(582d) Stiffness Induces Metabolic Reprogramming in Primary Hepatocytes | AIChE

(582d) Stiffness Induces Metabolic Reprogramming in Primary Hepatocytes


Moeller, M. - Presenter, University of Nebraska-Lincoln
Thulasingam, S., University of Nebraska-Lincoln
Kidambi, S., University of Nebraska - Lincoln
Liver is a complex organ and nexus of metabolism, with vital roles in detoxification, synthesis, and nutrient processing. Liver stiffness is a commonly used metric to diagnose and stage liver disease, and it has shown potential as a prognostic indicator in recent years. Despite the importance of liver stiffness in assessing disease severity and predicting health outcomes, it is not clear how stiffness contributes to liver dysfunction. To better understand effects of the physical microenvironment on liver function and disease, we used polymer film coated polydimethylsiloxane (PDMS) with tunable elastic modulus to mimic the range of liver tissue stiffness in healthy to fibrotic conditions. This approach provides a means to control stiffness corresponding to various stages of fibrosis, which is challenging in in vivo models. Primary hepatocytes isolated from rats were cultured on stiffness representing healthy and fibrotic states. Urea and albumin production (physiologic markers of hepatocytes) decreased when hepatocytes were cultured on fibrotic stiffness. We observed greater expression of lipogenic genes and lower expression of β-oxidation genes in hepatocytes cultured on fibrotic stiffness. Hepatocytes cultured on fibrotic stiffness exhibited reduced mitochondrial respiration and glycolytic capacity, as well as increased production of reactive oxygen species. Significantly increased intracellular oxidized glutathione were also observed in hepatocytes cultured on fibrotic stiffness versus healthy stiffness, implicating the possible mechanism for higher oxidative stress in the fibrotic environment. These data suggest a plausible mechanism that increased stiffness modulates hepatocyte function causing liver functional failure. Understanding the impact of stiffness on hepatocytes biology will provide significantly more nuanced data to aid drug development for liver fibrosis.