The Molecular Mechanisms of Hepatic Mitochondrial Dysfunction in Growth-Restricted Offspring with Hyperlipidemia
Abstract
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.