Metabolome profiling across liver lobes and metabolic shifts of the MASLD mice.

Abstract

Background: The mammalian liver executes its vital functions through intricate hepatic biochemistry. However, the complexity of the liver metabolome and its dynamic alterations during metabolic dysfunction-associated steatotic liver disease (MASLD) remain poorly understood.

Methods: We established progressive MASLD mouse models through high-fat diet (HFD) and high-fat/high-cholesterol (HFHC) dietary-feeding across multiple time points. Utilizing liquid chromatography-mass spectrometry (LC-MS)-based metabolomics and lipidomics, we systematically mapped the metabolome atlas of the mouse liver across five anatomical segments during the progression of MASLD.

Results: By integration of data from two assays, we structurally annotated 426 lipids and 118 polar metabolites. The temporal progression of HFD feeding (0, 8, and 16 weeks) resulted in gradual metabolic deterioration across various liver segments. In HFHC-fed mice, metabolic alterations surged sharply from 0 to 8 weeks, followed by moderate progression until 16 weeks in different liver segments. Elevated levels of glycerolipids and cholesteryl esters, along with fluctuating acylcarnitine and fatty acid levels across various liver segments, suggested impaired energy metabolism and disrupted fatty acid oxidation. As MASLD progresses, a shift in sphingolipid metabolism, linked to inflammation, was observed, accompanied by significant alterations in phospholipid turnover patterns. Additionally, amino acid profiles in the livers of HFD-fed and HFHC-fed mice were altered, potentially influencing the regulation of energy metabolism, inflammation, and oxidative stress. These metabolic changes in lipids and amino acids displayed segment-specific patterns, indicating varying sensitivities to inflammation and mitochondrial β-oxidation across different liver lobes. Notably, the left lateral lobe showed heightened sensitivity to metabolic disturbances during MASLD progression.

Conclusion: Our findings provided in-depth understanding in hepatic metabolites of MASLD, offering a comprehensive resource for further investigation.