40-OR: Lifestyle Treatment Significantly Resolved Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) by Altering Extrahepatic and Hepatocellular Fatty Acid Trafficking

• Published in: Diabetes (New York, N.Y.) Vol. 74; no. Supplement_1; p. 1
• Main Authors: GEORGE, JESSICA G., MUCINSKI, JUSTINE M., BOONE, KENDALL M., ANDERSON, JENNIFER, FORDHAM, TALYIA M., LASTRA, GUIDO, IBDAH, JAMAL A., SCOTT RECTOR, R., PARKS, ELIZABETH J.
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20.06.2025
• Subjects: Biopsy; Body weight loss; Cardiorespiratory fitness; Diet; Dual energy X-ray absorptiometry; Esterification; Fatty acids; Isotopes; Lipogenesis; Lipoproteins (very low density); Liver; Liver diseases; Physical fitness; Secretion; Skeletal muscle
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db25-40-OR

Introduction and Objective: The mechanisms by which lifestyle intensive treatments alter fatty acid (FA) flux to improve MASLD severity are unknown. We quantitated changes in lipid flux to understand how 9-months of diet and exercise altered the clearance and hepatic handling of FA derived from the diet, de novo lipogenesis (DNL), and adipose FA flux. Methods: Patients (9M/15F; BMI: 39.3±7.7 kg/m2; NAFLD activity score (NAS, range 0-8): 5.5±3.8; HbA1c: 7.3±1.5%) received either standard of care (SOC, n=8) or treatment (n=16). Stable isotopes were administered to quantitate nocturnal and fasting hepatic DNL, dietary, and adipose FA kinetics. Other methods included MRI, DEXA, an exercise treadmill test to assess cardiorespiratory fitness (VO2peak), and a liver biopsy at the study's end. Results: Compared to no significant changes observed in SOC subjects, treatment improved weight (-6.1%, P=0.003), fitness (+27% VO2peak, P=0.003), liver fat (-47%, P=0.01), DNL (-28%, P=0.01), and NAS (-46%, P=0.0001). Dietary FA spillover into the plasma FFA pool decreased 22% (P=0.02) with the greatest spillover reductions in those who increased appendicular lean mass index, a marker of skeletal muscle mass (r=0.734, P<0.001). VLDL-TG concentrations were maintained due to an 8% increase in hepatic use of FFA for VLDL-TG assembly and secretion (P=0.02). Reduced liver fat was associated with lower DNL (r=0.519), TG secretion from FFA (r=0.575), and total TG secretion rates (r=0.728, P<0.005 for all three). After treatment, subjects with lower DNL exhibited the most significant percentages of FFA routed out of the liver in VLDL-TG (r=0.717, P<0.0001). Conclusion: A loss of intracellular DNL FA availability results in greater use of plasma FFA for TG esterification and secretion. For MASLD patients undergoing diet and exercise, weight loss and fitness gains contribute peripheral and direct hepatic benefits which can contribute to disease resolution.