The findings of this study demonstrate a potential role of transcription factor (PPAR) in the pathogenesis of hepatic lipid dysregulation and inflammation in IUGR offspring. Notably, the hepatic transcription factors that modulate inflammation are downregulated in IUGR newborns and this trend persists in the adult IUGR offspring. Further, the relative upregulation of hepatic SREBP1 and fatty acid synthase favors the expression of lipogenic pathways, which leads to increased lipid synthesis and deposition. Thus, developmental hepatic dysregulation leads to programmed obesity-induced inflammation in IUGR offspring. It should be noted that only male newborns were examined due to the confounding effects of estrogen on adiposity and lipid metabolism.21,22
In the present study maternal food-restriction during pregnancy results in IUGR newborns with decreased protein expression of hepatic PPARα and PPARγ, increased expression of hepatic lipase and CRP, and no change seen in SREBP1 and fatty acid synthase. These results indicate that factors modulating inflammation are altered prior to the development of adiposity and hepatic steatosis. The reduced expression of hepatic PPARα and PPARγ is consistent with increased expression of hepatic CRP and normal hepatic triglyceride content. Studies have confirmed the anti-inflammatory responses of PPARα and PPARγ.4,12
This has been shown to occur via inhibition of inflammatory gene expression or via reduced secretion of cytokines and chemokines.7
Also, PPAR agonists are known to reduce circulating levels of inflammatory markers.4,7
In addition, PPARα prevents hepatic lipid storage by upregulating the expression of genes involved in fatty acid oxidation.5
Studies in mice fed a high-fat diet show that PPARα reduces hepatic steatosis by inducing mitochondrial, peroxisomal, and microsomal fatty acid oxidation.25
In contrast, PPARγ is known to facilitate lipogenesis by induction of SREBP1 which in turn activates fatty acid synthase.9
The increased expression of hepatic lipase seen in our study suggests increased fatty acid uptake by the liver though this would be dependent upon substrate availability. We have previously shown that IUGR newborns have decreased plasma triglycerides at 1 day of age.19
Thus, the results of the present study, in conjunction with the known effects of PPARα on fatty acid oxidation25
suggest that reduced fatty acid oxidation in concert with reduced lipogenesis prevents hepatic steatosis while enhancing inflammatory responses in IUGR newborns. Further, it is unclear if hepatic PPARα and PPARγ are regulated at a transcriptional or post-transcriptional level. It is believed that changes at the protein level would be most relevant to any potential impact on programmed inflammation. Transcriptional changes are not always evident in protein changes and post-transcriptional modification or degradation may also play a role.
When IUGR newborns are provided normal nursing and post-weaning diet, the adult offspring show continued downregulation of PPARα and PPARγ though now with new upregulation of lipogenic factor (SREBP1) and enzyme (fatty acid synthase). This is paralleled by increased hepatic triglyceride content in conjunction with increased plasma levels of CRP. The persistent reduced expression of hepatic PPARα and PPARγ is again consistent with increased plasma CRP levels though not with hepatic CRP expression. The apparent rationale for the dichotomy between liver and plasma CRP levels is unclear at this stage. However, since adipose tissue is also known to produce CRP, it is likely that in IUGR adult offspring, both liver and adipose tissue contribute to the circulating plasma CRP levels. In view of the fact that IUGR adult offspring are obese, the increased body fat may be a major source of elevated plasma CRP levels. Human studies have shown that in severely obese patients, plasma CRP levels are not a good diagnostic predictor of non-alcoholic steatohepatitis.26
The relative upregulation of both hepatic SREBP1 and fatty acid synthase in IUGR adult offspring favor the expression of lipogenic pathways, and thus increased hepatic lipid synthesis and deposition. Indeed, there is a concomitant increase in hepatic triglyceride content. However, despite decreased expression of PPARγ, SREBP1 gene expression is increased, which may be due to the combined effects of transcriptional signaling at the SREBP1c promoter as well as its post-transcriptional regulation. In addition to PPARγ, both insulin and liver X receptor alpha are known to induce SREBP1c transcription.16
Notably, these changes are seen in the adult IUGR offspring that are obese and exhibit elevated plasma triglyceride and insulin levels.18,19
Thus in IUGR adult offspring, increased hepatic lipogenesis with likely reduced fatty acid oxidation (though this needs further confirmation) contribute to hepatic steatosis. To demonstrate more pronounced manifestations of programmed hepatic steatosis future studies on IUGR offspring receiving a high fat diet may be required.
Studies in humans and animals have highlighted the influencial role of early nutrition on lipid metabolism.27-31
Barker et al32
have suggested that nutritionally impaired growth, particularly of the liver, during late gestation could result in permanent changes in lipid metabolism that persist until adult life. Recent studies on small-for gestational age infants report increased prevalence of abnormal lipid metabolism.33
Similarly, animal studies report enhanced hepatic lipogenesis due to increased expression of SREBP134,35
and fatty acid synthase36
in adult offspring of maternally protein/nutrient restricted dams. Numerous studies have further shown the association of increased SREBP1 expression with fatty liver.37
These changes may be due to both hepatic based gene expression as well as signaling from other programmed tissues such as skeletal muscle and adipose.
In conclusion, these results demonstrate that IUGR offspring exhibit reduced expression of hepatic PPARγ and PPARα which may be associated with the elevated hepatic CRP levels and triglyceride content. These findings suggest that developmental hepatic dysregulation may contribute to programmed obesity-induced inflammation in IUGR offspring.