Down-regulation of transcription factor peroxisome proliferator-activated receptor in programmed hepatic lipid dysregulation and inflammation in intrauterine growth-restricted offspring

Abstract

Objective: Intrauterine growth-restricted (IUGR) newborns have increased risk of obesity-induced fatty liver and inflammation. We hypothesized that IUGR-induced inhibition of hepatic peroxisome proliferator-activated receptors (PPARs) is associated with an increased inflammatory response.

Study design: Rat control dams received ad libitum food, whereas study dams were 50% food restricted from pregnancy day 10 to 21 (IUGR). Pups were nursed by control dams and weaned to ad libitum feed. Hepatic protein expression of transcription factors, lipid enzymes, triglyceride content, and C-reactive protein (CRP) levels were analyzed in 1 day and 9 month old male offspring.

Results: At 1 day of age, IUGR pups showed down-regulation of PPARalpha and PPARgamma and up-regulation of hepatic lipase and CRP. At 9 months of age, IUGR exhibited continued down-regulation of PPARalpha and PPARgamma with up-regulation of sterol regulatory element-binding protein-1 and fatty acid synthase. Furthermore, IUGR adults had increased hepatic triglyceride content and plasma CRP levels.

Conclusions: The results suggest that developmental hepatic dysregulation may contribute to programmed obesity-induced inflammation in IUGR offspring.

Figure 1. Protein Expression of Hepatic Transcription Factors

Hepatic protein expression of PPARα, PPARγ and SREBP1 (upper band) in male offspring from Control (■) and IUGR (□) groups. Data was normalized to β-actin and presented as fold difference. β-actin (lower band) was comparable between IUGR and Control offspring at both ages. The number of animals studied per group per age was 4 males from 4 litters. *P <0.01 vs. Control offspring.

Figure 2. Protein Expression of Hepatic Lipid Enzymes and Hepatic Triglyceride Content

Hepatic protein expression of fatty acid synthase and hepatic lipase (upper band), and hepatic triglyceride content in male offspring from Control (■) and IUGR (□) groups. Data was normalized to β-actin and presented as fold difference. β-actin (lower as band) fold was comparable between IUGR and Control offspring at both ages. The number of animals studied per group per age was 4 males from 4 litters. *P <0.01 vs. Control offspring.

Figure 3. Protein Expression of Hepatic CRP and Plasma CRP Levels

Hepatic protein expression of CRP (upper band) and plasma CRP levels in male offspring from Control (■) and IUGR (□) groups. Data was normalized to β-actin and presented as fold difference. β-actin (lower band) was comparable between IUGR and Control offspring at both ages. The number of animals studied per group per age was 4 males from 4 litters. *P <0.001 vs. Control offspring.