Moderate-altitude hypoxia is associated with attenuated diet-induced liver injury and coordinated carbon-metabolic and lipid remodeling.

Chronic mild hypoxia at moderate altitude (2260 m) has been linked to improved systemic metabolism, but its liver-specific associations under high-energy diets remain incompletely defined. In this study, age-matched male C57BL/6 J mice were maintained for 15 weeks at simulated low altitude (50 m) or moderate altitude (2260 m) while fed a normal diet (ND), high-fat diet (HFD), or HFD with 30% fructose (HFD + HFr). Hepatic outcomes were assessed using ultrasonography, histology, electron microscopy, serum biochemistry, targeted energy metabolomics, lipidomics, and immunoblotting. Compared with the corresponding low-altitude high-energy diet groups, mice at 2260 m showed lower diet-associated weight gain, hepatic steatosis, and ALT/AST elevations. Structural analyses showed reduced lipid-droplet accumulation and qualitatively improved mitochondrial ultrastructural appearance. Metabolomics showed coordinated decreases in steady-state intermediates across glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle relative to the 50 m HFD group, together with enzyme changes consistent with reduced lipogenic capacity and altered fatty-acid uptake/oxidation. Lipidomic profiling further showed lower accumulation of neutral lipids, including triglycerides and diacylglycerols, as well as sphingolipids, while phospholipid class-level composition appeared less disturbed. Overall, moderate-altitude exposure was associated with attenuation of high-energy-diet-related hepatic metabolic dysfunction and with coordinated metabolic remodeling. These findings identify chronic mild hypoxia as an important contextual factor associated with hepatic metabolic responses, while direct causal mechanisms require further validation.