P36 Impact of inducible Nitric Oxide Synthase (iNOS) on the aggressive progression of metabolic dysfunction-associated steatotic liver disease induced by choline-deficient high-fat diet

<h3></h3> Metabolic Dysfunction-Associated Steatotic Liver Disease (MAFLD) is a major global health concern and a multifaceted hepatic disorder associated with obesity, insulin resistance, and inflammatory and oxido-nitrosative stress pathways. Inducible nitric oxide synthase (iNOS), a key enzyme in nitric oxide production, has been implicated in various liver pathogenesis including MAFLD. The role of iNOS deficiency in the exacerbation of MAFLD has been a subject of debate and requires further evaluation. Hence, this study is designed to investigate the role of iNOS in the progression of MAFLD induced by a choline-deficient high-fat diet (CDHF) in mice, in comparison to wild-type (WT) and iNOS knockout (iNOS-/-) animals. Male C57BL/6 wild-type (WT) and iNOS knockout (iNOS-/-) mice were fed either a control diet or a CDHF diet for 10 and 20 weeks. Following the body weight, feeding period, metabolic function, oxidative stress, mitochondrial function, inflammatory response, and hepatic steatosis were evaluated. The mice deficient in iNOS subjected to the CDHF diet exhibited a pronounced exacerbation of MAFLD compared to WT mice. The results from the current study reveal the role of iNOS in MAFLD progression in mice fed with CDHF, by altering multiple metabolic facets including glucose metabolism, insulin sensitivity, oxidative stress, and mitochondrial dysfunction. Moreover, the decreased levels of antioxidant markers, mitochondrial biogenesis markers, and elevated levels of pro-inflammatory cytokines were observed in iNOS-/- mice, indicating a compromised defense mechanism against CDHF diet-induced liver injury in the absence of iNOS. Further, histopathological analysis revealed heightened hepatic steatosis, and inflammation, in iNOS-/- mice, indicating a possible protective role for iNOS in ameliorating CDHF diet-induced liver pathology. These findings underscore the conceivable protective function of iNOS in MAFLD, emphasizing its significance in modulating key pathological processes and paving a novel therapeutic target.