Comienzo de la escolaridad

6.1 Summary and Discussion

6.1.1

Chapter Three

The aim of Chapter Three was to elucidate the molecular mechanisms which may lead to long-term cholesterol dysregulation of MPR derived low birth weight offspring. Given placental insufficiency in humans can produce protein deficiency in the fetus, this maternal protein restriction model shares features in common with IUGR, which represents 8% of newborns1-3. The hypothesis was that IUGR offspring may lead to elevated cholesterol levels in adult offspring via repressive changes in histone modifications at the Cyp7a1 promoter. As shown in Chapter Three, long-term hepatic Cyp7a1 transcriptional repression in IUGR offspring derived from a low protein diet

during pregnancy and lactation underlies the increases in circulating and hepatic cholesterol levels in both sexes at postnatal day 21 and exclusively in the male offspring at postnatal day 130. This long-term repression in transcription was concomitant with diminished acetylation and enhanced methylation of histone H3 [K9,14], markers of chromatin silencing, surrounding the promoter region of Cyp7a1. These epigenetic

modifications originated in part due to diet-induced decreases in fetal hepatic Jmjd2a expression, a histone H3 [K9] demethylase. This chapter provides the first evidence highlighting the important role of epigenetic mechanisms (i.e. post-translational histone modifications) in predisposing under nutrition derived low birth weight offspring to increased risk of hypercholesterolemia. In addition, these findings overturn the dogma that fetal programming effects are permanent since restoration of proteins in the maternal diet during the neonatal period re-established the expression of Cyp7a1 to prevent hypercholesterolemia. This restoration was associated with an increase in LXR expression.

6.1.2

Chapter Four

The aim of Chapter Four was to determine whether nutritional mismatch in postnatal life of low birth weight offspring would lead to elevated hepatic endoplasmic reticulum (ER) stress in adulthood. The hypothesis was that MPR derived offspring faced with a

nutritional mismatch are at a higher risk of developing metabolic syndrome in adult life due to presence of elevated hepatic ER stress. As shown in Chapter Four, exclusively when MPR derived low birth weight offspring received a “nutritional mismatch” postpartum, did they display elevated hepatic ER stress markers, including an increase in X box binding protein 1 mRNA splicing levels and elevated ER chaperones (Glucose regulated protein 78 and 94) at postnatal day 130. This was concomitant with attenuated protein synthesis, as indicated by increased phosphorylation of eukaryotic initiation factor 2 alpha at Serine 51 residue. Interestingly, maintaining the low birth weight offspring on a low protein diet throughout life prevented hepatic ER stress. These findings suggest that in addition to epigenetic and transcriptional mechanisms underlying the ‘developmental origins of adult disease’, chronic activation of the ER stress pathway may also mediate long-term insulin resistance and hypercholesterolemia.

6.1.3

Chapter Five

Given that low birth weight children that undergo accelerated growth display an earlier onset of metabolic disease symptoms and are more likely to be prescribed medication to manage their symptoms (e.g. statins for hypercholesterolemia), the aim of Chapter Five was to investigate whether hepatic drug metabolism is altered in adult life of low birth weight offspring. In addition, it was of interest to determine whether this association is positively correlated in low birth offspring that display accelerated growth when faced with a nutritional mismatch postpartum. The hypotheses was that MPR derived low birth weight offspring may have an impaired ability to metabolize drugs in adulthood. As shown in Chapter Five, a low protein diet during pregnancy and lactation leads to increases in Cyp3a, Cyp2b and Cyp2c enzymatic activity (Vmax/Km) at postnatal day 130.

This was attributed primarily due to increases in mRNA levels of Cyp3a1, Cyp2b1 and Cyp2c11. These elevated mRNA levels originate in part due to induction in expression of constitute androstane receptor, which is known to activate gene transcription of these Cyp enzymes. Interestingly, low birth weight offspring that were maintained on low protein diet postpartum did not display any alterations in Cyp enzyme expression. Collectively, these findings suggest that a low birth weight offspring when faced with a nutritional mismatch postpartum may require greater doses of drugs, which are metabolized by

Cyp3a, Cyp2b and Cyp2c enzymes, in order to exert their therapeutic effects. This is an important finding as it is applicable to those individuals who are more likely to be prescribed medication (e.g. statins for hypercholesterolemia) for the management of the symptoms associated with the metabolic syndrome.

6.2 Future Directions

Chapter Three and Four of the thesis provide a mechanistic insight which improves our understanding of why low birth weight babies are predisposed to increased risk of metabolic syndrome. In identifying some of the underlying mechanisms, this thesis helps identify early life dietary and/or drug intervention strategies which can be potentially used to lower cholesterol and reduce the incidence of the metabolic syndrome. Such strategies could reduce the long-term use of cholesterol lowering drugs in adulthood. Moreover, considering that adults that were born low birth weight have a higher likelihood of prescribing these drugs, chapter Five emphasizes the importance of personalized pharmacological therapy in these individuals. However, upon collectively analyzing the findings from the thesis, it is critical to realize that there are a number of important questions that still need to be addressed. The following sections of the thesis aim to highlight some of these important questions.

6.2.1

Molecular Mechanisms Underlying Sex-Specific Effects