Doctor of Philosophy
Physiology and Pharmacology
Hardy, Daniel B.
Intrauterine growth restriction (IUGR) is a pathological condition characterized by low birth weight and poor organ development. Growth of the fetal liver is often compromised at the expense of other vital organs, thereby leading to hepatic dyslipidemia in the affected offspring. As such, epidemiological studies suggest an inverse relationship between birth weight and long-term metabolic health, while the occurrence of postnatal catch-up growth can exacerbate this relationship. Animal studies have shown that IUGR offspring exhibit impaired mitochondrial function, which likely contributes to the later development of metabolic pathologies. That said, the molecular mechanisms by which mitochondria are affected remain unknown. In this thesis, I aimed to characterize the molecular mechanisms by which hepatic mitochondrial dysfunction occurs in growth-restricted offspring with catch-up growth. To do this, we utilized two different rodent models of IUGR: (1) the maternal protein restriction (MPR) model of undernutrition, and (2) gestational exposure to D9-tetrahydrocannabinol (D9-THC). Offspring from both models underwent hepatic catch-up growth by three weeks of age, while adult male offspring from both models exhibited hepatic dyslipidemia. I demonstrated that male offspring further display aberrant markers of oxidative stress and mitochondrial dysfunction, including elevated p66Shc, 4-hydroxynonenol, and various antioxidant enzymes. These changes occurred exclusively following catch-up growth, suggesting that rapid postnatal weight gain is detrimental to mitochondrial metabolism and long-term metabolic health. I further found that the expression of microRNA-29 was significantly altered in the livers of adult male IUGR offspring from both models. My in vitro studies determined that miR-29 may be regulated by mitochondrial-induced oxidative stress, as treatment of HepG2 cells with rotenone and thapsigargin led to increased transcript abundance of miR-29. In addition, mRNA levels of fatty acid translocase (CD36), a membrane transporter protein involved in fatty acid uptake that is also a target of miR-29, was increased alongside miR-29. Overall, our data suggest that hepatic catch-up growth has great impact on mitochondrial function in growth-restricted offspring, and that this may occur in a sex-specific manner.
Summary for Lay Audience
Intrauterine growth restriction (IUGR) is a condition that affects 4–7% of all pregnancies. IUGR often occurs due to a poor maternal environment, and it results in low birth weight and poor fetal development. This can lead to increased fat storage within the liver, resulting in high risk for obesity, diabetes, and cardiovascular disease. This risk is worsened through a process called catch-up growth, whereby IUGR babies gain weight quickly during infancy and early childhood. Studies have found that the function of mitochondria, the major energy producers of the cell, becomes impaired with IUGR and contributes to the progression of disease. However, the role of catch-up growth in this process is not well understood. In this study, we used two different rodent models to study the effects of catch-up growth on mitochondria in the IUGR rat liver. In our first model, pregnant rats were fed a low protein diet, and followed by induction of catch-up growth after birth. In our second model, pregnant rats were injected with D9-tetrahydrocannabinol (D9-THC), the major component of cannabis that affects the brain. Both models resulted in IUGR, as offspring had low birth weight and small livers. Following catch-up growth, adult offspring from both models had elevated levels of fat in the liver. We believe that this occurs due to changes in (1) proteins responsible for fat production, and (2) mitochondrial proteins that control energy production and the production of toxic molecules. We also found that poor mitochondrial function leads to altered regulatory mechanisms of gene expression. Overall, these studies provide insight into the molecular causes of IUGR, and they may contribute to the development of therapies used in clinical practice during prenatal and postnatal life.
Oke, Shelby L., "The Molecular Mechanisms of Hepatic Mitochondrial Dysfunction in Growth-Restricted Offspring with Hyperlipidemia" (2022). Electronic Thesis and Dissertation Repository. 8588.
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