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Abstract

The imbalance between free radicals and antioxidant defense is defined as the critical factor in the progression of nonalcoholic fatty liver disease and obesity. Heme Oxygenase-1 (HO-1), an intrinsic antioxidant enzyme, significantly mitigates this imbalance. Sirtuin 1 (SIRT1), a protein belonging to the NAD-dependent deacetylase family linked to the cellular metabolic status of the chromatin structure, regulation of gene expression and notably influenced by redox imbalance. The hypothesis of this study suggests that fructose-induced obesity leads to an inflammatory and oxidative condition that promotes non-alcoholic steatohepatitis (NASH) development. We investigate the role of the hepatocyte HO-1-SIRT1 axis in attenuating steatohepatitis. This study analyzed the effects of fructose supplementation on hepatic lipid metabolism in murine hepatocytes and liver tissues of mice subject to a high-fructose diet. The experiments were conducted both in the presence and absence of Cobalt protoporphyrin (CoPP) (HO-1 inducer) and Tin mesoporphyrin (SnMP) (HO-1 activity inhibitor). Fructose supplementation promoted a significant increase in oxidative stress while concurrently resulting in the attenuation of HO-1 and SIRT1 levels within hepatocytes. Furthermore, fructose led to increased Fatty acid synthase (FAS) expression, as well as elevated triglyceride levels; these changes caused by fructose were significantly attenuated with CoPP intervention. Concurrently, the co-treatment of CoPP and siRNA targeting SIRT1 to hepatocytes increased FAS expression and triglyceride levels. This outcome postulates that HO-1 potentially operates upstream of SIRT1 within the signal transduction cascade and suppression of SIRT1 decreases the positive effects of HO-1. Markers of oxidative stress, blood pressure, insulin resistance, and lipogenesis significantly increased in a high-fructose diet, as well as, the HO-1 induction, led to an increase in SIRT1 expression, thus attenuating fructose-induced lipid accumulation. The positive effects of CoPP were reversed by SnMP. In summary, our study demonstrates that HO-1 induction alleviates fructose-induced NASH by activating SIRT1 gene expression. This finding highlights the potential of targeting the HO-1-SIRT 1 axis as a therapeutic strategy for treating NASH.