The role of HDL in developmental programming

The in utero environment can have long-lasting consequences to the offspring.

Indeed, fetuses with modified growth rates or exposed to a variety of stressors can be re-programmed, often promoting metabolic changes that lead to increased adiposity later in life.

Most of the studies on developmental programming have compared offspring of females fed low or high fat diets to induce differences in inflammation, circulating metabolites, or differences in adiposity, making it difficult to determine the key variable(s) responsible for programming.

The studies proposed here will directly investigate the role of maternal inflammation, independent of dietary factors and maternal adiposity, and the role of major innate anti-inflammatory pathways in developmental programming. Important circulating anti-inflammatory agents are high density lipoproteins (HDL).

HDL maintains inflammation either directly or through maintenance of cellular sterol balance via its ability to efflux cholesterol.

Though we and others have shown that mice with low HDL levels due to apolipoprotein A-I (apoA-I) ablation have greater inflammation during pregnancy, no studies have examined an association of maternal HDL or apoA-I with developmental programming.

The role that HDL may play in fetal outcomes has become more relevant as HDL has recently been shown to be dynamic during pregnancy, with dramatic changes occurring in subspeciation (different-sized HDL particles) and compositions of the different-sized particles.

Thus, we hypothesize that maternal HDL and/or apoA-I improves developmental programming of offspring of females fed an inflammation- inducing diet by mitigating fetal inflammation.

To test our hypothesis, mice with no apoA-I (KO) or apoA-I (WT) will be fed a diet to induce moderate inflammation and mated with males of the opposite genotype to generate heterozygous (Het) offspring.

As all females will be fed the same diet and have the same adiposity, we will be looking at the impact of one factor, that being maternal inflammation, on programming. The Het offspring, exposed to different maternal milieu, will be examined in the following two specific aims. Aim 1. Determine the role of maternal HDL and/or apoA-I in developmental programming of offspring.

We will examine the phenotype of Het offspring from WT or KO dams fed inflammation-inducing diets at several ages, including in utero.

We will attempt to “rescue” the offspring phenotype by blocking maternal inflammation and fetal inflammation with dietary resveratrol. Aim 2.

Determine the role of maternal HDL and/or apoA-I in developmental programming of offspring from an antigenic allogeneic pregnancy.

An allogeneic pregnancy (matings between mice of different strains) is more antigenic than syngeneic pregnancy as it results in fetal tissues that are genetically dissimilar from the pregnant female and requires optimally functioning immune cells.

We will study Het offspring from C57BL/6 females mated to BALB/c males of the opposite genotype and offspring phenotype examined.

Our studies are impactful as our results could open up a new area of treatments focusing on the use of apoA-I, recombinant HDL, or their downstream targets to improve the health of offspring during their lifespan.