The ANGPTL3-4-8 Axis in Normal Gestation and in Gestational Diabetes, and Its Potential Involvement in Fetal Growth

Abstract

Dyslipidemia in gestational diabetes has been associated with worse perinatal outcomes. The ANGPTL3-4-8 axis regulates lipid metabolism, especially in the transition from fasting to feeding. In this study, we evaluated the response of ANGPTL3, 4, and 8 after the intake of a mixed meal in women with normal glucose tolerance and gestational diabetes, and we assessed their gene expressions in different placental locations. Regarding the circulating levels of ANGPTL3, 4, and 8, we observed an absence of ANGPTL4 response after the intake of the meal in the GDM group compared to its presence in the control group. At the placental level, we observed a glucose tolerance-dependent expression pattern of ANGPTL3 between the two placental sides. When we compared the GDM pregnancies with the control pregnancies, a downregulation of the maternal side ANGPTL3 expression was observed. This suggests a dysregulation of the ANGPTL3–4–8 axis in GDM, both at the circulating level after ingestion and at the level of placental expression. Furthermore, we discerned that the expressions of ANGPTL3, 4, and 8 were related to birth weight and placental weight in the GDM group, but not in the control group, which suggests that they may play a role in regulating the transplacental passage of nutrients.

Effects of In Utero PFOS Exposure on Epigenetics and Metabolism in Mouse Fetal Livers

“…Our data showed that the maternal hepatokines, angiopoietin-like ( Angptl )-4, Angptl-8 , and SelenoP were significantly upregulated while ANgptl-6 was reduced (Figure B). Those hepatokines play crucial roles in lipid metabolism, inflammation, and insulin sensitivity and are essential for the development of the placenta and fetal growth. , Although the information on the relationship of ANGPTLs and placental inflammation is limited, the emerging roles of ANGPTLs in triggering inflammatory signals in multiple tissues have been reported. , In fact, inflammation is known to regulate placental angiogenesis, which is positively associated with the expression of cytokines . While the reduction in the expression of cytokine release from the placenta affects fetal development .…”

“…Those hepatokines play crucial roles in lipid metabolism, inflammation, and insulin sensitivity and are essential for the development of the placenta and fetal growth. 33 , 34 Although the information on the relationship of ANGPTLs and placental inflammation is limited, the emerging roles of ANGPTLs in triggering inflammatory signals in multiple tissues have been reported. 35 , 36 In fact, inflammation is known to regulate placental angiogenesis, which is positively associated with the expression of cytokines.…”

Epigenetic modifications of placenta in women with gestational diabetes mellitus and their offspring

“…Several studies have shown that the expression of FAT and TLR4 in the placenta of GDM patients significantly increases and is positively associated with neonatal weight[ 42 ]. The ANGPTL3-4-8 axis regulates lipid transport and protein expression and is related to fetal birth weight, body length and placental weight[ 43 ]. However, the dysregulated expression of this axis in the placenta of GDM patients has an impact on placental lipid transport and protein expression.…”