Role of Growth Hormone in the regulation of hepatic DNA integrity and pediatric MASLD outcomes

About This Grant

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease in children. Progression from fatty liver (FL) to inflammation/steatohepatitis (MASH), significantly increases the risk of cirrhosis, hepatocellular carcinoma and liver failure. Lack of effective treatments for this significant public health burden for children stem from gaps in MASLD pathophysiology specific to children. A unique aspect in children is ongoing liver growth, which is more pronounced prepubertally, and during which hepatocytes depend on nuclear and mitochondrial DNA integrity. We and others have found that hepatic inflammation and fibrosis is more severe in prepubertal children. Similarly, when compared for equal duration of high fat diet, weanling/prepubertal mice develop MASH/fibrosis much more rapidly than post pubertal mice. Increased MASLD severity correlated with greater hepatocyte nuclear and mitochondrial DNA damage, greater cell cycle arrest and restriction of liver regeneration in prepubertal mice and children. This heightened susceptibility to DNA damage in the prepubertal period was due to dysregulation of the Ataxia Telangiectasia Mutated (ATM) pathway, which oversees the cellular DNA damage/repair response. Identification of molecular mechanisms that influence the ATM pathway and DNA damage/repair would therefore be highly significant for pediatric MASLD. We found that inhibition of the ATM kinase significantly worsened MASLD outcomes in prepubertal mice but had little effect in post pubertal mice. As pubertal status profoundly impacted the disease modifying effect of the ATM pathway on MASLD, we hypothesize that pediatric MASLD progression beyond steatosis to MASH and fibrosis during childhood liver growth is linked to Growth Hormone (GH) regulation of hepatic DNA integrity via the ATM pathway. In our preliminary studies, GH protected HuH-7 cells from lipotoxicity, implying liver cell specific effect. This correlated with reduced nuclear and mitochondrial DNA damage and increased ATM gene and protein expression. Conversely, GH receptor antagonism exacerbated lipotoxicity, increased nuclear and mitochondrial DNA damage and reduced ATM expression in HuH-7 cells and prepubertal mice, additionally with rapid progression to MASH and fibrosis in prepubertal, but not in adult mice. Liver tissue of children and prepubertal mice with MASLD showed decreased expression of the liver specific GH targets: STAT5B and IGF1, in MASH vs fatty liver. GH has systemic pleiotropic effects, but we will elucidate its liver specific roles in impacting the ATM pathway for hepatic DNA damage/repair in pediatric MASLD. We will use genetically modified mice, cells, and clinical samples collected during my K08 award to the examine the hepatic GH-Jak/STAT5B axis in Aim 1 and the hepatic GH-STAT5B-IGF1/IGF1R axis in Aim 2. The clinical and research expertise of our investigative team and outstanding institutional environment will ensure completion of this project. We expect to identify downstream targets of GH and ATM in the liver specifically important for pediatric MASLD, which can be further studied in future R01 applications, to bridge critical gaps that currently impact pediatric MASLD.