Hypobaric hypoxia at 3,466 m suppresses hepatic bile acid metabolism and remodels the tumor lipidome in mice

Abstract

Systemic hypoxia induces whole-body metabolic adaptation, but its impact on tumor metabolism and hepatic bile acid (BA) pathways remains poorly defined. We investigated how high-altitude (HA) hypobaric hypoxia at 3,466 m affects tumor growth, tumor lipid metabolism, and liver BA regulation in mice bearing LLC1 lung carcinoma or E0771 mammary carcinoma. Moreover, we tested the contribution of hypoxia/HIF signaling and HNF4A knockdown to BA-related gene regulation in HepG2 cells. HA did not alter primary tumor growth, terminal tumor weight, necrosis, or hemorrhage in either model. However, LLC1 tumors from HA-acclimatized mice displayed a distinct lipid-metabolic profile, characterized by altered sterol and glycerophospholipid species, tendency toward reduced tumor free fatty acid content, and absence of detectable BAs, that were present in most low-altitude tumors. These tumor changes were accompanied by altered expression of lipid-handling genes, including increased Abca1 and Vdr and reduced Ptgs2 after FDR correction. Systemically, tumor-bearing mice at HA exhibited lower plasma BA levels, normalization of tumor-associated hepatomegaly, and reduced circulating IL-6. In the liver, HA and tumor burden produced overlapping, non-additive changes in BA synthesis, conjugation, and transport programs. In HepG2 cells, hypoxia and pharmacologic HIF stabilization reproduced BA-related transcripts, whereas partial HNF4A-knockdown selectively affected CYP7A1 and BAAT expression. These findings identify hepatic BA metabolism as a hypoxia-sensitive host pathway that links HA acclimatization to tumor lipid remodeling without necessarily altering primary tumor growth.