The role of hepatocyte specific eNOS and exercise in regulation of hepatic de novo lipogenesis and MASLD
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[EMBARGOED UNTIL 08/01/2026] Endothelial nitric oxide synthase (eNOS) is widely recognized for its role in vascular homeostasis; however, emerging evidence suggests that eNOS also serves other essential functions within non-endothelial cell types, including hepatocytes. Despite this, the hepatocyte-specific role of eNOS in lipid metabolism and its contribution to Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) remains poorly understood. In this study, we investigated the role of hepatocellular eNOS in regulating hepatic lipid accumulation, with a particular focus on one of the most prominent contributors to the development of this disease, de novo lipogenesis (DNL). Here, we used a hepatocytespecific eNOS knockout mouse model (eNOShep-/-), and lifestyle interventions (diet and exercise), to investigate the role of hepatocellular eNOS in DNL in MASLD development and its potential role in mediating the physiological response to exercise. Hepatocellular eNOS deficiency resulted in a MASLD phenotype, evidenced by elevations in steatosis, inflammation, and overall NAFLD activity score compared to eNOSfl/fl mice. eNOShep-/- animals exhibited trending increases in DNL assess by increased [³H]acetate incorporation into liver lipids and expression of key lipogenic enzymes (ACC, Fasn, Mxlpil, Srebf) at both the mRNA and protein levels. In vitro experiments confirmed these results, showing elevated [3H]acetate uptake in eNOShep-/- compared to eNOSfl/fl controls. Interestingly, exercise was unable to remediate elevations in DNL due to eNOS deletion, but did mitigate MASLD pathology, by reducing NAS and attenuating the inflammatory (Tnf-α Il-1β, Tgf-β) and fibrotic response (α-sma, Coll1a1) seen in eNOShep-/- fed a high carbohydrate diet. Taken together, these findings indicate that hepatocellular eNOS deficiency promotes hepatic lipid accumulation through increased DNL and exercise improves MASLD through mechanisms independent of decreased DNL when eNOS is not present.
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Ph. D