammation and inflammatory markers contribute to the pathogenesis of chronic diseases such as cardiovascular disease.In 2012,the mortality of chronic diseases reached 533/100 k in China,contributing to 86.6% of total number of death.Research has revealed that unhealthy eating patterns is one of most important risk factors.Therefore,regulation of inflammatory markers through dietary factors is beneficial for the primary prevention of chronic diseases.As the most consumed polyunsaturated fatty acids(PUFA),linoleic acid(C18:2 n-6,LA)and alpha-linolenic acid(C18:3 n-3,ALA)have gained more and more attentions for their roles in modulating inflammation.As LA and ALA share the same pathway for highly unsaturated fatty acids(HUFA)biosynthesis,competition exists between each other,making the dietary ratio of LA to ALA critical.However,the effect of dietary LA/ALA on inflammatory markers is not fully understood and controversies exist among different studies,preventing a concensus to be reached.Therefore,in this thesis,the effect of LA and ALA on blood inflammatory markers were investigated by meta-analysis and possible factors(characteristics of participants and experimental design)accounting for the conflicts among different clinical trials were also analyzed.Then,the present thesis investigated the effect of dietary LA/ALA and Fads2 on HUFA biosynthesis pathway and inflammatory cytokines in various tissues under health condition.At last,the effect of dietary LA/ALA on inflammatory markers under different extent of inflammation was studied and the underlying mechanism was investigated.The main results were as follows:First of all,a systematic review and meta-analysis was conducted to pool results from clinical trials that investigated the effect of increasing dietary ALA on inflammatory markers.A total of 31 papers involving 3032 participants from 13 countries in 5 continents were included.The concentrations of cytokines(tumor necrosis factor,interleukin-6,adiponectin and monocyte chemoattractant protein-1),acute-phase proteins(C-reactive protein,fibrinogen,activity and antigen concentration of plasminogen activator inhibitor-1 and serum amyloid A)and soluble adhesion molecules(intracellular adhesion molecule-1,vascular adhesion molecule-1and E-selectins)were not significantly affected by increasing dietary ALA(1-14g/day).However,results from subgroup analysis revealed that in elder(>50)or unhealthy subjects who are generally under increased state of low-grade chronic inflammation,ALA supplementation decreased the level of fibrinogen.In addition,meta-regresion analysis showed a significant negative relationship between effect size of ALA and baseline concentration of CRP,indicating that ALA might have a decreasing effect(beneficial)on CRP among subjects with high CRP levels.In conclusion,ALA supplementation dose not significantly affect blood inflammatory markers.However,in subjects with high levels of inflammation,ALA might be beneficial in reducing the concentration of CRP and fibrinogen.Then,based on available randomized controlled studies,the effect of dietary LA on inflammatory markers was investigated by meta-analysis.Results from 73 articles including 4209 people from 22 countries of 6 continents were pooled.Compared to plant-derived fatty acids(18C in length or shorter),increasing LA did not show a significant effect on cytokines,acute-phase proteins or adhesion molecules.However,both subgroup and meta-regression analysis suggested that more profound increase in LA intake might increase the concentration of CRP.Compared to long chain n-3 HUFA,LA increased CRP level,which was more significant in elder(>50)or unhealthy subjects.This is consistant with the results of ALA.Other inflammatory markers were not significantly affected by LA.Compared to conjugated linoleic acid,results suggested a neutral effect of LA on almost all inflammatory markers.Taken together,these findings suggest that inflammatory markers might not be affected by dietary LA in human.However,drastic elevation of LA intake might increase the concentration of some inflammatory markers.Next,as Fads2 is the rete-limiting step in the HUFA biosynthesis from LA and ALA,a heterozygous Fads2-null(HET)mouse model was used to investigate the effect of Fads2 genotype on HUFA biosynthesis pathway and pro-inflammatory cytokines in three different LA/ALA ratio(1:1,7:1 and 44:1).When LA/ALA was high(44:1),all four synthetic genes,Fads2,Fads1,Elovl5 and Elovl2,were up-regulated.The proportion of ARA was significantly increased in all tissues tested while EPA and DHA were drastically decreased compared to other dietary groups.In HET mice,as the expression of Fads2 was only half of that in the wild type(WT),compensatory induction of Fads1 was observed in liver,which was accompanied by a significant decreased of dihomo-γ-linolenic acid(C20:3 n-6,DGLA).Such change explains why the difference of ARA abundance between HET and WT was small.Overall,the diet showed a more significant effect than genotype on HUFA biosynthesis pathway.However,we found that neither LA/ALA nor Fads2 genotype showed significant effect on inflammatory cytokines gene expression in liver and brain under ununstimulated conditions.Finally,using an animal model with lipopolysaccharide(LPS)-induced inflammation,the effect of dietary HUFA precursor ratio,LA/ALA,on inflammatory marekrs under different extent of inflammation was investigated.After fed three diets with different LA/ALA ratios(1:1,7:1 and 44:1),mice were intraperitoneally injected with three doses of LPS: 0,5 or 50 μg/kg bodyweight.A strong positive correlation(r = 0.731 and 0.510 for 5 and 50 μg/kg,respectively)was observed between liver phospholipids arachidonic acid and prostaglandin E2(PGE2)in two LPS-treated groups,whereas brain PGE2 was not affected by LA/ALA ratios.Genes of Il1 b,Il6,Tnf and cyclooxygenase-2(Cox-2)were induced by LPS in a dose dependent manner.Among the high LPS(50 μg/kg)groups,mice with low LA/ALA ratio showed significantly lower Il1 b and Il6 mRNA expression in liver as well as Tnf in brain compared to other groups.PGE2 concentration was positively correlated with Il6(r=0.417)and Tnf(r=0.421)expression in liver in 50 μg/kg LPS group.Taken together,these data suggested that when the extant of inflammation reaches a certain point,low LA/ALA ratio could reduce expressions of inflammatory markers by inhibiting the PGE2 synthesis from ARA.Otherwise,a positive interaction between PGE2 and cytokines during inflammation might exacerbate or prolong the process and eventually increase the risk of chronic diseases.Taken together,when inflammation reaches certain extent,increasing ALA or drastic decrease of LA to achieve lower dietary LA/ALA might reduce the level of inflammatory markers.The mechanism involves the inhibition of the positive interaction between derivatives of PUFA and pro-inflammatory cytokines.In healthy subjects(where inflammation is minimum or absent),ALA and LA barely affect inflammatory markers.The current thesis provides theoretical basis for balanced dietary fat intake recommendation and policies on public nutrition and health.It is also important for future investigation on the mechanism underlying the effect of functional fatty acids on inflammatory response. |
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