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This research investigates how liver sinusoidal endothelial cells adapt their metabolism during the progression of diabetes-related metabolic dysfunction-associated steatotic liver disease (MASLD).

June 7, 2026

2487-P: Loss of Mitochondrial Fuel Flexibility in Liver Sinusoidal Endothelial Cells Marks Advanced Diabetes-Related MASLD

Key Points

This research investigates how liver sinusoidal endothelial cells adapt their metabolism during the progression of diabetes-related metabolic dysfunction-associated steatotic liver disease (MASLD).
Two-day-old male C57BL/6J mice received streptozotocin and a high-fat diet to induce diabetes; controls received vehicle and standard chow.
Isolated liver sinusoidal endothelial cells (LSECs) were analyzed using extracellular flux analysis for mitochondrial respiration and proteomic profiling via mass spectrometry.
Mitochondrial respiration was assessed with substrates pyruvate and palmitate, alongside fuel restriction assays.
At week 8, LSECs in advanced steatohepatitis (MASH) displayed increased TCA-linked (40-44%) and FAO-linked (102-108%) mitochondrial respiration compared to controls (all p<0.01).
By week 16, TCA-linked respiration and ATP production reduced, but FAO-linked respiration was maintained.
Proteomic analysis revealed significant remodeling, primarily affecting lipid metabolic pathways.

Abstract

Introduction and Objective: In type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) shows higher risk of progression to steatohepatitis (MASH) and fibrosis. We previously showed that mitochondrial respiration in sinusoidal endothelial cells (LSEC) is increased at early disease stages but declines with MASLD progression. How LSECs adapt their metabolism during disease progression remains unclear. We hypothesize that this mitochondrial flexibility is substrate-dependent and differs between fatty acid oxidation (FAO)- and tricarboxylic acid (TCA)-linked metabolism in the course of MASLD progression. Methods: Two-day-old male C57BL/6J mice received streptozotocin and were fed a high-fat diet from week 4 until week 8 or 16 to induce early or advanced diabetes-associated MASH; controls received vehicle and standard chow. Mouse LSECs were isolated by CD146-based magnetic sorting. Mitochondrial respiration was assessed by extracellular flux analysis in permeabilized cells using pyruvate or palmitate, and fuel restriction assays forcing reliance on glucose, glutamine, or fatty acids. Proteomic profiling was performed by liquid chromatography-mass spectrometry. Results: At week 8, LSECs from MASH showed increased basal respiration and mitochondrial ATP production for both TCA-linked (40-44%) and FAO-linked respiration (102-108%) compared with controls (all p0.01). At week 16, TCA-linked respiration and ATP production were reduced, whereas FAO-linked respiration was preserved. Spare respiratory capacity increased only at week 8 with forced fatty acid utilization. Proteomic analysis revealed extensive remodeling at both stages, predominantly involving lipid metabolic pathways. Conclusion: Diabetes-related MASLD exhibit enhanced mitochondrial flexibility with preferential fatty acid utilization in LSEC, whereas advanced MASH shows selective loss of TCA-linked respiration, identifying impaired endothelial fuel flexibility as feature of MASLD progression. Disclosure B. Dewidar: None. D. Ouwens: None. E. Rohbeck: None. S. Hartwig: None. M. Reina do Fundo: None. S. Lehr: None. J. Meister: None. H. Al-Hasani: None. M. Roden: Advisory Panel; Current; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Madrigal Pharmaceuticals, Inc., Novo Nordisk, Sanofi, Echosens. Funding Grants of the German Federal Ministry for Research (BMBF) to the German Center for Diabetes Research (DZD e. V.)

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