Autophagy: activation, function and regulation by a protein restricted diet during pregnancy and lactation

Low protein;Autophagy

Wang, Huan

关键词: Low protein;    Autophagy;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/89270/WANG-DISSERTATION-2015.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Developmental protein restriction is associated with numerous diseases including obesity, diabetes and cardiovascular disease, both in the mother and offspring. Recent intensive research efforts have focused on the mechanisms behind the effects of a maternal low protein diet on diseases in offspring. However, thus far, the mechanisms behind the physiological and molecular adaptations in the mother in response to protein restriction during pregnancy and lactation are not well understood. Because skeletal muscle and liver have a critical role in energy metabolism, including pregnancy and lactation-associated metabolic adaptations, the present study will investigate the genetic and epigenetic mechanisms behind the physiological changes that occur in response to a protein restricted diet during pregnancy and lactation in the skeletal muscle and liver of rat dams. The amino acid response (AAR) pathway is important in responding to stress, such as amino acid limitation, and our previous data show that a protein restriction diet during pregnancy induces the AAR pathway in placenta and causes stunted growth in the offspring. The central regulator of the AAR pathway is the activating transcription factor 4, ATF4. It has been shown that ATF4 can regulate macroautophagy in response to amino acid limitation. The process of autophagy is essential for the maintenance of cellular homeostasis, and our results show that a gestational low protein (LP) diet induces the mRNA expression of autophagy-related genes in the skeletal muscle of rat dams and male offspring, providing strong evidence of maternal programming. Additionally, our study shows that a gestational and lactational LP diet stimulates autophagy and hepatic lipid accumulation, and decreases expression of histone deacetylase-3 (Hdac3) in the liver of rat dams. Histone acetylation is associated with increased gene transcription. Specifically, it has been reported that HDAC3 inhibition induces LC3B expression, a primary autophagy marker and lipid accumulation. More importantly, we show that amino acid limitation induces autophagy through HDAC3-dependent expression of LC3B and its increased association with lipid droplets in a hepatic cell line, HepG2. Investigating the role that HDAC3 may play in the activation of LC3B and lipid accumulation will bring valuable insight into the epigenetic control of hepatic lipid accumulation by a LP diet during pregnancy and lactation in rat dams. In summary, our results demonstrate that protein restriction during gestation and lactation induces autophagy in skeletal muscle and liver, respectively; investigating the epigenetic regulation of autophagy will shed light on potential therapies that could diagnose and treat imbalanced maternal nutrition-related metabolic disorders in mother and offspring.