Intrauterine growth restriction and differential patterns of hepatic growth and expression of IGF1, PCK2, and HSDL1 mRNA in the sheep fetus in late gestation

Abstract

Fetal adaptations to periods of substrate deprivation can result in the programming of glucose intolerance, insulin resistance, and metabolic dysfunction in later life. Placental insufficiency can be associated with either sparing or sacrifice of fetal liver growth, and these different responses may have different metabolic consequences. It is unclear what intrahepatic mechanisms determine the differential responses of the fetal liver to substrate restriction. We investigated the effects of placental restriction (PR) on liver growth and the hepatic expression of SLC2A1, IGF1, IGF2, IGF1R, IGF2R, PPARGC1A, PPARA, PRKAA1, PRKAA2, PCK2, and HSDL1 mRNA in fetal sheep at 140-145 days of gestation. A mean gestational arterial partial pressure of oxygen less than 17 mmHg was defined as hypoxic, and a relative liver of weight more than 2 SD below the mean liver weight of controls was defined as reduced liver growth. Fetuses therefore were defined as control-normoxic (C-N; n = 9), PR-normoxic (PR-N; n = 7), PR-hypoxic (PR-H; n = 8), or PR-hypoxic reduced liver growth (PR-H RLG; n = 4). Hepatic SLC2A1 mRNA expression was highest (P < 0.05) in the PR-H fetuses, in which liver growth was maintained. Expression of IGF1 mRNA was decreased (P < 0.05) only in the PR-H RLG group. Hepatic expression of HSDL1, PPARGC1A, and PCK2 mRNA also were increased (P < 0.05) in the PR-H RLG fetuses. The present study highlights that intrahepatic responses to fetal substrate restriction may exist that protect the liver from decreased growth and, potentially, from a decreased responsiveness to the actions of insulin in postnatal life.

FIG. 1.

A) Fetal weight (kg) at 140–145 days of gestation in C-N, PR-N, PR-H, and PR-H RLG fetuses (P < 0.001). B) Mean gestation arterial PO₂ in C-N, PR-N, PR-H, and PR-H RLG fetuses (P < 0.001). C) Relative liver weight (g/kg body weight) in C-N, PR-N, PR-H, and PR-H RLG fetuses (P < 0.005). Different lowercase letters denote mean values that are significantly different from each other.

FIG. 2.

Effect of placental restriction and chronic fetal hypoxia on hepatic SLC2A1 (A), HSDL1 (B), PPARGC1A (C), and PCK2 (D) mRNA expression in C-N, PR-N, PR-H, and PR-H RLG fetuses. The mRNA expression was normalized to the expression of the ribosomal protein, large, P0 (RPLP0). Different lowercase letters denote mean values that are significantly different from each other (SLC2A1, HSDL1, and PPARGC1A, P < 0.05; PCK2, P < 0.001).

FIG. 3.

Effect of placental restriction and chronic fetal hypoxia on hepatic IGF1 mRNA expression normalized to the expression of acidic ribosomal protein, large, subunit P0 (RPLPO) in C-N, PR-N, PR-H, and PR-H RLG fetuses. Different lowercase letters denote mean values that are significantly different from each other (P < 0.05).