The retromer subunit VPS35 sits at the crossroads of hepatic cholesterol homeostasis, proliferation and liver cancer
The retromer subunit VPS35 sits at the crossroads of hepatic cholesterol homeostasis, proliferation and liver cancer
The endo-lysosomal network is a dynamic system of membrane-bound organelles that regulates the intracellular trafficking of membrane proteins and their associated cargos, including proteins and lipids. By controlling processes such as nutrient sensing, signal transduction, and lipid and protein turnover, it serves as a critical regulator of cellular homeostasis. Disruptions in this network are strongly associated with human diseases, including neurodegenerative disorders, metabolic diseases, and cancer.
The retromer complex, composed of VPS26, VPS29, and VPS35, plays a key role in endosomal cargo sorting and trafficking. Although its molecular functions have been extensively studied in vitro, its role at the organismal level remains incompletely understood. In this thesis, we investigate the hepatic role of retromer in cholesterol homeostasis, proliferation and hepatocellular carcinoma (HCC). We demonstrate that hepatic retromer is essential for systemic cholesterol homeostasis by regulating receptor-mediated cholesterol uptake, as well as lysosomal cholesterol handling. In addition, we show that VPS35 plays a context-dependent role in hepatocellular proliferation. It controls hepatocellular proliferation early in life but not in adult livers or during liver regeneration. In a chemically induced HCC model, VPS35 deficiency reduces the incidence of lesions while promoting tumor growth, suggesting a non-canonical role in tumorigenesis. Finally, we demonstrate that retromer is critical for liver health, as acute loss of VPS35 leads to liver injury, fibrosis, and hepatocellular proliferation.
In summary, this thesis of Markus Barbosa provides new insights into the metabolic and physiological roles of retromer in the liver and highlights its importance in cholesterol homeostasis, liver function, and disease.