Targeting hepatic stellate cell metabolism to treat steatotic liver disease

PROJECT ABSTRACT / SUMMARY Hepatic stellate cells (HSC) are fibroblasts of the liver that are normally localized in the perisinusoidal space of the lobule. In response to liver injury, secreted factors from hepatocytes, macrophages, and other cells trigger a program of activation in HSC. Activated HSC proliferate and migrate to sites of injury and begin secreting components of the extracellular matrix including collagens and other extracellular proteins that make up fibrotic lesions. While HSC activation is important for maintaining liver structural homeostasis and injury repair, the chronic, unrestrained activation of HSC can lead to cirrhosis and liver failure. Prior research conducted in vitro has suggested that high rates of metabolic flux are required to support proliferation, migration, and production and secretion of extracellular matrix proteins by HSC. Glucose uptake and utilization are robustly increased in HSC by activating stimuli. Work conducted during the prior period of support demonstrated that inhibition of the mitochondrial pyruvate carrier (MPC), which prevented mitochondrial metabolism of pyruvate, an end product of glycolysis, diminished HSC activation in vitro and in vivo. Glutamine is another important metabolic substrate in HSC and serves not only as a TCA cycle input through glutaminolysis, but also as a precursor for proline and other amino acids that are enriched in collagen. Our preliminary data demonstrate that inhibition of either the MPC or glutaminolysis is sufficient to attenuate stellate cell activation. Since inhibitors of the MPC and glutaminolysis are in clinical development, these findings suggest a viable way to target HSC activation by metabolic modulation. However, a mechanistic understanding of how modifying mitochondrial metabolism inhibits HSC activation is still lacking. The goal of this application is to understand the metabolic and molecular mechanisms by which inhibiting mitochondrial pyruvate and glutamine metabolism suppress HSC activation. We have hypothesized that the hypoxia inducible factor 1α (HIF1α) transcription factor is regulated by mitochondrial metabolism and plays a key role in HSC activation in metabolic dysfunction-associated steatotic liver disease (MASLD). The proposed work will dissect the mechanisms by which mitochondrial metabolism regulates HIF1α stability and examine whether HIF1α inactivation in HSC abrogates the development of fibrosis in mouse models of MASLD. In addition, we will examine how modulating mitochondrial metabolism influences the interactions between HSC and other parenchymal and non-parenchymal cells of the liver and verify some of our findings in human subjects with MASLD. These studies will markedly advance our understanding of HSC metabolism in vivo, provide a wealth of new information for the field, and potentially identify metabolic vulnerabilities as novel therapeutic targets.