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. 2012 Oct;207(4):308.e1-6.
doi: 10.1016/j.ajog.2012.07.033. Epub 2012 Jul 31.

Nutrient sensor-mediated programmed nonalcoholic fatty liver disease in low birthweight offspring

Diana Wolfe  1 , Ming Gong, Guang Han, Thomas R Magee, Michael G Ross, Mina Desai
Affiliations

Nutrient sensor-mediated programmed nonalcoholic fatty liver disease in low birthweight offspring

Diana Wolfe et al. Am J Obstet Gynecol. 2012 Oct.

Abstract

Objective: We hypothesized that gestationally programmed nonalcoholic fatty liver disease in low-birthweight offspring is mediated through nutrient sensors nicotinamide adenine dinucleotide+-dependent histone deacetylase (SIRT1) and AMP-activated protein kinase (AMPK).

Study design: Pregnant dams received ad libitum food or were 50% food restricted from pregnancy days 10-21 to produce control and low-birthweight newborn offspring, respectively. All pups were nursed by control dams and weaned to ad libitum feed. We determined hepatic SIRT1 and AMPK activities and protein expression of lipid targets in low-birthweight and control fetuses, newborns, and adult offspring (3 months).

Results: Low-birthweight fetuses demonstrated increased prenatal hepatic SIRT1 activity, although with increased lipogenesis. After birth, low-birthweight newborn offspring undergo postnatal suppression of hepatic SIRT1 and AMPK activities in conjunction with increased lipogenesis, decreased lipolysis, and increased fat stores.

Conclusion: These findings suggest that undernutrition stress in utero may program hepatic nutrient sensors to perceive normal postnatal nutrition as a state of nutrient excess with the induction of hepatic lipid storage.

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Conflict of interest statement

Disclosure: None of the authors have a conflict of interest

Figures

Fig. 1
Fig. 1. Hepatic SIRT1 Deacetylase Activity and AMPK Activation
Nuclear extract were obtained from LBW and Control livers at ages of e20, p1, 3 months. SIRT1 activity was determined and values expressed as AU unit (absorbance at A540 normalized by total protein) (A). Total protein was extracted from liver tissue and Western blots were performed with anti-pAMPK and anti-AMPK primary antibodies (B and C). Data are mean ± SE of n=4–6 per group; * p < 0.05 vs. Control at respective ages.
Fig. 2
Fig. 2. Hepatic Fatty Oxidative Factors (PGC-1α and HNF-4α)
Total protein was extracted from LBW and Control livers at ages of e20, p1, 3 months. Protein expression was determined by Western blot using anti-PGC-1α and anti-HNF-4α a primary antibodies. Representative Western blots (A) and densitometric analysis (B & C) are shown. Data are mean ± SE of n=4–6 per group; * p < 0.05 vs. Control at respective ages.
Fig. 3
Fig. 3. Hepatic Lipogenic Factors (SREBP-1c and FAS) and Lipid Accumulation
Total protein was extracted from LBW and Control livers at ages of e20, p1, 3 months. Protein expression was determined by Western blot using anti-SREBP-1c and anti-FAS primary antibodies. Representative Western blots (A) and densitometric analysis (B & C) are shown. Oil Red O and H & E staining from 3 month old Control and LBW offspring (D; magnification ×200). Data are mean ± SE of n=4–6 per group; * p < 0.05 vs. Control at respective ages.
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