Taken together, dysregulated epigenetic modifications are crucial for HFD induced fibroblast activation, proliferation and apoptosis resistance, all of which are dominant contributors to the progression of lung fibrosis (Figure 2).
4. Chronic Inflammation
Chronic inflammation played important roles in the progression of PF
[106][96]. In addition to the above mentioned repair mechanisms: activation of lung epithelium stem cells and fibroblast upon injury, the immune response was simultaneously triggered to protect the tissue from further damages
[107][97]. However, this process is out of control with chronic repeated injuries (typically observed in lung fibrosis)
[108,109][98][99]. Due to continuous inflammation, secretion of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor α (TNFα) will be increased which could further augment wound healing process by facilitating matrix deposition and subsequently resulted in fibrotic progression
[103,104][93][94]. Therefore identification of factors participating in the onset and progression of inflammation is vital for comprehensively understanding inflammation related disorders such as PF
[106,110][96][100].
Nutritional factors contributed to the formation of pro-inflammatory niche
[111][101] and chronic low-grade inflammation induced by altered metabolic homeostasis appeared to be vital for the pathogenesis of organ fibrosis
[112][102]. Chronic HFD has been linked with low-grade systemic inflammation in obesity
[113][103]. Particularly, the consumption of western type HFD could provoke chronic metabolic inflammation which subsequently contributed to the progression of chronic diseases such as nonalcoholic steatohepatitis and lung fibrosis
[114][104]. In HFD related obesity, adipocytes and macrophages in the adipose tissue generated pro-inflammatory cytokines such as TNFα and IL-6 which could provoke systemic inflammation and contribute to the progression of lung fibrosis
[115,116][105][106]. A recent report showed that mice displayed increased pulmonary neutrophile accumulation and collagen deposition by feeding with HFD
[25] and mice feed on HFD exhibited granulomatous lung inflammations which subsequently lead to progressive lung fibrosis
[117][107]. However, the mechanisms through which HFD provoked inflammation response remained unclear. It has been well established that epigenetic modifications upon environmental factor stimulation played a fundamental role in regulation of inflammatory gene transcription
[110,118,119,120][100][108][109][110]. Worse still, the adverse effects of the inflammatory state may induce epigenetic changes that perpetuate inflammation
[121][111]. Therefore,
wthe researche
rs postulated that epigenetic signature alterations induced by HFD may exacerbate inflammatory responses, thereby influencing progression of chronic inflammatory disease such as lung fibrosis
[101,110,118][91][100][108]. In support of this, integrative epigenome wide association study showed that promoter methylation of
TNFA were decreased with consumption of dietary fat
[122][112] suggesting a nutrient epigenomic regulation of pro-inflammatory factors
[123][113]. Accordingly high cholesterol and HFD would lead to low-grade pulmonary inflammation through activating TLR4/NFκB signaling
[45][35] while significant lower methylation of CpGs in the first exon of the
TLR4 were observed in obese individuals, indicating epigenetic regulation of TLR4 expression in obesity
[48][38]. Mice fed on HFD exhibited significant reduced DNA methylation at the promoter of
Pparγ1 which was critical for pro-inflammatory macrophages activation
[124][114]. In adipose tissue, the DNMT3a methyltransferase was markedly increased which was accompanied by elevated expression of inflammatory cytokines such as TNFα and MCP-1, implying the role of DNMT3a in obesity related inflammation
[125][115]. Similarly, increased expression of DNMT3b was found in adipose tissue macrophages and involved in the polarization of macrophage and inflammation
[126][116]. In mice, HFD led to hypermethylation of the
Ankrd26 which in turn contributed to enhanced secretion of pro-inflammatory factors
[127][117]. Consistently, epigenetic silencing of the
ANKRD26 by promoter methylation was related to pro-inflammatory state in obese individuals
[128][118]. In addition to DNA methylation, significant association between expression of histone deacetylases and inflammation status was demonstrated in obese individuals
[129][119]. Upon HFD treatment the levels of sphingosine-1-phosphate were increased
[130][120] which subsequently inhibited histone deacetylases activity and increased histone acetylation at H3K9, H4K8 and H3K18, thereby promoting pro-inflammatory cytokines in BALF
[131][121]. Accordingly, sphingosine-1-phosphate was reported to be increased in IPF patients and could facilitate disease progression
[132,133][122][123]. Moreover ncRNAs, due to their versatile roles in the regulation of gene expression, are widely involved in HFD induced chronic inflammation. Consumption of high-fat or high calorie (rich in fat) diet was shown to increase inflammatory response by altering miRNA expression
[134,135][124][125] and bioinformatics study showed that a miRNAs network significantly associated with obesity related inflammation
[136][126] and deregulated circulating inflammatory miRNAs contributed to the elevated inflammatory state in obesity
[137][127]. Besides, adipocyte-secreted exosomal miR-34 was progressively increased with the development of dietary obesity and subsequent systemic inflammation
[138][128]. In the same way, HFD could increase miR-155 in adipocyte-derived microvesicles which could induce M1 macrophage polarization, thereby causing chronic inflammation
[139][129]. HFD could further down regulate miR-30 by DNA methylation which facilitated M1 macrophages polarization
[140][130]. Although the pro-inflammatory M1 macrophages are usually regarded as anti-fibrotic in lung fibrosis, they could exacerbate the inflammatory status of the lung injury and evoke the fibrotic response in lung fibrosis patients through activation of the TLR4 signaling
[141][131]. Worse still, the maternal HFD could further hinder the lung development and function of offspring by epigenetic modulations
[142,143][132][133] for example, maternal HFD could lead to offspring tissue inflammation through down regulation of miR-706
[144][134]. Since HFD could also suppress the expression of miR-26a and stimulate expression of pro-inflammatory cytokines such as TNFα
[145][135] while decreasing TNFα was demonstrated to improve lung function of PF patient
[146][136] therefore, this provide us with novel target for treating HFD related PF. Taken together the above evidence highlighted the crucial roles of epigenetic regulated inflammation in HFD induced lung fibrosis (
Figure 3).
Figure 3. Epigenetically activation of inflammatory related genes play significant roles in fostering inflammation niche by HFD, thereby facilitating lung fibrosis progression. (
a): HFD promotes TLR4 expression through demethylation of CpGs in the first exon whereby lead to low-grade pulmonary inflammation; (
b): HFD led to hypermethylation of the
Ankrd26 promoter region which in turn contribute to enhanced secretion of pro-inflammatory factors; (
c): HFD increases histone acetylation at H3K9, H4K8, H3K18 which promoted pro-inflammatory cytokines in BALF; (
d): Consumption of high-fat or high calorie diet (rich in fat) is shown to increase inflammatory response by altering miRNA expression such as increasing miR-155 and down regulating miR-30 could induce M1 macrophage polarization, thereby causing chronic inflammation.
5. Clinical Perspectives
In tThe
current review weresearchers emphasized the important roles of epigenetic regulation in HFD related lung fibrosis. HFD is well accepted as a critical factor leading to the obesity
[11]. Paradoxically, previous multicenter study showed that body weight loss predicted worse survival of PF patients
[147][137]. This issue was due to the currently used body weight measurement which neglected the body mass composition
[148][138]. Actually individuals with the same body mass may varied in composition including fat mass (FM) and fat-free mass (FFM; or lean mass) which played different roles in health outcomes
[148,149][138][139]. Large prospective cohort studies demonstrated that increased FM could significantly increase the risk while FFM reduced the risk of inflammation related and respiratory diseases
[149,150][139][140] which mean that hidden loss of FFM or lean mass rather than weight loss was related to increased systemic inflammatory
[151][141] since elevated expression of inflammation related genes were induced by HFD related FM increase
[152][142]. On the contrary increased proportion of FFM was associated with better lung condition
[153][143] which could be attributed to lower inflammation.
It is well established that high intake of polyunsaturated fatty acids (PUFAs) has been associated with reduction of adiposity and increases in lean body mass
[154][144]. However in the last decades, the daily diets FA intake has dramatically changed from monounsaturated and PUFAs rich pattern to a westernized pattern characterized by a high content in SFAs
[155][145]. Accordingly, a previous comparative study showed that SFAs intake could increase the risk of PF
[13] while the beneficial effects of PUFAs on mitigating lung fibrosis have been demonstrated in many studies. Intake of fish oil rich in eicosapentaenoic acid decreased bleomycin induced lung hydroxyproline accumulation
[156][146]. Furthermore, the mitigation of lung fibrosis has been demonstrated with long-chain ω-3 PUFA docosahexaenoic acid
[157][147] and short-chain ω-3 PUFA
[158,159][148][149]. A relevant case showed that maternal diet supplied with docosahexaenoic acid could alleviate lung fibrosis and improve lung function in offspring by reducing collagen deposition and lessening inflammation
[160][150]. These anti-fibrotic properties of PUFA could be mediated through inhibiting EMT in human AEC2s
[161][151] and through activating PPARγ signaling
[162][152]. Since HFD is critical contributor to fat body mass increase and obesity
[11,152][11][142] while intake of PUFAs has been associated with reduction of adiposity and increases in fat-free body mass
[154][144] therefore, an adequate dietary PUFAs intake might reduce the risk of HFD related lung fibrosis. Indeed observational data from a cohort of 104 Japanese patients showed that SFAs intake may be an independent risk factor for PF
[13] while consumption of fruit was associated with a reduced risk
[163][153]. Therefore a shift of dietary habit should be recommended for individuals with a high fat mass to avoid the occurrence of PF. Alternatively, an relative easy way for HFD individual to reduce the risk of lung fibrosis might be exercise since a latest study demonstrated that aerobic exercise could alleviate PF by ameliorating HFD induced inflammatory response and neutrophil infiltration
[164][154].
6. Conclusions
Recently, lung fibrosis is recognized as a metabolic disease and abnormal lipid signature was observed both in serum and BALF of PF patients and mice model, suggesting that lipid metabolism was unbalanced in lung fibrosis. Consistently clinical observation and animal studies showed that HFD was associated with the progression of lung fibrosis
[14,18,21,24,25][14][18][21][24][25]. However, the mechanisms of individuals with HFD are susceptible to lung fibrosis remained unclear. Since genomic mutation induced by HFD is very low, it is highly probable that epigenetic changes might contribute to HFD related lung fibrosis.
In tThe
current review we researchers highlight the vital roles of epigenetic dysregulation in HFD induced PF from the perspective of epithelial cell injury, abnormal fibroblast activation and chronic inflammation. This knowledge opens new possibilities for a potential use of epigenetic signatures as biomarkers for diagnosis and targets for PF management
[110][100]. Currently, there is no cure for PF except for lung transplantation therefore, revealing the potential pathogenic factors and possible mechanisms would contribute to the prevention and treatment of this deadly disease. Due to the reversible nature, intervention methods targeting dysregulated epigenetic regulation represented a promising way to treat lung fibrosis
[165,166,167][155][156][157]. For a long tim
e the
weresearchers have studied on the therapeutic effects of miRNAs mimics in treating lung fibrosis
[168,169][158][159]. Recently,
wthe researche
rs generated MRG-229, a next-generation miR-29 mimic with improved stability and potential for targeted delivery which showed significant anti-fibrotic effects on human precision cut lung slices and mice lung fibrosis model and showed no adverse effects on non-human primates cynomolgus monkeys
[168][158]. Accordingly, delivering circRNA SCAR using nanoparticle could suppress fibroblast activation in HFD treated mice
[102][92]. The above evidence demonstrated the vital roles of targeting abnormal epigenetic regulation in ameliorating PF progression.
In summary,
ourthe re
view search not only unveil the important roles of epigenetic regulation in HFD mediated PF but also provide potential ways to deal with this issue. For patients they could change their diet habitat and do more aerobic exercise
[158,159,164][148][149][154] while for scientific researchers or drug developers, unveiling the epigenetic mechanism of HFD related lung fibrosis will provide novel targets to treat this deadly disease.